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Nanocomposite for cancer targeted drug delivery
Nanocomposite for cancer targeted drug delivery
14
Dinesh K. Mishra1, Khushwant S. Yadav 2,T, Bala Prabhakar2 and R.S. Gaud1 1 School of Pharmacy & Technology Management, NMIMS-Shirpur Campus, SVKM’s NMIMS Deemed to be University, Maharashtra, India, 2Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS Deemed to be University, Mumbai, Maharashtra, India
14.1
Introduction
Nanocomposites involve materials which have at least one physical dimension in the nanometer range. Nanocomposite science generates a flexible platform for designing some new nanomaterials that have different properties and functionalities make it suitable for its newer applications especially in drug targeting area, more specifically in cancer targeting. The drawbacks associated with conventional chemotherapy like frequent dosing, severe side effects, and lack of specificity of anticancer drugs, necessities use of modified novel drug delivery systems [1]. The lack of cell specificity of such drugs necessitates use of targeted drug delivery. Nanocomposites design and construct has efficient multifunctional moieties needed for both targeting and controlling the delivery of the entrapped anticancer drug. Bionanocomposites like nanogels are internalized by the target cells, avoid accumulation in nontarget tissues, and minimize harmful side effects. Hence, to minimize healthy cell toxicity during chemotherapy nanoparticulate drug delivery systems hold promise in efficacy and increased rate of patient survival. The molecular transactions communicate with each other inside the human body and the engineered biological nanomachines communicate with them at the molecular level [2]. Targeting of specific cell, tissue, or organ is possible due to molecular communication between the nanocomposite and the biological part involved. Biological communication of drug loaded nanocomposites with the cancer cell receptors is responsible for achieving targeted delivery. In this chapter, various nanocomposites designed and grafted for targeted delivery of cancer cells and tissues are described. The additive features of developed nanoparticles like imaging as well as the control drug release characteristics have also been briefly discussed. Newer approaches in designing the targeted nanoparticles have been elaborated in order to understand the progress of nanocomposite science like aptamers and fusogenic peptide targeted small interfering RNA (siRNA) delivery. Many conventional targeting moieties are still capable enough
[email protected] (Corresponding Author)
Applications of Nanocomposite Materials in Drug Delivery. DOI: https://doi.org/10.1016/B978-0-12-813741-3.00014-5 © 2018 Elsevier Inc. All rights reserved.
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and researchers are exploring these molecules for effective targeting of cancer cells. Furthermore magnetic nanocomposites, clay-based nanocomposites, and graphene nanocomposites have been touched upon covering their advantages, composition, and application in cancer cell targeting.
14.2
Nanocomposite for cancer targeted drug delivery
The combination of different treatments in cancer therapy and harmful effects associated with killing of healthy cells during chemotherapy has drawn massive attention in development of targeted drug delivery. The superior anticancer ability of nanocomposites has attracted attention of many scientists toward development of nanosized composite materials for treatment of cancer. Nanocomposites have more than one nanoscaled materials which may be a combination of hard and soft nanomaterials. This makes the drug delivery system more versatile in terms of conjugating drugs to soft materials like polymeric nanogel or combining drugs with hard materials like metals. Some of the important functions of nanocomposite are listed below to highlight their role in cancer targeted drug delivery: 1. Nano-based chemotherapeutics can be functionalized to selectively deliver drugs at the site of tumor. 2. The nanocomposites can be formulated with enhanced half-life (t1/2) of the entrapped drug. 3. These can be made long circulating to be present in systemic circulation for a longer duration. 4. Nanocomposites have more than one nanosized metal or polymer, hence different physico-chemical properties can be obtained by combination of dissimilar materials. 5. Newer modifications are possible like, functionalization of fluorinated graphene with Fe3O4 for targeting cancer [3]. 6. The size and surface chemistry of nanocomposites can be modified to alter the effects of cytotoxicity. 7. The hydrophobic nature of fluorinated graphene can be modified to water-soluble fluorinated graphene oxide by making it more dispersible. 8. Photothermal therapy using nanocomposites is minimal invasive and useful in removal of targeted cancer cells. 9. Larger surface area of nanocomposites is useful for efficient biomolecular loading. 10. Abundant functional groups associated with nanocomposites allow bioconjugation making them important candidate for cancer chemotherapy. 11. Nanocomposites have unique structures with strong interactive moieties for multiresponsiveness. 12. Pluronic-based polymeric nanocomposites can be used for in vivo cancer imaging after intravenous injection or oral administration [4]. 13. Nanoconjugates can be encapsulated in quantum dots for bioimaging and efficient cancer diagnosis. 14. Simultaneous cancer diagnosis and cancer therapy is possible with nanocomposites by incorporating magnetic core-shell nanostructure with two photothermal agents (polypyrrole and gold nanoshell) for multimodality imaging as well as guided photothermal cancer therapy [5].
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15. Nanocomposites can be conjugated with ligands such as folic acid (FA) for targeting to specific cancer cells by efficient internalization thereby improving therapeutic efficacy [6].
14.3
Polymer nanocomposites
Efficient delivery of anticancer drugs to the targeted site or cells for a prolonged period of time would provide clinical response over an extended period of time. Polymeric nanoparticles can be tailored efficiently for delivering a desired therapeutic amount of dose to the site in a controlled or sustained manner. Biodegradable polymer-based nanocomposites loaded with anticancer agents are useful for controlled as well as targeted drug delivery because they may increase the drug concentration in cancer tissues and ultimately enhance antitumor efficacy. Rajan et al. prepared chitosan (CS)-based poly oxalate nanocarriers, which released cisplatin for a sustained period of time after degradation of the nanocomposites formulated in conjugation with ethylene glycol (EG) [7]. The drug release depended on both diffusion and erosion of the composite. The drug release from the four different composites; oxalic acid (OA)-EG, succinic acid (SA)-EG, citric acid (CA)-EG, and tartaric acid (TA)-EG was compared. Release from CS-EG-OA or CS-EG-SA was almost linear and depended upon the pH level of the released medium. Cellular uptake studies on MCF-7 cells were conducted by confocal microscopy for all the developed formulations. It was observed that all nanocarriers entered the cancer cells. In fact clear presence of the developed nanocomposites was observed in both cytoplasm and nucleus indicating clear cellular uptake. Thus, all the four composites, CSEG-OA, CS-EG-SA, CS-EG-CA, and CS-EG-TA as carriers for cisplatin have potential to target the whole cell cytoplasm without cellular hindrances. Such nanocomposites are potential carriers for controlled and targeted drug delivery for cancer therapy. 5-Fluorouracil (5-FU) is an antimetabolite which is a pyrimidine analog which interferes with synthesis of DNA and RNA. However, acquired drug resistance (ADR) is observed with repeated use of 5-FU. Dhanavel et al. suggested codelivery of curcumin (CUR) with 5-FU to overcome ADR. Such symbiotic treatment with CUR would lead to inhibition of drug resistance by sensitization of cancer cells [8]. The authors prepared CS/palladium-5% nanocomposite as the nanocarrier and loaded both 5-FU and CUR. Cytotoxicity studies on human colon tumor cell line, HT-29 cells by MTT assay for 24 h showed concentration dependent toxicity. Palladium embedded CS matrix nanocomposite encapsulating dual drugs, 5-FU, and CUR showed more efficiency than single drug. Dual drug encapsulation showed better inhibitory effect on HT-29 cells over 5-FU, CUR monotherapy (Table 14.1). This was attributed to the sustained release of the drug from the nanocomposite matrix. Such nanocomposites could also be utilized for simultaneous release of multiple therapeutic agents during chemotherapy. Hyaluronidase (HYL) is an enzyme which is useful in degrading matrix. Due to its degradation nature, it enhances the diffusion of drugs from the carrier to the
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Table 14.1
Applications of Nanocomposite Materials in Drug Delivery
Cytotoxicity study on cancer cell lines
Sr. No.
Drug/ formulation
Duration of exposure
Cancer cells
IC50
Reference
1
5-FU
24 h
18.3 μg/mL
[8]
CUR
24 h 24 h
2
5-FU 1 CUR CS/Pd NC 5FU-CS/Ag NC
3
5-FU CS/Ag/ MWCNT NC Pure GDM
24 h
GDM NC
24 h
Curcumin/ZnO NPs
24 h
Nanocurcumin
24 h
Curcumin-loaded PMMA-PEG/ ZnO NC
24 h
HT-29 cells HT-29 cells HT-29 cells MCF-7 cells MCF-7 cells MCF-7 cells MCF-7 cells AGS cancer cells AGS cancer cells AGS cancer cells
4
24 h 24 h
21.5 μg/mL 14.6 μg/mL 100 μg/mL
[9]
50 μg/mL 150 nm
[10]
26.42 nm 0.05 μg/mL
[11]
B0.05 μg/mL 0.01 μg/mL
NC: nanocomposite, IC: inhibitory concentration. It is interesting to note that the IC50 value of the NC is much lower than the plain/free drug, hence the total therapeutic anticancer dose is reduced by using NC.
cells. This results in easy penetration of the anticancer drug into the tumors. Rajan et al. conjugated some polymers with HYL with an aim to specifically target the anticancer drug 5-FU to the cancer cells [12]. Nanocomposites formulated with chitosan-hyaluronidase-5-fluorouracil (CS-HYL-5-FU), CS-HYL-5-FU polyethylene glycol (CS-HYL-5-FU-PEG), and CS-HYL-5-FU PEG-gelatin (CS-HYL5-FU-PEG-G). The CS-HYL-5-FU-PEG-G nanocomposite not only increased the bioavailability of 5-FU but also had a controlled release of the drug. In vitro enzymatic degradation assay of the nanocomposite explains the inverse relation of degradation to the amount of polymer composites which showed that a decrease in enzymatic degradation was proportional to the grafting ratio of the polymer. Cytotoxicity study conducted on the colon cancer cell lines COLO-205 and HT-29 confirmed that the CS-HYL-PEG-G nanocomposite was best in killing the cancer cells compared to CS-HYL and CS-HYL-PEG. These results were also attributed to the controlled release of the drug from the composite. The authors further concluded that the combination of CS with PEG and gelatin coatings were useful in prolonging the release of 5-FU until it reaches to the target site and hence have better potential for controlled and targeted drug delivery systems.
