Current strategies for different paclitaxel-loaded Nano-delivery Systems towards therapeutic applications for ovarian carcinoma: A review article

Journal of Controlled Release 311–312 (2019) 125–137

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Review article

Current strategies for different paclitaxel-loaded Nano-delivery Systems towards therapeutic applications for ovarian carcinoma: A review article Alaa M. Khalifaa, Manal A. Elsheikhb, Amr M. Khalifac, Yosra S.R. Elnaggard,e,

T

⁎

a

Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan Department of pharmaceutics, Faculty of Pharmacy, Damanhur University, Damanhur, Egypt c Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy d Head of International Publication and Nanotechnology Consultation Center INCC, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Egypt e Department of Pharmaceutics Faculty of Pharmacy, Alexandria University, Egypt b

A R T I C LE I N FO

A B S T R A C T

Keywords: Ovarian cancer Chemotherapy Paclitaxel Nanoparticles Multidrug resistance Poor solubility

Ovarian carcinoma (OC) is one of the leading causes of death among gynecologic malignancies all over the world. It is characterized by high mortality rate because of the lack of early diagnosis. The first-line chemotherapeutic regimen for late stage epithelial ovarian cancer is paclitaxel in combination to carboplatin. However, in most of cases, relapse occurs within six months despite the initial success of this chemotherapeutic combination. A lot of challenges have been encountered with the conventional delivery of paclitaxel in addition to the occurrence of severe off-target toxicity. One major problem is poor paclitaxel solubility which was improved by addition of Cremophor EL that unfortunately resulted in hypersensitivity side effects. Another obstacle is the multi drug resistance which is the main cause of OC recurrence. Accordingly, incorporation of paclitaxel, solely or in combination to other drugs, in nanocarrier systems has grabbed attention of many researchers to circumvent all these hurdles. The current review is the first article that provides a comprehensive overview on multi-faceted implementations of paclitaxel loaded nanoplatforms to solve delivery obstacles of paclitaxel in management of ovarian carcinoma. Moreover, challenges in physicochemical properties, biological activity and targeted delivery of PTX were depicted with corresponding solutions using nanotechnology. Different categories of nanocarriers employed were collected included lipid, protein, polymeric, solid nanoemulsion and hybrid systems. Future perspectives including imperative research considerations in ovarian cancer therapy were proposed as well.

1. Introduction

essential role in the difficulty of early diagnosis and in the disease progression [7]. Generally, in contrast to most solid tumors, OC possesses great propensity to metastasize within the peritoneum rather than dissemination through vasculature. Therefore, peritoneal metastasis remains the major cause of high morbidity and mortality rates in OC [8]. It was proposed that, ovarian cancers are classified into two types: type I and type II. Regarding type I ovarian carcinomas; they are of low-grade serous, limited to the ovary and are genetically stable (lack genetic mutations of TP53 genes). On the other hand, type II ovarian carcinomas, are extremely aggressive, develop quickly and mostly present in advanced stage. The latter covers conventional high-grade serous carcinoma (HGS), malignant mixed mesodermal tumors (carcinosarcoma) and undifferentiated carcinoma. In addition, many studies reported that, high-grade serous ovarian cancer (HGS-OvCa) exhibits mutations in TP53 gene and represents 80% of ovarian cancers that

1.1. Ovarian Cancer prevalence and mortality Ovarian carcinoma (OC) is the most fatal gynecological malignancy among women worldwide which is known for its significant morbidity and mortality, partly because it is often diagnosed at advanced stage [1]. Every year in the United States of America about 21,550 females suffer from ovarian cancer and 14,600 females die from it [2]. In 2012, there were an approximated 239,000 new cases of ovarian cancer worldwide, leading to more than 140,000 deaths [3]. Worldwide, ovarian cancer is considered the seventh ranked cancer, the eighth most predominant cause of death and one of the lowest cancer survival rates. [4–6]. Evidences throughout the literature reported that, the lack of early symptoms, physical signs and sensitive tumor biomarkers have an

⁎ Corresponding author at: Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, 1 Khartoum Square, Azarita, Messalla Post Office, P.O.Box 21521, Alexandria, Egypt. E-mail addresses: [email protected], [email protected] (Y.S.R. Elnaggar).

https://doi.org/10.1016/j.jconrel.2019.08.034 Received 10 July 2019; Received in revised form 27 August 2019; Accepted 28 August 2019 Available online 30 August 2019 0168-3659/ © 2019 Elsevier B.V. All rights reserved.

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may result in death [9–11]. 1.2. Challenges in ovarian cancer treatment Currently, it is still challenging to deal with the relapsed or advanced stage ovarian cancer. This leads to declined rate of survival and poor life quality for patients with ovarian cancer. The reasons behind may be due to the absence of early diagnostic methods and high chemoresistance rate. Consequently, researchers have been doing massive investigations devoted towards the understanding, diagnosis and treatment of ovarian cancer. Multidrug resistance (MDR) is the main mechanism by which many tumors develop chemoresistance. It is one of the principle barriers to the successful clinical therapy of various types of cancer [12–14]. Throughout the history, recurrent ovarian cancer continues to exist among the most clinically challenging incidents because of its lasting trajectory towards MDR. Generally, different mechanisms underlying chemotherapeutic resistance encompass reduced drug uptake, increased drug efflux, activation of detoxifying proteins, triggering DNA repair process, and disruption of apoptotic signaling pathway. Recent studies demonstrated two types of genes, pump and non-pump gene types which are responsible for MDR in ovarian cancers [15]. The Pump type induced resistance correlates to the P-glycoprotein (P-gp) overexpression which pumps chemotherapeutic drugs out of the cancerous cells [16]. The non-pump gene type is represented as cell death defense pathway which is triggered by members of the inhibitors of apoptosis protein family such as BCL-2 and Survivin oncogenic proteins [17,18]. Furthermore, chemo-resistance of ovarian cancers may be aroused as well from a tiny population of tumor cells of ovarian cancerous tissue known as ovarian cancer stem cells (OCSCS). These tiny groups are well known for their great power of chemo-resistance, tumorigenesis, self-renewal and differentiation into diverse cell types of malignant ovarian cancer. Examples of some of ovarian cancer stem cell markers are CD44, CD133, CD117 and ALDH1A1 proteins [19]. Therefore, ovarian cancer cells that overexpress one of those (CSCS markers), especially CD44+, are largely relates with the recurrence and progression of ovarian cancer [20]. Over the last decade, special externalized cellular vesicles (40–100 nm) were discovered and referred as exosomes. These exosomes represent parts of extracellular microenvironment which are formed by the inward budding and separation of late endosomes and mainly responsible for intercellular communications. Many evidences showed that exosomes are vigorously released in pathophysiological conditions including inflammation, immunoregulation, tumorgenesis and metastasis. Regarding ovarian cancer exosomes, they are considered as a signaling factor in the microenvironment of the tumor and greatly responsible for OC metastasis and chemoresistance [13]. The main mechanisms depend on exosomes cargos such as gelatinolytic enzymes, immunosuppressive factors and cancer-associated adipocytes/ fibroblasts. These bioactive cargos are respectively responsible for cancer cell invasion, supporting immune evasion in ovarian cancer and transporting miRNA to cancer cells increasing OC chemoresistance [8].