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In another study, 5-FU was encapsulated in a CS-based nanocomposite which showed a sustained and prolonged release useful for chemotherapy. Nivethaa et al. synthesized CS/silver and CS/silver/multiwalled carbon nanotube (MWCNT) nanocomposites and encapsulated 5-FU inside the composites [9]. The authors compared the drug release profiles and found that 5-FU was released slowly from the CS/Ag/MWCNT nanocomposite as compared to CS/Ag nanocomposite. This led the authors to predict that carbon nanotubes (CNT)-based nanocomposites perforated the cellular membrane and transported the encapsulated drug directly to the cells. Hence, such delivery systems would be useful for killing more of cancer cells than the healthy cells. This was supported by the cytotoxicity studies done against the breast cancer cell line MCF-7. The IC50 values (Table 14.1) visibly point out that 5-FU encapsulated into the CS/Ag/MWCNT nanocomposite was better in term of cytotoxicity destruction of the carcinogenic MCF-7 cells when compared to 5FU encapsulated CS/Ag nanocomposite. Prabhu et al. developed a polymeric-based superparamagnetic iron oxide (SPION) nanocomposite loaded with geldanamycin (GDM) which showed passive targeting to cancer cells [10]. One of the most important findings of the study was that the developed GDM nanocomposites had vanquished or reduced normal cell toxicity, which has prime significance during chemotherapy. Secondly, the developed nanocomposite had a reduced hepatic toxicity. It was reported that the polymeric GDM nanocomposite had a significant delay in tumor progression and hence the authors concluded this formulation to be a potential candidate in clinical use in cancer therapy. Rasoulzadeh and Namazi loaded doxorubicin (Dox) in carboxymethyl cellulose/ graphene oxide (CMC/GO) nanocomposite hydrogel for controlled release of the anticancer drug. CMC was used as the pH sensitive polymer [13]. This nanocomposite is not only capable of controlling the release of the entrapped drug but also the pH sensitive polymer (CMC) is capable to release of drug at required physiological pH. The in vitro cytotoxicity study of the formulation done on human colon cancer cells (SW480) the GO-CMC/DOX has the potential for selectively killing cancer cells in vitro. Dhivya et al. synthesized curcumin-loaded PMMA-PEG/ZnO bionanocomposite for targeting the gastric cancer cells [11]. It was postulated that the nanoparticles enter into the cytoplasm where the polymer degrades and release the entrapped curcumin at the available lower pH. The nanocomposite so developed had not only the benefits associated with better drug loading as it had larger amount of curcumin but also advantages of increased bioavailability of curcumin at the site of action. Herein the authors showed that there was inhibition of tumor cell growth through apoptosis. To understand the apoptosis corridor total cell cycle analysis was done. The obtained results pointed out that curcumin increases the G1 cells but decreases the S- cells and the down regulation of cyclin D1 expression causes the DNA damage. This phenomenon of cell cycle arrest and DNA damage eventually leads to cell death. The promising results of the study showed that the curcumin-loaded PMMA-PEG/ZnO bionanocomposite are therapeutically useful composite for loading hydrophobic drugs with increased bioavailability. The near future will have more of such low-risk, high efficacious bionanocomposites which will induce apoptosis for better chemotherapy.
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14.4
Applications of Nanocomposite Materials in Drug Delivery
Aptamer targeted nanocomposites
Various types of drug delivery systems have been designed to offer better cancer cell targeting. Cancer cell targeting using antibodies has been used by many researchers and promising results have been reported. However, antibodies have long blood residence that creates in vivo imaging issues due to high background signals. Therefore, a novel nanomaterial like aptamer, an oligonucleotide was explored for glioblastoma cell for better targeting efficiency [14]. The aptamer binds specifically with tenascin-C which is an extracellular protein playing a key role in tumor cell migration and proliferation. The nanocomposite material was prepared by using dendrimers-modified quantum dots that helps in cancer cell imaging. Dendrimers are branched spherical molecules that offer different sites of conjugation with different molecules. Polyamidoamine was used as polymer with thiol functional group for the preparation of dendrimer in which cadmium selenide quantum dots solution was added. The dendrimer-quantum dots (dQDs) nanoparticles were decorated with aptamer for its targeting efficiency (Fig. 14.1). The conjugation of aptamer with dQDs (Apt-dQDs) was characterized by agarose gel electrophoresis using 2% agarose gel stained with ethidium bromide dye. Apt-dQDs nanocomposite was evaluated for its cell targeting and binding efficiency on U251 glioblastoma cells culture. The results suggested that Apt-dQDs bind strongly with glioblastoma cells. So, such nanocomposite nanoprobes have high cancer targeting and cell imaging abilities.
14.5
Fusogenic peptide targeted siRNA delivery
Various approaches have been applied for the management and targeting of cancer cells. Gene silencing technique by the use of siRNA is the major breakthrough in
Figure 14.1 Apt-dQDs nanoprobe for cancer cell targeting and imaging.
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the treatment of cancer as it showed promising results in vivo and in vitro. With the help of this method, the diseased gene function is inhibited and ultimately the cancer cell could not survive. But effective delivery and targeting are key issues to the success of this technique and many nanocomposite delivery systems have been designed that could successfully deliver siRNA. Magnetic mesoporous silica nanoparticles (M-MSNs) have been exploited due to their least cytotoxicity, better biocompatibility, ability to accommodate large amount of drug, and control drug release characteristics as the candidate of choice to design nanocomposite. To construct nanocomposite, siRNA was encapsulated inside the M-MSN and further siRNA-M-MSN was coated with polyethylenimine (PEI). The targeting ability of such nanocomposite was introduced with fusogenic peptide system-KALA. In vivo anticancer activity suggested that the expression level of vascular endothelial growth factor which is responsible for the growth and metastasis of tumor was decreased with VEGF-siRNA-M-MSN-PEI-KALA nanocomposite treatment as compared to negative control [15].
14.6
Hyaluronic acid targeted nanocomposites
Nanocomposite designing requires better understanding of the targeting moiety and also the appropriate method of preparation so as to achieve a stable and effective nanosystem. HA available in extracellular matrix of connective, epithelial, and neural tissues helps in the proliferation and migration of cell and cellular component. HA transports the cancer cells to a noncancerous site and thus causes metastasis and proliferation of cancer cells. Thus, HA is one of the markers of cancer growth. HA receptors like cluster determinant 44 (CD44) are over expressed at the time of the cancer. The interactions of CD44 with HA cause the internalization of the CD44. So the HA-CD44 interaction mechanism can be exploited for the targeted delivery of anticancer drug to the tumor cells through the preparation of nanocomposites with HA as a polymer. Recently, theranostic nanosystem was developed for the delivery of anticancer drug resveratrol (RSV) based on HA matrix. RSV is estrogen diethylstilbestrol and is lipophilic in nature. The nanocomposite was designed by using HA-ceramide (HACE) and soluplus (SP) by electrospraying technique. The HACE and SP matrix was dissolved in methanol. The resulting solution was filled in syringe with stainless steel needle and was sprayed over stainless steel sheet with the help of syringe pump at 1 mL/h flow rate. Further, the formulation was removed from the sheet and was characterized. Cellular uptake studies of the HACE-SP-RSV nanocomposite was studied on MDA-MB-231 cells which showed promising results. The in vivo distribution studies were conducted on MB-231 tumor-xenografted mouse model by near infrared fluorescence approach of imaging which also suggested better tumor targetibility [16]. Thus the fabrication of nanocomposites depends on, (1) selection of target for better drug delivery to the cancer cell and (2) better method of preparation of nanocomposites. During the last decade, MSNs have come out as an attractive carrier for control and targeted anticancer drug delivery. Many modifications and functionalization of
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Applications of Nanocomposite Materials in Drug Delivery
MSNs have shown versatile properties of a carrier system. In one such approach, calcium phosphate (CaP) as a mineral for bio-mineralization of MSNs was developed with functional organic-inorganic hybrid materials with HA [17]. In this research, initially layer of HA was absorbed electrostatically on MSN which was previously amino functionalized and loaded with rhodamine B dye or Dox. The carboxyl group of HA was further used for the nucleation of CaP to produce CaP mineral nanoshell. To make the system more efficient for targeting the cancer cells, an additional layer of HA to the mineral surface was chelated. The targeting efficiency was checked on MDA-MB-231 cells. The results suggested that the killing efficiency of MSN-Cap-HA-Dox nanoparticles was remarkably increased as compared to free Dox. The activity was found to increase with increase in the concentration of nanoparticles.
14.7
Folic acid targeted nanocomposites
FA is an essential biomolecule involved in DNA biosynthesis, also known as vitamin B9 or vitamin Bc. FA enters inside the cell by three different mechanisms: (1) reduced folate carrier (RFC), (2) proton coupled folate transporter, and (3) folate receptor (FAR). FAR is a cell surface glycosyl phosphatidyl inositol anchored glycopeptides, which causes FA internalization into the cells in vesicles form by endocytotic pathway. FARs are over expressed in various epithelial tissue cancers like cancer of ovary, mammary gland, prostate, throat, nose, and brain. Thus, FA could be the targeting moiety that can deliver the anticancer drug via specific interaction with cell expressing FARs. So nanocomposites can be designed with folate decoration. Very recently, aminated starch/ZnO coated iron oxide nanocomposite was developed with FA as targeting molecule for the delivery of curcumin, a natural anticancer drug [18]. In this study, the starch was first aminated and the aminated solution of starch and pre-swelled as well as sonicated solution of ZnO was coated onto iron oxide core. The drug curcumin was then loaded in the aqueous dispersion of nanocomposite. Finally, the conjugation of FA with nanoparticles was carried out. The cell viability study on human lymphocytes suggested that the nanocomposite is biocompatible. Cell viability and uptake study were also performed on two cancer cell lines, that is, HepG2 and MCF7 cells and both showed significant results in FA targeted nanocomposites.
14.8
Magnetic nanocomposites for cancer cell targeting
Nanostructured magnetic materials have tremendous applications especially in the field of biomedical sciences and nanomedicine and hence these materials have received great attention in drug delivery area. Many researchers have developed magnetic nanocomposites for the targeted delivery of anticancer drugs.
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Chemotherapy and radiation therapy have been used for the treatment of cancer since long time. It has been observed that the effectiveness of these therapies can be improved by the concept of “Hyperthermia,” in which cancer cells are heated to the temperature of about 41 C 45 C. Several methods have been adapted to heat the cancer cells either locally or by some invasive method and heating probes. However, these methods are uncomfortable and even affect the noncancerous surrounding cells. Nanocomposite science had developed novel nanocarriers that generate the hyperthermia in cancerous cell in the form of drug delivery system. Hydrogel nanocomposite of poly (ethylene glycol) methyl ether methacrylate and dimethacrylate in which Fe3O4 nanoparticles was seeded as magnetite was designed and developed [19]. The nanocomposite was tested on glioblastoma cell culture. The hydrogel was remotely heated and controlled by alternating electromagnetic field. The hydrogel can be heated to hyperthermic temperature of 41 C 44 C or thermoablative temperature of 61 C 64 C depending upon the strength of magnetic field as illustrated in Fig. 14.2. It has been observed that under cell culture conditions, the cancerous cell killed at thermablative temperature. The hydrogel can be used along with chemotherapy or radiation therapy and it can be heated to hyperthermic temperature for the effective management of cancer. Similarly, pulsating release of drug can be obtained by magnetic hydrogel nanocomposites. The application of alternating magnetic field (AMF) increases the temperature that leads to the collapse of hydrogel polymer with the release of imbibed water along with anticancer drug. Satarkar and Hilt prepared poly (Nisopropylacrylamide) hydrogels in which Fe3O4 was incorporated for pulsating response [20]. Vitamin B12 and methylene blue were used as model drugs. When AMF was applied, squeezing of hydrogel took place which causes burst release of drug and as soon as AMF stopped, gel swells back and the drug releases slowly by diffusion mechanism. By this way, a pulsating drug release that acts as an ON/OFF switch for desirable delivery of drug can be achieved.
Magnetic hydrogel targeted at cancer cells
Magnetic Hydrogel heating to hypothermic temperature by electromagnetic field application at cancer cells.
Figure 14.2 Electromagnetic heating of nanocomposite magnetic hydrogel for cancer therapy.
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Applications of Nanocomposite Materials in Drug Delivery
Recently magnetic nanocomposite using CS/CMC polymer was designed for the delivery of potent anticancer drug paclitaxel (PTX) [21]. The nanocarrier was fabricated in such a way that the magnetite (Fe2O4) and PTX was loaded in polymeric matrix of CS/CMC and were decorated with FA as targeting moiety to the cancer cells. Such nanocomposite performed dual role, one for the targeted delivery of PTX and second for the cancer cell imaging via a magnetic nanoparticles. Many nanocomposites have been designed by exploring the magnetic nanoparticle property of heating upon exposure to electromagnetic field. More recently, CSPEG-polyvinylpyrrolidone (PVP) (CS-PEG-PVP) polymer-based nanocomposites were designed for the targeted delivery of curcumin and conjugating the nanoparticle with Fe3O4. The drug delivery system was tested for its anticancer activity in Caco-2 and HCT-116 cell lines and results suggested that the activity increased significantly as compared to nonmagnetic nanoparticles [22]. Gelatine-based magnetic hydrogel nanocomposites were designed for the delivery of anticancer drug Dox [23]. The hydrogel matrix was prepared by free radical catalyzing reaction of acrylamide with bis-acrylamide in the presence of ammonium per sulphate and N,N,N1,N1-tetramethylethylenediamine (TMEDA)(PAM matrix) along with gelatine (GE). In this hydrogel matrix of PAM-GE, magnetic nanoparticles of Fe2O4 and mineral magnetite were incorporated (Fig. 14.3). The nanocomposite hydrogel was characterized by FTIR, X-ray diffraction, SEM (scanning electron microscopy), transmission electron microscopy, thermogravimetric analysis, blood compatibility studies, etc. The drug Dox was loaded in about 50 mg of hydrogel sample by immersing the hydrogel in 20 mL drug solution (5 mg/20 mL distilled water) and in vitro release of the drug was studied spectrophotometrically. Numerous approaches are currently being explored for the use of iron oxide for nanocomposite construction and have widely accepted because of unique properties of iron oxide, but due to large surface availability and dipole-dipole interaction many times the magnetic nanoparticles agglomerate and create problem in designing of delivery system. To overcome the problem, many surface modification protocols have been adapted. Very recently, magnetic nanoparticles of poly (5-amidoisophthalicacid)/Fe3O4 were surface modified by β-cyclodextrin and organic molecule with hydrophilic outer surface and lipophilic inner core for the delivery of lipophilic anticancer drug docetaxel. The nanocomposite was made
PAM Matrix Gelatine Fe2O4
Figure 14.3 Nanocomposite of PAM-GE-Fe2O4.
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target efficient by the introduction of FA. These nanocarriers showed significant anticancer property when studied on HeLa and MDA-MB-231 cell lines [24]. Apart from theranostic application, magnetic nanocomposites have been utilized for the construction of biosensors for the quick and easy detection of cancer. Epidermal growth factor receptor (EGFR) is overexpressed in case of tumor. Earlier methods for detection of EGFR like immunohistochemistry, analysis at DNA, RNA, and protein level are time consuming and expensive. So magnetic nanocomposite-based inexpensive biosensors were developed for the easy detection of cancer in relatively less time [25]. A nanocomposite was designed with Fe3O4, N-trimethyl chitosan (TMC) and gold. Fe3O4/TMC/Au nanocomposite was than tagged with nanobodies (VHH) of EGFR specific antibodies. The above constructed nanoimmuno biosensor was treated with the sample that contains EGFR. Further the complex, that is, Fe3O4/TMC/Au-VHH-EGFR was added to PT/antibody (primary antibodies specific for EGFR) modified electrodes and then 1M HCl was added and preoxidation of Au nanoparticles was volumetrically detected at constant potential.
14.9
Clay-based nanocomposites for cancer cell targeting
Innovations in designing nanoparticles have incorporated unique features to the drug delivery system for the better management of cancer. Nanocomposites for cancer targeting are well explored with different nanocarrier materials. Clay has also been candidate of choice used by many researchers due to biocompatible, nontoxic, natural occurrence, and low cost properties. Halloysite (Hal) is natural occurring clay made from aluminosilicate and available in nanotube structure form. A nanocomposite hydrogel was crafted from the combination of Hal-sodium sodium hyaluronate (SA)/poly (hydroxyethyl methacrylate) (HEMA) for the delivery of anticancer drug, 5-FU used for the treatment of colon cancer [26]. The advantage of this nanocomposite is that the drug can be encapsulated in hydrogel as well as in the shell of Hal nanotubes. The drug (5-FU) was incorporated in Hal nanotubes and hydrogel by placing the nanocomposite in vacuum followed by pulling and breaking the vacuum as shown in Fig. 14.4. Such drug delivery system is pH sensitive and when it experiences pH of colon, rapid release of drug took place and can be used for the oral delivery of 5-FU. Variety of clay has been identified for the development of novel nanocomposites. Palygorskite (Pal) is hydrated magnesium aluminum silicate has been widely used for the preparation of nanocomposite for cancer targeting and imaging due to its nanostructure, fibrous form, low cost, and large surface area. Pal was grafted by polyethyleneimine (PEI) by coupling grafting technique. The nanocomposite was also coupled with FA for targeting to the cancer cell and fluorescein isothiocyanate (FI) for imaging the cancer cells. The Pal-PEI-FA-FI nanocarrier was further tested for cellular uptake efficiency on HeLa cell line with over expressed FARs. The
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Applications of Nanocomposite Materials in Drug Delivery
Release of drug 5-FU from Halloysite nanotube lumen
Figure 14.4 SA-HEMA-Hal nanocomposite for the delivery of anticancer drug 5-FU for colon cancer.
confocal microscopy suggested that cellular uptake of nanocomposite of Pal-PEIFA-FI was greater as compared to Pal-PEI-FI nanocomposite, which indicates the necessary role of folate conjugation for better targeting of the cancer cells [27]. A more complex drug delivery system based on laponite clay was developed. Laponite consisting of one magnesium octahedral layer between two silicon tetrahedral layers has been widely used clay due to its large surface are, biocompatibility and nontoxic nature. It has been also used in combination with other polymers for the targeted delivery of anticancer drug. Recently, a unique nanocomposite was designed using laponite for the dual delivery of drugs [28]. An antimicrobial drug ciprofloxacin (CIP) and anticancer drug, methotrexate (MTX) were simultaneously delivered in one nanocomposite formulation of laponite polymer combination. Such preparation is beneficial for the cancer patients prone to multidrug resistance. The nanocomposite consisting of P(NIPAAm-MAA), and MADQ-AcImIL&LP, that is, n-isopropyl acryl amide, methacrylic acid and 2-(methacryloyloxy) ethyl trimethyl ammonium chloride- 3-methyl 1-[2-(acryloxy)-ethyl] imidazolium chloride ionic liquid monomer, and laponite was synthesized and the antimicrobial activity of this nanocomposite was examined by minimum inhibitory concentration method against Pseudomonas aeruginosa and Escherichia coli. The anticancer activity was determined on MCF7 breast cancer cell line. Both the studies showed effectiveness of the nanocomposite as compared to the free drug.