Fig. 1. Chemical structure of paclitaxel.

off-white crystalline appearance. It possesses a fusion point near 216–217 °C and corresponding molecular weight of 853.9 g/mol [26]. Regarding PTX solubility, it is highly lipophilic, non-ionic, practically insoluble in water (less than 0.03 mg/ml) and it is soluble in organic solvents [22,27,28]. Concerning the anticancer mechanism of action, it promotes and stabilizes microtubules by inhibiting their depolymerization, Thereby, the exposed cells are arrested in the G2/M phase through binding to the β tubulin protein subunits which leads to antimitotic effect and eventually apoptosis through cell signaling cascade [29,30]. Despite of being one of the highly effective chemotherapeutic agents ever developed for cancer therapy but it was not feasible commercially and quite complicated. The reason behind is that, bioavailability of PTX is poor following oral administration mainly due to its hydrophobicity, enterocyte efflux via P-gp and hepatic presystemic metabolism by cytochrome P450 [22,31–34]. Regarding the systemic administration, evidences suggested that, the intraperitoneal PTX administration is more beneficial and advantageous than intravenous route [35,36]. It may be due to that; ovarian cancer has a high tendency to metastasize in the peritoneum rather than the vasculature. PTX pharmacokinetics is characterized by biphasic decline in plasma concentration, the first quick decline is a result of the distribution of the drug to the central compartment and its elimination. The second phase is due to the efflux of the drug out of the peripheral compartment [34]. The primary route of systemic elimination of paclitaxel occurs via hepatic first pass metabolism and biliary excretion, which may account for the marked interpatient variability in systemic clearance [37]. Additionally, PTX suffers from significant multi drug resistance (MDR) which results in diminished response rate and failure of the chemotherapy. Some mechanisms causing PTX resistance include reduced influx of drug into the tumor cell and phenotypic alteration in the tumor microenvironment. Besides existence of membrane bound transporters such as P-gp which pump out the cytotoxic drugs, along with cytochrome P-450 metabolizing enzymes. Finally, the overexpression of CD-44 (ovarian cancer stem cell marker), the anti-apoptotic BCL2 protein and survivin play a crucial role in PTX resistance as well [24,38–40]. Many attempts throughout literature have been adopted to overcome PTX poor water solubility and multi-drug resistance, consequently, improving PTX anticancer activity. The first commercialized PTX formulation against advanced epithelial ovarian carcinoma is Taxol®. Such formulation was prepared through solubilization of PTX in 1:1 mixture of (polyoxyethylated castor oil) Cremophor EL to overcome PTX hydrophobicity. Nevertheless, lots of hurdles through the usage of this vehicle have been reported related to the toxicity of the solubilizer (CrEL) [41]. The elevated level of nonionic surfactant that required for parenteral administration of PTX causes serious severe side effects. These include; anaphylactic hypersensitivity reactions, neurotoxicity and nephrotoxicity [24,28,42]. As a result, the time span of intravenous

1.3. Conventional therapeutic approaches: an emphasize on paclitaxel The first approach for treatment of patients with advanced epithelial ovarian carcinoma is primary surgical resection of the disease followed by platinum-based chemotherapeutics. However, most patients suffered from either residual or recurrent disease, so adjuvant chemotherapy with interval surgical debulking was a necessity [21–23]. A class of antineoplastic agents, called Taxol, was noted in clinical trials to have no cross-resistance with the platinum compounds [22,24]. A first taxane-member in clinical trials is paclitaxel (PTX) which is one of the most effective chemotherapeutic drugs for treatment of variant types of malignancies. Besides, in 1992, Food and Drug Administration (FDA) approved PTX for ovarian and breast cancer treatment [25]. PTX (Fig. 1, C47H51NO14) is a diterpenoid pseudoalkaloid with white to 126

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chemokine receptor inhibitors or histone deacetylase inhibitors (HDACi). The former combination significantly limited tumor proliferation, sensitized the ovarian cancerous cells to low concentration of PTX and reduced the occurrence of adverse events [55]. The second combination of PTX with HDACi (suberoylanilide hydroxamic acid), was reported to circumvent the resistance of ovarian cancer cells to PTX. The mechanism behind this was the significant synergistic antitumor effect through growth inhibition and apoptosis [56]. Recently, investigations on further inclusion of 5-flurouracil to the latter combination had gained a huge interest. Since, it resulted into cell cycle arrest and inhibition of cell proliferation more stronger than single or two combined chemotherapy [57].

(IV) infusion of Taxol® was routinely prolonged to 6 h or longer. In addition, a premedication routine consisting of diphenhydramine, dexamethasone, and cimetidine was initiated [43]. Concerning the multi-drug resistance as an obstacle in PTX delivery, the use of functional P-gp inhibitors (cyclosporine A, verapamil or borneol) was investigated as a useful approach to overcome chemoresistance [15,16,44]. However, most of those functional inhibitors in combination to PTX did not have clinical approval because of their undesirable side effects and toxicities. Many recent studies have focused on gene silencing strategies and novel nano-platforms to overcome PTX chemoresistance that will be illustrated in detail in the following sections. 1.4. Chemotherapeutic combinations with paclitaxel

2. Approaches addressing paclitaxel pharmaceutical obstacles and considerations as a monotherapy: nanotechnology approaches

Improving the anticancer efficacy against resistant ovarian cancer may be attained using combination of chemotherapeutic agents. This depends on the theory which postulated that one drug-resistant tumor cells will be sensitive to another drug with a different mechanism of action. Besides, the synergistic potential between drugs, which would enhance the effectiveness and reduce the toxicity profile [45]. The typical first line combination therapy for treatment of ovarian carcinoma is the combination of paclitaxel and platinum-based agents. Such combination is considered as a benchmark for ovarian cancer treatment subsequent to the debulking surgery [21]. A clinical trial evaluated two different formulations carboplatin–paclitaxel and cisplatin–paclitaxel had been performed. The results showed that the former was more tolerated since it showed better toxicity profile. Moreover, the regimen that contains carboplatin provided a slight elevation in efficacy with 16% reduced risk of death over cisplatin [46]. Despite the initial success of this chemotherapeutic combination, relapse of the disease occurred in almost all patients. Majority of these relapsed tumors develop chemoresistance which is the main obstacle for the best chemotherapeutic outcome [12,13]. An open-label randomized phase II study was achieved on patients who were resistant to platinum drugs or with relapsed ovarian cancer. This study examined progression-free survival (PFS) of monoclonal antibodies, seribantumab, combined with weekly PTX versus PTX alone. In spite of seribantumab addition did not show any improvement in PFS, however it resulted in better efficacy and much more benefits [47]. Furthermore, combination of farletuzumab with the standard chemotherapeutic regimen of carboplatin and taxane was clinically evaluated. Such combination showed more specificity against the folate receptor-alpha, which is over expressed in ovarian cancerous tissues. However, anemia was recorded in large proportion of patients who received farletuzumab compared to placebo group [3,48]. Another combination therapy aimed to enhance progression-free survival includes paclitaxel with one of anti-VEGF (Vascular endothelial growth factor) drugs, pazopanib [49,50]. Open-label, randomized phase II trial was performed to investigate the efficacy of this combination therapy versus PTX alone. The combination resulted in marked improvement of progression-free survival than PTX solely. However, this combination led to more aggressive toxicity profile that strongly correlated to addition of pazopanib [51]. One more clinical trial (phase III) was carried out in 2016, investigated the addition of geldanamycin antitumor antibiotic to PTX. Results revealed a synergistic effect in growth suppression of cancerous tissues and apoptosis circumventing MDR towards paclitaxel [52]. A new approach was developed that investigated the use of oncolytic viruses, reovirus (Reolysin®), in combination with PTX for relapsed ovarian treatment. These viruses possess the ability to selectively replicate, affect and destroy cancerous cells without affecting normal healthy tissues [53]. However, aggressive toxicity profile especially severe neutropenia as well as severe respiratory adverse effects were recorded. Consequently, the researchers did not recommend such approach for further investigation [54]. On the other hand, sensitizing the ovarian cancerous cells to PTX is considered an additional approach to improve the anticancer efficacy of PTX. This strategy was implemented by using combinations either with