14.10
Graphene nanocomposites
Graphene-based materials (such as GO, reduced GO) have shown promise for the treatment of cancer because of their good near infrared absorbance, large specific surface area, and abundant functional for efficient biomolecular loading, bioconjugation and targeting. Graphene-based nanocomposites have shown enormous medical applications in cancer therapeutics especially in terms of subcellular targeting, cellular imaging,
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and drug delivery. To increase the cellular uptake of grapheme-based composites, these are often functionalized with polymers such a PEG, PEI, gelatin, or CS. One of the advantages associated with loading drugs on graphene is that the resultant nanocomposite would be more stable and avoids premature release just outside the target cell. Nuclear delivery of anticancer drugs can be done using a bio-functionalized reduced GO. To deliver doxorubicin specifically to the nucleus of HER2 overexpressing breast cancer cells, it was covalently conjugated to GO then reduced to form Poly-L-lysine (PLL) functionalized reduced GOs (rGOs), and subsequently labeled with anti-HER2 antibodies [29]. PLL, the cationic polymer was chosen as it penetrates cell and organelle membranes for better internalization. Also PLL makes the composite of positive charge and has better interactions with negatively charged cell membrane, in doing so efficient cellular uptake of the nanocarrier is possible. The authors demonstrated clearly the cellular uptake pathways, and found that the uptake of rGO-PLL was not affected by clathrin-mediated endocytosis, macropinocytosis, and caveolae-mediated endocytosis. It was reported that the main uptake route of anti-HER2-rGO-PLL was via macropinocytosis and it was due to passive diffusion, rGO-PLL entered the cells. Interleukin-6 (IL-6) has a role in regulation of immune and inflammatory responses. The healthy humans have IL-6 in serum in the range of 10 75 pg mL21 but in cancer patients its concentration elevates to the ng mL21 range. For detection of IL-6, Liu et al. prepared an electrochemiluminescence (ECL) immunosensor by the combination of GO/PANi nanocomposite and CdSe QDs [30]. The ECL immunosensor had high sensitivity, good reproducibility, stability, and wide linear range. In fact, ECL immunosensor has a sensitive response to IL-6 in a linear range of 0.0005 10 ng mL21 which has great potential for the clinical detection.
References [1] G. Soni, K.S. Yadav, Applications of nanoparticles in treatment and diagnosis of leukemia, Mater. Sci. Eng. C 47 (2015) 156 164. [2] G. Soni, K.S. Yadav, Communication of drug loaded nanogels with cancer cell receptors for targeted delivery, Modeling, Methodologies and Tools for Molecular and Nano-Scale Communications, Springer International Publishing, 2017, pp. 503 515. [3] J. Du, J. Liu, P. Gong, M. Tian, L. Sun, S. Ji, et al., Construction of a novel fluorinated graphene-based magnetic nanocomposite and its application in cancer photochemotherapy, Mater. Lett. 196 (2017) 165 167. [4] M. Chu, H. Li, Q. Wu, F. Wo, D. Shi, Pluronic-encapsulated natural chlorophyll nanocomposites for in vivo cancer imaging and photothermal/photodynamic therapies, Biomaterials 35 (29) (2014) 8357 8373. [5] L. Han, Y. Zhang, Y. Zhang, Y. Shu, X.W. Chen, J.H. Wang, A magnetic polypyrrole/ iron oxide core/gold shell nanocomposite for multimodal imaging and photothermal cancer therapy, Talanta 171 (2017) 32 38. [6] Y.H. Park, S.Y. Park, I. In, Direct noncovalent conjugation of folic acid on reduced graphene oxide as anticancer drug carrier, J. Ind. Eng. Chem. 30 (2015) 190 196.
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[7] M. Rajan, M. Murugan, D. Ponnamma, K.K. Sadasivuni, M.A. Munusamy, Polycarboxylic acids functionalized chitosan nanocarriers for controlled and targeted anticancer drug delivery, Biomed. Pharmacother. 83 (2016) 201 211. [8] S. Dhanavel, E.A.K. Nivethaa, V. Narayanan, A. Stephen, In vitro cytotoxicity study of dual drug loaded chitosan/palladium nanocomposite towards HT-29cancer cells, Mater. Sci. Eng. C 75 (2017) 1399 1410. [9] E.A.K. Nivethaa, S. Dhanavel, A. Rebekah, V. Narayanan, A. Stephen, A comparative study of 5-fluorouracil release from chitosan/silver and chitosan/silver/MWCNT nanocomposites and their cytotoxicity towards MCF-7, Mater. Sci. Eng. C 66 (2016) 244 250. [10] S. Prabhu, P. Ananthanarayanan, S.K. Aziz, S. Rai, S. Mutalik, S.R.B. Sadashiva, Enhanced effect of geldanamycin nanocomposite against breast cancer cells growing in vitro and as xenograft with vanquished normal cell toxicity, Toxicol. Appl. Pharmacol. 320 (2017) 60 72. [11] R. Dhivya, J. Ranjani, P.K. Bowen, J. Rajendhran, J. Mayandi, J. Annaraj, Biocompatible curcumin loaded PMMA-PEG/ZnO nanocomposite induce apoptosis and cytotoxicity in human gastric cancer cells, Mater. Sci. Eng. C 80 (2017) 59 68. [12] M. Rajan, V. Raj, A.A. Al-Arfaj, A.M. Murugan, Hyaluronidase enzyme core-5fluorouracil-loaded chitosan-PEG-gelatin polymer nanocomposites as targeted and controlled drug delivery vehicles, Int. J. Pharm. 453 (2) (2013) 514 522. [13] M. Rasoulzadeh, H. Namazi, Carboxymethyl cellulose/graphene oxide bionanocomposite hydrogel beads as anticancer drug carrier agent, Carbohydr. Polym. 168 (2017) 320 326. [14] Z. Li, P. Huang, R. He, J. Lin, S. Yang, X. Zhang, et al., Aptamer-conjugated dendrimer-modified quantum dots for cancer cell targeting and imaging, Mater. Lett. 64 (3) (2010) 375 378. [15] X. Li, Y. Chen, M. Wang, Y. Ma, W. Xia, H. Gu, A mesoporous silica nanoparticle PEI fusogenic peptide system for siRNA delivery in cancer therapy, Biomaterials 34 (4) (2013) 1391 1401. [16] S.Y. Lee, J.J. Lee, J.H. Park, J.Y. Lee, S.H. Ko, J.S. Shim, et al., Electrosprayed nanocomposites based on hyaluronic acid derivative and Soluplus for tumor-targeted drug delivery, Colloids Surf. B Biointerfaces 145 (2016), pp. 267-234. [17] Z. Chen, Z. Li, Y. Lin, M. Yin, J. Ren, X. Qu, Biomineralization inspired surface engineering of nanocarriers for pH-responsive, targeted drug delivery, Biomaterials 34 (4) (2013) 1364 1371. [18] C. Saikia, M.K. Das, A. Ramteke, T.K. Maji, Evaluation of folic acid tagged aminated starch/ZnO coated iron oxide nanoparticles as targeted curcumin delivery system, Carbohydr. Polym. 157 (2017) 391 399. [19] S.A. Meenach, J.Z. Hilt, K.W. Anderson, Poly (ethylene glycol)-based magnetic hydrogel nanocomposites for hyperthermia cancer therapy, Acta Biomater. 6 (3) (2010) 1039 1046. [20] N.S. Satarkar, J.Z. Hilt, Magnetic hydrogel nanocomposites for remote controlled pulsatile drug release, J. Control. Release 130 (3) (2008) 246 251. [21] S. Bano, M. Afzal, M.M. Waraich, K. Alamgir, S. Nazir, Paclitaxel loaded magnetic nanocomposites with folate modified chitosan/carboxymethyl surface; a vehicle for imaging and targeted drug delivery, Int. J. Pharm. 513 (1) (2016) 554 563. [22] G. Prabha, V. Raj, Preparation and characterization of polymer nanocomposites coated magnetic nanoparticles for drug delivery applications, J. Magn. Magn. Mater. 408 (2016) 26 34.
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[23] N.N. Reddy, K. Varaprasad, S. Ravindra, G.S. Reddy, K.M.S. Reddy, K.M. Reddy, et al., Evaluation of blood compatibility and drug release studies of gelatin based magnetic hydrogel nanocomposites, Colloids Surf. A 385 (1) (2011) 20 23. [24] R. Tarasi, M. Khoobi, H. Niknejad, A. Ramazani, L. Ma’mani, S. Bahadorikhalili, et al., β-Cyclodextrin functionalized poly (5-amidoisophthalicacid) grafted Fe 3 O 4 magnetic nanoparticles: a novel biocompatible nanocomposite for targeted docetaxel delivery, J. Magn. Magn. Mater. 417 (2016) 451 459. [25] K. Omidfar, M. Darzianiazizi, A. Ahmadi, M. Daneshpour, H. Shirazi, A high sensitive electrochemical nanoimmunosensor based on Fe 3 O 4/TMC/Au nanocomposite and PT-modified electrode for the detection of cancer biomarker epidermal growth factor receptor, Sens. Actuators B 220 (2015) 1311 1319. [26] K.M. Rao, S. Nagappan, D.J. Seo, C.S. Ha, pH sensitive halloysite-sodium hyaluronate/ poly (hydroxyethyl methacrylate) nanocomposites for colon cancer drug delivery, Appl. Clay Sci. 97 (2014) 33 42. [27] S. Han, F. Liu, J. Wu, Y. Zhang, Y. Xie, W. Wu, et al., Targeting of fluorescent palygorskite polyethyleneimine nanocomposite to cancer cells, Appl. Clay Sci. 101 (2014) 567 573. [28] F.B. Zeynabad, R. Salehi, M. Mahkam, Design of pH-responsive antimicrobial nanocomposite as dual drug delivery system for tumor therapy, Appl. Clay Sci. 141 (2017) 23 35. [29] X.T. Zheng, X.Q. Ma, C.M. Li, Highly efficient nuclear delivery of anti-cancer drugs using a bio-functionalized reduced graphene oxide, J. Colloid Interface Sci. 467 (2016) 35 42. [30] P.Z. Liu, X.W. Hu, C.J. Mao, H.L. Niu, J.M. Song, B.K. Jin, et al., Electrochemiluminescence immunosensor based on graphene oxide nanosheets/polyaniline nanowires/CdSe quantum dots nanocomposites for ultrasensitive determination of human interleukin-6, Electrochim. Acta 113 (2013) 176 180.