In fact, conventional chemotherapy, either single drug or in combination, resulted in treatment failure which is due to either drug resistance, pharmacologic or toxicity issues. In addition, conventional chemotherapeutics distribute throughout the body, where they affect both cancerous and normal tissues causing aggressive toxicity profile [58,59]. Over the past two decades, the research has witnessed a remarkable growth on the use of nanotechnology for therapeutic applications especially oncology [60–68]. Regarding this purpose, diverse drug delivery strategies as illustrated in Table 1, have been evolved to circumvent the current drawbacks of the conventional ovarian cancer treatment [69–73]. These include; avoidance of rapid drug clearance after systemic delivery and enhancement the pharmacokinetic parameters of the drug. Moreover, increase the drug-tumor accumulation, overcome the MDR, reduce the off-target toxicity consequently, achieve much more efficient treatment [74,75]. As a result, application of nanotechnology approach is considered crucial for the delivery of PTX for ovarian cancer treatment. 2.1. Targeting efficiency Many researchers have been trying to achieve a “magic bullet” concept in drug delivery systems especially nanocarriers that will particularly target actives to cancerous tissue [76] . As mentioned previously, the multi drug resistance (MDR) to PTX is mainly due to over expression of P-gp which in turn reduces the intracellular PTX level. Furthermore, the over expression of cell surface proteins, especially CD44, was associated with PTX chemoresistance. Consequently, several approaches were developed throughout the literature either by inhibiting p-gp or by actively targeting protein receptors the overexpressed on ovarian cancer tissue [77]. These receptors involve folate receptor, luteinizing hormone releasing hormone receptor (LHRH), follicle stimulating hormone receptor (FSHR), CD44, HER-2 and EGFR [40,75,78,79]. In this regards, L. Fan et al. developed and evaluated the actively targeted PTX through loading it inside a conjugated Folliclestimulating hormone polypeptide-nanoparticle (FSHP-NP). This nanoplatform successfully delivered PTX directly to the ovarian tumor cells that overexpresses (FSHR) in patients diagnosed with ovarian cancer associated with lymph node metastasis. This study concluded that (FSHP-NP-PTX) can outstandingly inhibit cell proliferation of NuTu-19 cell line, and it can deliver PTX into the lymph nodes in vivo [80]. Another research paper by X. Zhang et al. successfully developed and investigated an FSHR targeted nanoparticle formulation (FSH81-NPPTX) where FSH β 81–95 peptide act as a targeting ligand to actively target FSHR-positive ovarian cancerous cells. The results showed an improvement of cytotoxic effect of PTX in vitro and an enhancement of antitumor efficacy of PTX with reduced side effects in vivo [81]. Another study by X.Y. Xiong et al. investigated the use of biotinylated polymeric nanoparticles to deliver paclitaxel for ovarian cancer treatment. Biotinylated Pluronic F127/poly (lactic acid) block copolymers 127

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Table 1 Paclitaxel-based Nano formulations for ovarian cancer treatment as a monotherapy. Type of nano-carrier

Approaches

FSHP-NP

Folic acid-poly (lactic-co-glycolic acid) nanoparticles (FA/PLGA NPs) Biotinylated Pluronic F127/poly (lactic acid) block copolymers Folic acid-coupled PEGylated nano-paclitaxel liposome (FA-NP)

Active targeting to the ovarian tumor cells that overexpresses (FSHR) Active targeting to FSH β 81–95 peptide ligand Active targeting the folate receptors overexpressed in ovarian cancerous tissues Active targeting by biotinylated anti-CA125 antibody as targeting ligand Actively targeting folate receptors overexpressed in ovarian cancer

Hayaluronic Acid coated PTX-loaded cationic lipid nanoparticles (HA-PTX-NLCs)

HA actively targets the CD44++ ovarian cancerous cells.

Solid nanoemulsions (HSNs)

Hyaluronan ligand to actively target CD44 receptors Active tumor targeting through folic acid ligand and folate receptors interaction. Enhance poor paclitaxel solubility Enhance poor paclitaxel solubility Enhance poor paclitaxel solubility Prolonged paclitaxel half-life

(FSH81-NP-PTX)

Polylactic acid PEG-PLA-FA-NP block co-polymer Tetra branched peptide carrier (NT4) Pluronic P105 polymeric micelles NK105 polymeric micelles Self-micro emulsifying drug delivery system of paclitaxel containing poly(lactide-co-glycolide) Lipocores

Method of assessment

lipid-dendrimer hybrid (LDH) Nano system

Prolonged paclitaxel half-life and improved systemic stability. Prolonged paclitaxel half-life

Amphiphilic linear-dendritic copolymer (telodendrimer) (PEG5k-CA8 NPs)

Prolonged paclitaxel half-life with passive accumulation in ovarian cancer tissues

Nanotaxol (liposomes encapsulated paclitaxel)

Nanotaxol intraperitoneal administration

Poly lactic acid-loaded paclitaxel

polymeric nanoparticles (200 nm) was administered via intraperitoneal route Intraperitoneal route of drug administration

An in-situ hydrogel depot containing paclitaxel nanocrystals (PNC)

• NuTu-19 OC cell line and SKOV-3 cell lines • Caov-3 mice bearing Caov-3 human ovarian tumors • Nude homozygous female nude mice subcutaneously • Athymic injected human OCSCs (xenograft method) and SKOV-3 cells • OVCAR-3 implanted in Balb/C nude mice • OVCAR-3 cell lines • SKOV3/TAX SKOV3 peritoneal xenograft model of • Paclitaxel-sensitive paclitaxel-resistant ovarian tumor. cells • SKOV3 cells • SKOV3/PTX bearing SKOV3 ovarian cancer cells xenografts. • Mice • SKOV-3 cells TCC® HTB77™ (CD44+) OVCAR3 (CD44–) • A2780, SKOV3 and HO8910 cells ovarian cancer cell line • SKOV-3 ovarian cancer cell lines. • SKOV-3/PTX and OVCAR-3 ovarian cancer cells • MCAS ovarian tumor cell line SKOV-3 • Human human ovarian cancer cells bearing • SKOV-3 immunocompromised mice model. • Human ovarian tumor OvCar3 implanted in SCID mice cell line • IGROV-1 cell line • SKOV-3 cells • SKOV3-luc xenograft model and orthotopic • subcutaneous intraperitoneal model. cell line inoculated into the ovarian • Taxol®-resistant tissue of SCID mice. • Ovarian carcinoma xenografts in (F344) rats • SKOV3 • mice bearing SKOV3 ovarian tumor xenografts

References [80] [81] [20] [82] [83]

[85]

[86] [106] [90] [91] [92] [108]

[107] [109] [105]

[101] [99] [100]

which in turn resulted in extensive potent apoptotic potential of paclitaxel. In addition, the proliferation of ovarian tumor tissues was remarkably inhibited and prolongation of the survival time was observed [83,84]. On one hand, L. Wang & E. Jia developed an actively targeted nanocarrier of hyaluronic acid coated PTX-loaded in cationic lipid nanoparticles (HA-PTX-NLCs). The antineoplastic efficacy of such nanoplatform was evaluated both in vitro in SKOV3 and SKOV3/PTX cells as well as in vivo in mice bearing SKOV3 cells xenografts. Results revealed that, a sustained release profile was achieved that led to maintained PTX efficiency and circumventing the MDR effect. Furthermore, the biodegradable and biocompatible HA-PTX-NLCs were found to reduce the IC50 of PTX dramatically thus very low toxicity profile with enhanced antitumor activity [85]. On the other hand, it was reported that, the over-expression of CD-44 receptors in SKOV-3 cells enabled the use of hyaluronan as an actively targeted ligand moiety. In this concern, a hyaluronan coated solid nanoemulsions (HSNs) was successfully fabricated for actively delivered paclitaxel to the + CD-44 receptors on ovarian cancer cells. The pharmacokinetic parameters were enhanced by increasing the retention and accumulation of PTX as well as prolonging the circulation time in the blood. Besides, an improvement of tumor growth suppression and decreased toxicity profile in vivo were observed compared to free Taxol. Finally, PTX-HSNs were extremely effective for the delivery of a high maximum tolerated dose of PTX to ovarian cancer cells overexpressing CD44. Consequently, novel PTXHSNs had been led to an improvement of PTX active targeting with lower side effects [86].