14
Dinesh K. Mishra1, Khushwant S. Yadav 2,T, Bala Prabhakar2 and R.S. Gaud1 1 School of Pharmacy & Technology Management, NMIMS-Shirpur Campus, SVKM’s NMIMS Deemed to be University, Maharashtra, India, 2Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS Deemed to be University, Mumbai, Maharashtra, India
14.1
Introduction
Nanocomposites involve materials which have at least one physical dimension in the nanometer range. Nanocomposite science generates a flexible platform for designing some new nanomaterials that have different properties and functionalities make it suitable for its newer applications especially in drug targeting area, more specifically in cancer targeting. The drawbacks associated with conventional chemotherapy like frequent dosing, severe side effects, and lack of specificity of anticancer drugs, necessities use of modified novel drug delivery systems [1]. The lack of cell specificity of such drugs necessitates use of targeted drug delivery. Nanocomposites design and construct has efficient multifunctional moieties needed for both targeting and controlling the delivery of the entrapped anticancer drug. Bionanocomposites like nanogels are internalized by the target cells, avoid accumulation in nontarget tissues, and minimize harmful side effects. Hence, to minimize healthy cell toxicity during chemotherapy nanoparticulate drug delivery systems hold promise in efficacy and increased rate of patient survival. The molecular transactions communicate with each other inside the human body and the engineered biological nanomachines communicate with them at the molecular level [2]. Targeting of specific cell, tissue, or organ is possible due to molecular communication between the nanocomposite and the biological part involved. Biological communication of drug loaded nanocomposites with the cancer cell receptors is responsible for achieving targeted delivery. In this chapter, various nanocomposites designed and grafted for targeted delivery of cancer cells and tissues are described. The additive features of developed nanoparticles like imaging as well as the control drug release characteristics have also been briefly discussed. Newer approaches in designing the targeted nanoparticles have been elaborated in order to understand the progress of nanocomposite science like aptamers and fusogenic peptide targeted small interfering RNA (siRNA) delivery. Many conventional targeting moieties are still capable enough
[email protected] (Corresponding Author)
Applications of Nanocomposite Materials in Drug Delivery. DOI: https://doi.org/10.1016/B978-0-12-813741-3.00014-5 © 2018 Elsevier Inc. All rights reserved.
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and researchers are exploring these molecules for effective targeting of cancer cells. Furthermore magnetic nanocomposites, clay-based nanocomposites, and graphene nanocomposites have been touched upon covering their advantages, composition, and application in cancer cell targeting.
14.2
Nanocomposite for cancer targeted drug delivery
The combination of different treatments in cancer therapy and harmful effects associated with killing of healthy cells during chemotherapy has drawn massive attention in development of targeted drug delivery. The superior anticancer ability of nanocomposites has attracted attention of many scientists toward development of nanosized composite materials for treatment of cancer. Nanocomposites have more than one nanoscaled materials which may be a combination of hard and soft nanomaterials. This makes the drug delivery system more versatile in terms of conjugating drugs to soft materials like polymeric nanogel or combining drugs with hard materials like metals. Some of the important functions of nanocomposite are listed below to highlight their role in cancer targeted drug delivery: 1. Nano-based chemotherapeutics can be functionalized to selectively deliver drugs at the site of tumor. 2. The nanocomposites can be formulated with enhanced half-life (t1/2) of the entrapped drug. 3. These can be made long circulating to be present in systemic circulation for a longer duration. 4. Nanocomposites have more than one nanosized metal or polymer, hence different physico-chemical properties can be obtained by combination of dissimilar materials. 5. Newer modifications are possible like, functionalization of fluorinated graphene with Fe3O4 for targeting cancer [3]. 6. The size and surface chemistry of nanocomposites can be modified to alter the effects of cytotoxicity. 7. The hydrophobic nature of fluorinated graphene can be modified to water-soluble fluorinated graphene oxide by making it more dispersible. 8. Photothermal therapy using nanocomposites is minimal invasive and useful in removal of targeted cancer cells. 9. Larger surface area of nanocomposites is useful for efficient biomolecular loading. 10. Abundant functional groups associated with nanocomposites allow bioconjugation making them important candidate for cancer chemotherapy. 11. Nanocomposites have unique structures with strong interactive moieties for multiresponsiveness. 12. Pluronic-based polymeric nanocomposites can be used for in vivo cancer imaging after intravenous injection or oral administration [4]. 13. Nanoconjugates can be encapsulated in quantum dots for bioimaging and efficient cancer diagnosis. 14. Simultaneous cancer diagnosis and cancer therapy is possible with nanocomposites by incorporating magnetic core-shell nanostructure with two photothermal agents (polypyrrole and gold nanoshell) for multimodality imaging as well as guided photothermal cancer therapy [5].
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15. Nanocomposites can be conjugated with ligands such as folic acid (FA) for targeting to specific cancer cells by efficient internalization thereby improving therapeutic efficacy [6].
14.3
Polymer nanocomposites
Efficient delivery of anticancer drugs to the targeted site or cells for a prolonged period of time would provide clinical response over an extended period of time. Polymeric nanoparticles can be tailored efficiently for delivering a desired therapeutic amount of dose to the site in a controlled or sustained manner. Biodegradable polymer-based nanocomposites loaded with anticancer agents are useful for controlled as well as targeted drug delivery because they may increase the drug concentration in cancer tissues and ultimately enhance antitumor efficacy. Rajan et al. prepared chitosan (CS)-based poly oxalate nanocarriers, which released cisplatin for a sustained period of time after degradation of the nanocomposites formulated in conjugation with ethylene glycol (EG) [7]. The drug release depended on both diffusion and erosion of the composite. The drug release from the four different composites; oxalic acid (OA)-EG, succinic acid (SA)-EG, citric acid (CA)-EG, and tartaric acid (TA)-EG was compared. Release from CS-EG-OA or CS-EG-SA was almost linear and depended upon the pH level of the released medium. Cellular uptake studies on MCF-7 cells were conducted by confocal microscopy for all the developed formulations. It was observed that all nanocarriers entered the cancer cells. In fact clear presence of the developed nanocomposites was observed in both cytoplasm and nucleus indicating clear cellular uptake. Thus, all the four composites, CSEG-OA, CS-EG-SA, CS-EG-CA, and CS-EG-TA as carriers for cisplatin have potential to target the whole cell cytoplasm without cellular hindrances. Such nanocomposites are potential carriers for controlled and targeted drug delivery for cancer therapy. 5-Fluorouracil (5-FU) is an antimetabolite which is a pyrimidine analog which interferes with synthesis of DNA and RNA. However, acquired drug resistance (ADR) is observed with repeated use of 5-FU. Dhanavel et al. suggested codelivery of curcumin (CUR) with 5-FU to overcome ADR. Such symbiotic treatment with CUR would lead to inhibition of drug resistance by sensitization of cancer cells [8]. The authors prepared CS/palladium-5% nanocomposite as the nanocarrier and loaded both 5-FU and CUR. Cytotoxicity studies on human colon tumor cell line, HT-29 cells by MTT assay for 24 h showed concentration dependent toxicity. Palladium embedded CS matrix nanocomposite encapsulating dual drugs, 5-FU, and CUR showed more efficiency than single drug. Dual drug encapsulation showed better inhibitory effect on HT-29 cells over 5-FU, CUR monotherapy (Table 14.1). This was attributed to the sustained release of the drug from the nanocomposite matrix. Such nanocomposites could also be utilized for simultaneous release of multiple therapeutic agents during chemotherapy. Hyaluronidase (HYL) is an enzyme which is useful in degrading matrix. Due to its degradation nature, it enhances the diffusion of drugs from the carrier to the
326
Table 14.1
Applications of Nanocomposite Materials in Drug Delivery
Cytotoxicity study on cancer cell lines
Sr. No.
Drug/ formulation
Duration of exposure
Cancer cells
IC50
Reference
1
5-FU
24 h
18.3 μg/mL
[8]
CUR
24 h 24 h
2
5-FU 1 CUR CS/Pd NC 5FU-CS/Ag NC
3
5-FU CS/Ag/ MWCNT NC Pure GDM
24 h
GDM NC
24 h
Curcumin/ZnO NPs
24 h
Nanocurcumin
24 h
Curcumin-loaded PMMA-PEG/ ZnO NC
24 h
HT-29 cells HT-29 cells HT-29 cells MCF-7 cells MCF-7 cells MCF-7 cells MCF-7 cells AGS cancer cells AGS cancer cells AGS cancer cells
4
24 h 24 h
21.5 μg/mL 14.6 μg/mL 100 μg/mL
[9]
50 μg/mL 150 nm
[10]
26.42 nm 0.05 μg/mL
[11]
B0.05 μg/mL 0.01 μg/mL
NC: nanocomposite, IC: inhibitory concentration. It is interesting to note that the IC50 value of the NC is much lower than the plain/free drug, hence the total therapeutic anticancer dose is reduced by using NC.
cells. This results in easy penetration of the anticancer drug into the tumors. Rajan et al. conjugated some polymers with HYL with an aim to specifically target the anticancer drug 5-FU to the cancer cells [12]. Nanocomposites formulated with chitosan-hyaluronidase-5-fluorouracil (CS-HYL-5-FU), CS-HYL-5-FU polyethylene glycol (CS-HYL-5-FU-PEG), and CS-HYL-5-FU PEG-gelatin (CS-HYL5-FU-PEG-G). The CS-HYL-5-FU-PEG-G nanocomposite not only increased the bioavailability of 5-FU but also had a controlled release of the drug. In vitro enzymatic degradation assay of the nanocomposite explains the inverse relation of degradation to the amount of polymer composites which showed that a decrease in enzymatic degradation was proportional to the grafting ratio of the polymer. Cytotoxicity study conducted on the colon cancer cell lines COLO-205 and HT-29 confirmed that the CS-HYL-PEG-G nanocomposite was best in killing the cancer cells compared to CS-HYL and CS-HYL-PEG. These results were also attributed to the controlled release of the drug from the composite. The authors further concluded that the combination of CS with PEG and gelatin coatings were useful in prolonging the release of 5-FU until it reaches to the target site and hence have better potential for controlled and targeted drug delivery systems.