was loaded with Paclitaxel and was investigated for its targeting and antitumor efficacy. Active targeting was accomplished by using biotinylated anti-CA125 antibody that particularly target the CA-125 protein (ovarian cancer biomarker) that is over-expressed on OVCAR-3 cells but absent on SKOV-3 cells. The results recorded that, PTX was delivered in much higher concentration to OVCAR-3 than SKOV-3 cells consequently, much potent targeted antineoplastic effect was obtained [82]. Many of the previous studies made use of the highly expressed folate receptors on the ovarian cancer cells in the actively targeted delivery approach of paclitaxel. For instance, Abou-ElNaga, Mutawa et al. developed polymeric nanoparticles (PLGA nanoparticles) loaded with PTX and the surface was decorated with folic acid as a targeting ligand. They investigated the biological activity of PTX-loaded FA/ PLGA NPs in human ovarian cancer stem cells in vitro and in vivo xenografts. The results of in vitro studies led to enhancement of PTX cytotoxicity and significant reduction in PTX IC50. On the other hand, in vivo results revealed that PLGA nanoparticles can be loaded by hydrophobic PTX thus prevented its degradation and led to controlled release profile with decreased side effects [20]. In addition, report by Tong et al. aimed to reverse resistance towards paclitaxel by formulating folic acid-coupled PEGylated nano-paclitaxel liposome (FANP). The targeting ability and efficacy was deeply investigated both in vitro and in vivo in SKOV3/TAX cell lines and peritoneal xenograft model of paclitaxel-resistant ovarian cancer respectively. It was significantly clear that nano-PTX particles were successfully encapsulated in the lipophilic DSPE-PEG2000 liposome. The uptake and accumulation of PTX in tumor site was much more significant than PEGylated nano-paclitaxel liposome lacking folic acid. Consequently, the results showed that, PTX chemoresistance was successfully circumvented

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advantages through delivering the therapeutics in nanocarrier drug delivery vehicles [97,98]. Lu, Li et al. prepared a polymer-based drug delivery system (PLA) for paclitaxel about 200 nm to be injected intraperitoneally in ovarian carcinoma xenografts (F344) rats to evaluate the efficacy and lymphatic targeting. In vitro MTT cytotoxicity assay revealed that paclitaxel nanoparticle had similar IC50 value when compared to that of free paclitaxel. Therefore, they concluded that paclitaxel loading nanoparticle had antitumor effect in vitro similar to that of free PTX. In addition to the in vivo antitumor studies that resulted in lower weight of the tumor and lower ascites volume in comparison with free paclitaxel as well as increase in the drug concentration in the tumor site. Lu, Li et al. concluded that it was the first time for synthetic paclitaxel nanoparticle PLA to significantly inhibit the growth of ovarian tumor in vivo via intraperitoneal administration with reduced toxicity profile [99]. Another recent study evidenced that IP hydrogel depot nano-system is a promising approach for ovarian cancer treatment. In this regard, PTX nanocrystals as a hydrogel depot was administered in the peritoneal cavity and investigated for its efficacy against ovarian cancer. Results revealed a significant concentration of paclitaxel was accumulated at the site of the tumor. Besides, the depot effect results in prolonging the survival time in vivo and hence, a remarkable cell killing effect was obtained compared to the microparticulate PTX in SKOV3 cell culture [100]. A comparative research held by Shen, Li et al. concerned with the appraisal of the efficacy of intraperitoneal Nano-Taxol (liposome encapsulated paclitaxel) versus intravenously route and versus free Taxol. The in vivo cytotoxicity results revealed that intravenous free Taxol, intraperitoneal free Taxol and intravenously administered Nano-Taxol poorly controlled the proliferation of the ovarian tumor tissues. In contrast, treatment of the ovarian cancer by intraperitoneal Nano-Taxol significantly reduced the tumor size and even eradicated it. Furthermore, the intraperitoneal delivery of Nano-Taxol extensively prolonged the survival time and improved PTX bioavailability [101].