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In another study, 5-FU was encapsulated in a CS-based nanocomposite which showed a sustained and prolonged release useful for chemotherapy. Nivethaa et al. synthesized CS/silver and CS/silver/multiwalled carbon nanotube (MWCNT) nanocomposites and encapsulated 5-FU inside the composites [9]. The authors compared the drug release profiles and found that 5-FU was released slowly from the CS/Ag/MWCNT nanocomposite as compared to CS/Ag nanocomposite. This led the authors to predict that carbon nanotubes (CNT)-based nanocomposites perforated the cellular membrane and transported the encapsulated drug directly to the cells. Hence, such delivery systems would be useful for killing more of cancer cells than the healthy cells. This was supported by the cytotoxicity studies done against the breast cancer cell line MCF-7. The IC50 values (Table 14.1) visibly point out that 5-FU encapsulated into the CS/Ag/MWCNT nanocomposite was better in term of cytotoxicity destruction of the carcinogenic MCF-7 cells when compared to 5FU encapsulated CS/Ag nanocomposite. Prabhu et al. developed a polymeric-based superparamagnetic iron oxide (SPION) nanocomposite loaded with geldanamycin (GDM) which showed passive targeting to cancer cells [10]. One of the most important findings of the study was that the developed GDM nanocomposites had vanquished or reduced normal cell toxicity, which has prime significance during chemotherapy. Secondly, the developed nanocomposite had a reduced hepatic toxicity. It was reported that the polymeric GDM nanocomposite had a significant delay in tumor progression and hence the authors concluded this formulation to be a potential candidate in clinical use in cancer therapy. Rasoulzadeh and Namazi loaded doxorubicin (Dox) in carboxymethyl cellulose/ graphene oxide (CMC/GO) nanocomposite hydrogel for controlled release of the anticancer drug. CMC was used as the pH sensitive polymer [13]. This nanocomposite is not only capable of controlling the release of the entrapped drug but also the pH sensitive polymer (CMC) is capable to release of drug at required physiological pH. The in vitro cytotoxicity study of the formulation done on human colon cancer cells (SW480) the GO-CMC/DOX has the potential for selectively killing cancer cells in vitro. Dhivya et al. synthesized curcumin-loaded PMMA-PEG/ZnO bionanocomposite for targeting the gastric cancer cells [11]. It was postulated that the nanoparticles enter into the cytoplasm where the polymer degrades and release the entrapped curcumin at the available lower pH. The nanocomposite so developed had not only the benefits associated with better drug loading as it had larger amount of curcumin but also advantages of increased bioavailability of curcumin at the site of action. Herein the authors showed that there was inhibition of tumor cell growth through apoptosis. To understand the apoptosis corridor total cell cycle analysis was done. The obtained results pointed out that curcumin increases the G1 cells but decreases the S- cells and the down regulation of cyclin D1 expression causes the DNA damage. This phenomenon of cell cycle arrest and DNA damage eventually leads to cell death. The promising results of the study showed that the curcumin-loaded PMMA-PEG/ZnO bionanocomposite are therapeutically useful composite for loading hydrophobic drugs with increased bioavailability. The near future will have more of such low-risk, high efficacious bionanocomposites which will induce apoptosis for better chemotherapy.
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14.4
Applications of Nanocomposite Materials in Drug Delivery
Aptamer targeted nanocomposites
Various types of drug delivery systems have been designed to offer better cancer cell targeting. Cancer cell targeting using antibodies has been used by many researchers and promising results have been reported. However, antibodies have long blood residence that creates in vivo imaging issues due to high background signals. Therefore, a novel nanomaterial like aptamer, an oligonucleotide was explored for glioblastoma cell for better targeting efficiency [14]. The aptamer binds specifically with tenascin-C which is an extracellular protein playing a key role in tumor cell migration and proliferation. The nanocomposite material was prepared by using dendrimers-modified quantum dots that helps in cancer cell imaging. Dendrimers are branched spherical molecules that offer different sites of conjugation with different molecules. Polyamidoamine was used as polymer with thiol functional group for the preparation of dendrimer in which cadmium selenide quantum dots solution was added. The dendrimer-quantum dots (dQDs) nanoparticles were decorated with aptamer for its targeting efficiency (Fig. 14.1). The conjugation of aptamer with dQDs (Apt-dQDs) was characterized by agarose gel electrophoresis using 2% agarose gel stained with ethidium bromide dye. Apt-dQDs nanocomposite was evaluated for its cell targeting and binding efficiency on U251 glioblastoma cells culture. The results suggested that Apt-dQDs bind strongly with glioblastoma cells. So, such nanocomposite nanoprobes have high cancer targeting and cell imaging abilities.
14.5
Fusogenic peptide targeted siRNA delivery
Various approaches have been applied for the management and targeting of cancer cells. Gene silencing technique by the use of siRNA is the major breakthrough in
Figure 14.1 Apt-dQDs nanoprobe for cancer cell targeting and imaging.
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the treatment of cancer as it showed promising results in vivo and in vitro. With the help of this method, the diseased gene function is inhibited and ultimately the cancer cell could not survive. But effective delivery and targeting are key issues to the success of this technique and many nanocomposite delivery systems have been designed that could successfully deliver siRNA. Magnetic mesoporous silica nanoparticles (M-MSNs) have been exploited due to their least cytotoxicity, better biocompatibility, ability to accommodate large amount of drug, and control drug release characteristics as the candidate of choice to design nanocomposite. To construct nanocomposite, siRNA was encapsulated inside the M-MSN and further siRNA-M-MSN was coated with polyethylenimine (PEI). The targeting ability of such nanocomposite was introduced with fusogenic peptide system-KALA. In vivo anticancer activity suggested that the expression level of vascular endothelial growth factor which is responsible for the growth and metastasis of tumor was decreased with VEGF-siRNA-M-MSN-PEI-KALA nanocomposite treatment as compared to negative control [15].
14.6
Hyaluronic acid targeted nanocomposites
Nanocomposite designing requires better understanding of the targeting moiety and also the appropriate method of preparation so as to achieve a stable and effective nanosystem. HA available in extracellular matrix of connective, epithelial, and neural tissues helps in the proliferation and migration of cell and cellular component. HA transports the cancer cells to a noncancerous site and thus causes metastasis and proliferation of cancer cells. Thus, HA is one of the markers of cancer growth. HA receptors like cluster determinant 44 (CD44) are over expressed at the time of the cancer. The interactions of CD44 with HA cause the internalization of the CD44. So the HA-CD44 interaction mechanism can be exploited for the targeted delivery of anticancer drug to the tumor cells through the preparation of nanocomposites with HA as a polymer. Recently, theranostic nanosystem was developed for the delivery of anticancer drug resveratrol (RSV) based on HA matrix. RSV is estrogen diethylstilbestrol and is lipophilic in nature. The nanocomposite was designed by using HA-ceramide (HACE) and soluplus (SP) by electrospraying technique. The HACE and SP matrix was dissolved in methanol. The resulting solution was filled in syringe with stainless steel needle and was sprayed over stainless steel sheet with the help of syringe pump at 1 mL/h flow rate. Further, the formulation was removed from the sheet and was characterized. Cellular uptake studies of the HACE-SP-RSV nanocomposite was studied on MDA-MB-231 cells which showed promising results. The in vivo distribution studies were conducted on MB-231 tumor-xenografted mouse model by near infrared fluorescence approach of imaging which also suggested better tumor targetibility [16]. Thus the fabrication of nanocomposites depends on, (1) selection of target for better drug delivery to the cancer cell and (2) better method of preparation of nanocomposites. During the last decade, MSNs have come out as an attractive carrier for control and targeted anticancer drug delivery. Many modifications and functionalization of
330
Applications of Nanocomposite Materials in Drug Delivery
MSNs have shown versatile properties of a carrier system. In one such approach, calcium phosphate (CaP) as a mineral for bio-mineralization of MSNs was developed with functional organic-inorganic hybrid materials with HA [17]. In this research, initially layer of HA was absorbed electrostatically on MSN which was previously amino functionalized and loaded with rhodamine B dye or Dox. The carboxyl group of HA was further used for the nucleation of CaP to produce CaP mineral nanoshell. To make the system more efficient for targeting the cancer cells, an additional layer of HA to the mineral surface was chelated. The targeting efficiency was checked on MDA-MB-231 cells. The results suggested that the killing efficiency of MSN-Cap-HA-Dox nanoparticles was remarkably increased as compared to free Dox. The activity was found to increase with increase in the concentration of nanoparticles.
14.7
Folic acid targeted nanocomposites
FA is an essential biomolecule involved in DNA biosynthesis, also known as vitamin B9 or vitamin Bc. FA enters inside the cell by three different mechanisms: (1) reduced folate carrier (RFC), (2) proton coupled folate transporter, and (3) folate receptor (FAR). FAR is a cell surface glycosyl phosphatidyl inositol anchored glycopeptides, which causes FA internalization into the cells in vesicles form by endocytotic pathway. FARs are over expressed in various epithelial tissue cancers like cancer of ovary, mammary gland, prostate, throat, nose, and brain. Thus, FA could be the targeting moiety that can deliver the anticancer drug via specific interaction with cell expressing FARs. So nanocomposites can be designed with folate decoration. Very recently, aminated starch/ZnO coated iron oxide nanocomposite was developed with FA as targeting molecule for the delivery of curcumin, a natural anticancer drug [18]. In this study, the starch was first aminated and the aminated solution of starch and pre-swelled as well as sonicated solution of ZnO was coated onto iron oxide core. The drug curcumin was then loaded in the aqueous dispersion of nanocomposite. Finally, the conjugation of FA with nanoparticles was carried out. The cell viability study on human lymphocytes suggested that the nanocomposite is biocompatible. Cell viability and uptake study were also performed on two cancer cell lines, that is, HepG2 and MCF7 cells and both showed significant results in FA targeted nanocomposites.
14.8
Magnetic nanocomposites for cancer cell targeting
Nanostructured magnetic materials have tremendous applications especially in the field of biomedical sciences and nanomedicine and hence these materials have received great attention in drug delivery area. Many researchers have developed magnetic nanocomposites for the targeted delivery of anticancer drugs.
Nanocomposite for cancer targeted drug delivery
331
Chemotherapy and radiation therapy have been used for the treatment of cancer since long time. It has been observed that the effectiveness of these therapies can be improved by the concept of “Hyperthermia,” in which cancer cells are heated to the temperature of about 41 C 45 C. Several methods have been adapted to heat the cancer cells either locally or by some invasive method and heating probes. However, these methods are uncomfortable and even affect the noncancerous surrounding cells. Nanocomposite science had developed novel nanocarriers that generate the hyperthermia in cancerous cell in the form of drug delivery system. Hydrogel nanocomposite of poly (ethylene glycol) methyl ether methacrylate and dimethacrylate in which Fe3O4 nanoparticles was seeded as magnetite was designed and developed [19]. The nanocomposite was tested on glioblastoma cell culture. The hydrogel was remotely heated and controlled by alternating electromagnetic field. The hydrogel can be heated to hyperthermic temperature of 41 C 44 C or thermoablative temperature of 61 C 64 C depending upon the strength of magnetic field as illustrated in Fig. 14.2. It has been observed that under cell culture conditions, the cancerous cell killed at thermablative temperature. The hydrogel can be used along with chemotherapy or radiation therapy and it can be heated to hyperthermic temperature for the effective management of cancer. Similarly, pulsating release of drug can be obtained by magnetic hydrogel nanocomposites. The application of alternating magnetic field (AMF) increases the temperature that leads to the collapse of hydrogel polymer with the release of imbibed water along with anticancer drug. Satarkar and Hilt prepared poly (Nisopropylacrylamide) hydrogels in which Fe3O4 was incorporated for pulsating response [20]. Vitamin B12 and methylene blue were used as model drugs. When AMF was applied, squeezing of hydrogel took place which causes burst release of drug and as soon as AMF stopped, gel swells back and the drug releases slowly by diffusion mechanism. By this way, a pulsating drug release that acts as an ON/OFF switch for desirable delivery of drug can be achieved.
Magnetic hydrogel targeted at cancer cells
Magnetic Hydrogel heating to hypothermic temperature by electromagnetic field application at cancer cells.
Figure 14.2 Electromagnetic heating of nanocomposite magnetic hydrogel for cancer therapy.
332
Applications of Nanocomposite Materials in Drug Delivery
Recently magnetic nanocomposite using CS/CMC polymer was designed for the delivery of potent anticancer drug paclitaxel (PTX) [21]. The nanocarrier was fabricated in such a way that the magnetite (Fe2O4) and PTX was loaded in polymeric matrix of CS/CMC and were decorated with FA as targeting moiety to the cancer cells. Such nanocomposite performed dual role, one for the targeted delivery of PTX and second for the cancer cell imaging via a magnetic nanoparticles. Many nanocomposites have been designed by exploring the magnetic nanoparticle property of heating upon exposure to electromagnetic field. More recently, CSPEG-polyvinylpyrrolidone (PVP) (CS-PEG-PVP) polymer-based nanocomposites were designed for the targeted delivery of curcumin and conjugating the nanoparticle with Fe3O4. The drug delivery system was tested for its anticancer activity in Caco-2 and HCT-116 cell lines and results suggested that the activity increased significantly as compared to nonmagnetic nanoparticles [22]. Gelatine-based magnetic hydrogel nanocomposites were designed for the delivery of anticancer drug Dox [23]. The hydrogel matrix was prepared by free radical catalyzing reaction of acrylamide with bis-acrylamide in the presence of ammonium per sulphate and N,N,N1,N1-tetramethylethylenediamine (TMEDA)(PAM matrix) along with gelatine (GE). In this hydrogel matrix of PAM-GE, magnetic nanoparticles of Fe2O4 and mineral magnetite were incorporated (Fig. 14.3). The nanocomposite hydrogel was characterized by FTIR, X-ray diffraction, SEM (scanning electron microscopy), transmission electron microscopy, thermogravimetric analysis, blood compatibility studies, etc. The drug Dox was loaded in about 50 mg of hydrogel sample by immersing the hydrogel in 20 mL drug solution (5 mg/20 mL distilled water) and in vitro release of the drug was studied spectrophotometrically. Numerous approaches are currently being explored for the use of iron oxide for nanocomposite construction and have widely accepted because of unique properties of iron oxide, but due to large surface availability and dipole-dipole interaction many times the magnetic nanoparticles agglomerate and create problem in designing of delivery system. To overcome the problem, many surface modification protocols have been adapted. Very recently, magnetic nanoparticles of poly (5-amidoisophthalicacid)/Fe3O4 were surface modified by β-cyclodextrin and organic molecule with hydrophilic outer surface and lipophilic inner core for the delivery of lipophilic anticancer drug docetaxel. The nanocomposite was made
PAM Matrix Gelatine Fe2O4
Figure 14.3 Nanocomposite of PAM-GE-Fe2O4.
Nanocomposite for cancer targeted drug delivery
333
target efficient by the introduction of FA. These nanocarriers showed significant anticancer property when studied on HeLa and MDA-MB-231 cell lines [24]. Apart from theranostic application, magnetic nanocomposites have been utilized for the construction of biosensors for the quick and easy detection of cancer. Epidermal growth factor receptor (EGFR) is overexpressed in case of tumor. Earlier methods for detection of EGFR like immunohistochemistry, analysis at DNA, RNA, and protein level are time consuming and expensive. So magnetic nanocomposite-based inexpensive biosensors were developed for the easy detection of cancer in relatively less time [25]. A nanocomposite was designed with Fe3O4, N-trimethyl chitosan (TMC) and gold. Fe3O4/TMC/Au nanocomposite was than tagged with nanobodies (VHH) of EGFR specific antibodies. The above constructed nanoimmuno biosensor was treated with the sample that contains EGFR. Further the complex, that is, Fe3O4/TMC/Au-VHH-EGFR was added to PT/antibody (primary antibodies specific for EGFR) modified electrodes and then 1M HCl was added and preoxidation of Au nanoparticles was volumetrically detected at constant potential.
14.9
Clay-based nanocomposites for cancer cell targeting
Innovations in designing nanoparticles have incorporated unique features to the drug delivery system for the better management of cancer. Nanocomposites for cancer targeting are well explored with different nanocarrier materials. Clay has also been candidate of choice used by many researchers due to biocompatible, nontoxic, natural occurrence, and low cost properties. Halloysite (Hal) is natural occurring clay made from aluminosilicate and available in nanotube structure form. A nanocomposite hydrogel was crafted from the combination of Hal-sodium sodium hyaluronate (SA)/poly (hydroxyethyl methacrylate) (HEMA) for the delivery of anticancer drug, 5-FU used for the treatment of colon cancer [26]. The advantage of this nanocomposite is that the drug can be encapsulated in hydrogel as well as in the shell of Hal nanotubes. The drug (5-FU) was incorporated in Hal nanotubes and hydrogel by placing the nanocomposite in vacuum followed by pulling and breaking the vacuum as shown in Fig. 14.4. Such drug delivery system is pH sensitive and when it experiences pH of colon, rapid release of drug took place and can be used for the oral delivery of 5-FU. Variety of clay has been identified for the development of novel nanocomposites. Palygorskite (Pal) is hydrated magnesium aluminum silicate has been widely used for the preparation of nanocomposite for cancer targeting and imaging due to its nanostructure, fibrous form, low cost, and large surface area. Pal was grafted by polyethyleneimine (PEI) by coupling grafting technique. The nanocomposite was also coupled with FA for targeting to the cancer cell and fluorescein isothiocyanate (FI) for imaging the cancer cells. The Pal-PEI-FA-FI nanocarrier was further tested for cellular uptake efficiency on HeLa cell line with over expressed FARs. The
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Release of drug 5-FU from Halloysite nanotube lumen
Figure 14.4 SA-HEMA-Hal nanocomposite for the delivery of anticancer drug 5-FU for colon cancer.
confocal microscopy suggested that cellular uptake of nanocomposite of Pal-PEIFA-FI was greater as compared to Pal-PEI-FI nanocomposite, which indicates the necessary role of folate conjugation for better targeting of the cancer cells [27]. A more complex drug delivery system based on laponite clay was developed. Laponite consisting of one magnesium octahedral layer between two silicon tetrahedral layers has been widely used clay due to its large surface are, biocompatibility and nontoxic nature. It has been also used in combination with other polymers for the targeted delivery of anticancer drug. Recently, a unique nanocomposite was designed using laponite for the dual delivery of drugs [28]. An antimicrobial drug ciprofloxacin (CIP) and anticancer drug, methotrexate (MTX) were simultaneously delivered in one nanocomposite formulation of laponite polymer combination. Such preparation is beneficial for the cancer patients prone to multidrug resistance. The nanocomposite consisting of P(NIPAAm-MAA), and MADQ-AcImIL&LP, that is, n-isopropyl acryl amide, methacrylic acid and 2-(methacryloyloxy) ethyl trimethyl ammonium chloride- 3-methyl 1-[2-(acryloxy)-ethyl] imidazolium chloride ionic liquid monomer, and laponite was synthesized and the antimicrobial activity of this nanocomposite was examined by minimum inhibitory concentration method against Pseudomonas aeruginosa and Escherichia coli. The anticancer activity was determined on MCF7 breast cancer cell line. Both the studies showed effectiveness of the nanocomposite as compared to the free drug.
14.10
Graphene nanocomposites
Graphene-based materials (such as GO, reduced GO) have shown promise for the treatment of cancer because of their good near infrared absorbance, large specific surface area, and abundant functional for efficient biomolecular loading, bioconjugation and targeting. Graphene-based nanocomposites have shown enormous medical applications in cancer therapeutics especially in terms of subcellular targeting, cellular imaging,
Nanocomposite for cancer targeted drug delivery
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and drug delivery. To increase the cellular uptake of grapheme-based composites, these are often functionalized with polymers such a PEG, PEI, gelatin, or CS. One of the advantages associated with loading drugs on graphene is that the resultant nanocomposite would be more stable and avoids premature release just outside the target cell. Nuclear delivery of anticancer drugs can be done using a bio-functionalized reduced GO. To deliver doxorubicin specifically to the nucleus of HER2 overexpressing breast cancer cells, it was covalently conjugated to GO then reduced to form Poly-L-lysine (PLL) functionalized reduced GOs (rGOs), and subsequently labeled with anti-HER2 antibodies [29]. PLL, the cationic polymer was chosen as it penetrates cell and organelle membranes for better internalization. Also PLL makes the composite of positive charge and has better interactions with negatively charged cell membrane, in doing so efficient cellular uptake of the nanocarrier is possible. The authors demonstrated clearly the cellular uptake pathways, and found that the uptake of rGO-PLL was not affected by clathrin-mediated endocytosis, macropinocytosis, and caveolae-mediated endocytosis. It was reported that the main uptake route of anti-HER2-rGO-PLL was via macropinocytosis and it was due to passive diffusion, rGO-PLL entered the cells. Interleukin-6 (IL-6) has a role in regulation of immune and inflammatory responses. The healthy humans have IL-6 in serum in the range of 10 75 pg mL21 but in cancer patients its concentration elevates to the ng mL21 range. For detection of IL-6, Liu et al. prepared an electrochemiluminescence (ECL) immunosensor by the combination of GO/PANi nanocomposite and CdSe QDs [30]. The ECL immunosensor had high sensitivity, good reproducibility, stability, and wide linear range. In fact, ECL immunosensor has a sensitive response to IL-6 in a linear range of 0.0005 10 ng mL21 which has great potential for the clinical detection.
References [1] G. Soni, K.S. Yadav, Applications of nanoparticles in treatment and diagnosis of leukemia, Mater. Sci. Eng. C 47 (2015) 156 164. [2] G. Soni, K.S. Yadav, Communication of drug loaded nanogels with cancer cell receptors for targeted delivery, Modeling, Methodologies and Tools for Molecular and Nano-Scale Communications, Springer International Publishing, 2017, pp. 503 515. [3] J. Du, J. Liu, P. Gong, M. Tian, L. Sun, S. Ji, et al., Construction of a novel fluorinated graphene-based magnetic nanocomposite and its application in cancer photochemotherapy, Mater. Lett. 196 (2017) 165 167. [4] M. Chu, H. Li, Q. Wu, F. Wo, D. Shi, Pluronic-encapsulated natural chlorophyll nanocomposites for in vivo cancer imaging and photothermal/photodynamic therapies, Biomaterials 35 (29) (2014) 8357 8373. [5] L. Han, Y. Zhang, Y. Zhang, Y. Shu, X.W. Chen, J.H. Wang, A magnetic polypyrrole/ iron oxide core/gold shell nanocomposite for multimodal imaging and photothermal cancer therapy, Talanta 171 (2017) 32 38. [6] Y.H. Park, S.Y. Park, I. In, Direct noncovalent conjugation of folic acid on reduced graphene oxide as anticancer drug carrier, J. Ind. Eng. Chem. 30 (2015) 190 196.
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Applications of Nanocomposite Materials in Drug Delivery
[7] M. Rajan, M. Murugan, D. Ponnamma, K.K. Sadasivuni, M.A. Munusamy, Polycarboxylic acids functionalized chitosan nanocarriers for controlled and targeted anticancer drug delivery, Biomed. Pharmacother. 83 (2016) 201 211. [8] S. Dhanavel, E.A.K. Nivethaa, V. Narayanan, A. Stephen, In vitro cytotoxicity study of dual drug loaded chitosan/palladium nanocomposite towards HT-29cancer cells, Mater. Sci. Eng. C 75 (2017) 1399 1410. [9] E.A.K. Nivethaa, S. Dhanavel, A. Rebekah, V. Narayanan, A. Stephen, A comparative study of 5-fluorouracil release from chitosan/silver and chitosan/silver/MWCNT nanocomposites and their cytotoxicity towards MCF-7, Mater. Sci. Eng. C 66 (2016) 244 250. [10] S. Prabhu, P. Ananthanarayanan, S.K. Aziz, S. Rai, S. Mutalik, S.R.B. Sadashiva, Enhanced effect of geldanamycin nanocomposite against breast cancer cells growing in vitro and as xenograft with vanquished normal cell toxicity, Toxicol. Appl. Pharmacol. 320 (2017) 60 72. [11] R. Dhivya, J. Ranjani, P.K. Bowen, J. Rajendhran, J. Mayandi, J. Annaraj, Biocompatible curcumin loaded PMMA-PEG/ZnO nanocomposite induce apoptosis and cytotoxicity in human gastric cancer cells, Mater. Sci. Eng. C 80 (2017) 59 68. [12] M. Rajan, V. Raj, A.A. Al-Arfaj, A.M. Murugan, Hyaluronidase enzyme core-5fluorouracil-loaded chitosan-PEG-gelatin polymer nanocomposites as targeted and controlled drug delivery vehicles, Int. J. Pharm. 453 (2) (2013) 514 522. [13] M. Rasoulzadeh, H. Namazi, Carboxymethyl cellulose/graphene oxide bionanocomposite hydrogel beads as anticancer drug carrier agent, Carbohydr. Polym. 168 (2017) 320 326. [14] Z. Li, P. Huang, R. He, J. Lin, S. Yang, X. Zhang, et al., Aptamer-conjugated dendrimer-modified quantum dots for cancer cell targeting and imaging, Mater. Lett. 64 (3) (2010) 375 378. [15] X. Li, Y. Chen, M. Wang, Y. Ma, W. Xia, H. Gu, A mesoporous silica nanoparticle PEI fusogenic peptide system for siRNA delivery in cancer therapy, Biomaterials 34 (4) (2013) 1391 1401. [16] S.Y. Lee, J.J. Lee, J.H. Park, J.Y. Lee, S.H. Ko, J.S. Shim, et al., Electrosprayed nanocomposites based on hyaluronic acid derivative and Soluplus for tumor-targeted drug delivery, Colloids Surf. B Biointerfaces 145 (2016), pp. 267-234. [17] Z. Chen, Z. Li, Y. Lin, M. Yin, J. Ren, X. Qu, Biomineralization inspired surface engineering of nanocarriers for pH-responsive, targeted drug delivery, Biomaterials 34 (4) (2013) 1364 1371. [18] C. Saikia, M.K. Das, A. Ramteke, T.K. Maji, Evaluation of folic acid tagged aminated starch/ZnO coated iron oxide nanoparticles as targeted curcumin delivery system, Carbohydr. Polym. 157 (2017) 391 399. [19] S.A. Meenach, J.Z. Hilt, K.W. Anderson, Poly (ethylene glycol)-based magnetic hydrogel nanocomposites for hyperthermia cancer therapy, Acta Biomater. 6 (3) (2010) 1039 1046. [20] N.S. Satarkar, J.Z. Hilt, Magnetic hydrogel nanocomposites for remote controlled pulsatile drug release, J. Control. Release 130 (3) (2008) 246 251. [21] S. Bano, M. Afzal, M.M. Waraich, K. Alamgir, S. Nazir, Paclitaxel loaded magnetic nanocomposites with folate modified chitosan/carboxymethyl surface; a vehicle for imaging and targeted drug delivery, Int. J. Pharm. 513 (1) (2016) 554 563. [22] G. Prabha, V. Raj, Preparation and characterization of polymer nanocomposites coated magnetic nanoparticles for drug delivery applications, J. Magn. Magn. Mater. 408 (2016) 26 34.
Nanocomposite for cancer targeted drug delivery
337
[23] N.N. Reddy, K. Varaprasad, S. Ravindra, G.S. Reddy, K.M.S. Reddy, K.M. Reddy, et al., Evaluation of blood compatibility and drug release studies of gelatin based magnetic hydrogel nanocomposites, Colloids Surf. A 385 (1) (2011) 20 23. [24] R. Tarasi, M. Khoobi, H. Niknejad, A. Ramazani, L. Ma’mani, S. Bahadorikhalili, et al., β-Cyclodextrin functionalized poly (5-amidoisophthalicacid) grafted Fe 3 O 4 magnetic nanoparticles: a novel biocompatible nanocomposite for targeted docetaxel delivery, J. Magn. Magn. Mater. 417 (2016) 451 459. [25] K. Omidfar, M. Darzianiazizi, A. Ahmadi, M. Daneshpour, H. Shirazi, A high sensitive electrochemical nanoimmunosensor based on Fe 3 O 4/TMC/Au nanocomposite and PT-modified electrode for the detection of cancer biomarker epidermal growth factor receptor, Sens. Actuators B 220 (2015) 1311 1319. [26] K.M. Rao, S. Nagappan, D.J. Seo, C.S. Ha, pH sensitive halloysite-sodium hyaluronate/ poly (hydroxyethyl methacrylate) nanocomposites for colon cancer drug delivery, Appl. Clay Sci. 97 (2014) 33 42. [27] S. Han, F. Liu, J. Wu, Y. Zhang, Y. Xie, W. Wu, et al., Targeting of fluorescent palygorskite polyethyleneimine nanocomposite to cancer cells, Appl. Clay Sci. 101 (2014) 567 573. [28] F.B. Zeynabad, R. Salehi, M. Mahkam, Design of pH-responsive antimicrobial nanocomposite as dual drug delivery system for tumor therapy, Appl. Clay Sci. 141 (2017) 23 35. [29] X.T. Zheng, X.Q. Ma, C.M. Li, Highly efficient nuclear delivery of anti-cancer drugs using a bio-functionalized reduced graphene oxide, J. Colloid Interface Sci. 467 (2016) 35 42. [30] P.Z. Liu, X.W. Hu, C.J. Mao, H.L. Niu, J.M. Song, B.K. Jin, et al., Electrochemiluminescence immunosensor based on graphene oxide nanosheets/polyaniline nanowires/CdSe quantum dots nanocomposites for ultrasensitive determination of human interleukin-6, Electrochim. Acta 113 (2013) 176 180.