2.2. Poor solubility Nano-based formulations are considered as promising carrier systems to improve the poor aqueous solubility of hydrophobic drugs through nano-solubilization techniques [60,87,88]. Many formulation attempts have been focused to improve PTX water solubility using alternative non-Cremophor formulations. Paclical® is another recent entry in the area of nano-PTX formulations based on “vitamin A" derivatives. It is able to form micelles of particle size around 40 nm for solubilization of the hydrophobic drug PTX. In addition it was reported that Paclical possesses pharmacokinetics parameters similar to Abraxane [89]. The results of clinical trial (phase III) in patients with OC showed enhanced overall survival of combination between Paclical and carboplatin in comparison to patients who received Taxol and carboplatin. Another approach that focused on improving PTX hydrophilicity was through conjugating it with tumor selective tetra branched peptide carrier (NT4). Basically, NT4 particularly targets the cancerous cells by attaching to sulfated glycosaminoglycans and specific endocytic receptors which are considered as tumor markers. Brunetti, Pillozzi et al. studied and evaluated the biological action of NT4paclitaxel in vitro in SKOV-3 ovarian cancer cell lines however, it was not tested in in vivo ovarian cancer model. Besides, it was suggested that this modification in PTX led to improvement in pharmacokinetic profile through increasing its hydrophilicity which in return decreased the toxic side effects of organic solvents [90]. Reports concerning with PTX solubilization suggested a formulation of paclitaxel-loaded pluronic P105 polymeric micelles. Such micellar formulation was appraised against human ovarian cancerous cell line (SKOV-3). The results showed the enhanced solubility of PTX, reversed the resistance to PTX in comparison with free PTX and significant increase of PTX cellular uptake with well controlled release profile [91]. Another strategy involved the use of novel NK105 block copolymers that composed of hydrophilic PEG and modified hydrophobic polyaspartate. Such polymeric micelles nanoparticles facilitate the incorporation of the hydrophobic PTX in the core of the micelles via simple self-association process. Results implemented that although both NK105 and free PTX showed equivalent cytotoxic activity on MCAS and OVCAR-3 cell lines. However, NK105 showed superiority in antitumor activity in comparison to the free drug. In addition, the NK105 block copolymer possessed a clinical advantage of being Cremophor-free, i.v injectable and nonimmunogenic [92]. Nanoxel™ is A novel pH sensitive non-Cremophor polymeric nanomicelles that specifically targets tumors. Its antitumor efficiency and intracellular accumulation of PTX was compared with two other commercially available Cremophor-based formulations: Abraxane ™ and Intaxel™. Results revealed that Nanoxel™ possessed a superior cellular uptake of PTX to ovarian cancer cell line (PA-1) compared to the conventional Cremophor-based formulation [93].

2.4. Prolongation of PTX half-life Several studies investigated the incorporation of paclitaxel in diverse types of nanocarriers to enhance its pharmacokinetic profile and hence, circumvent the encountered barriers in ovarian cancer treatment. To date, Abraxane® is a novel human serum albumin nanoaggregate of paclitaxel which shows a major advancement in the field of chemotherapy. It was the first commercial product depends on the albumin-bound nanoparticles platform and was approved by FDA for treatment of different forms of cancers including lung cancer, pancreatic cancer and breast cancer [59]. Interestingly, albumin has been used for developing controlled and sustained drug delivery system because of its long circulation half-life [78]. Since (Abraxane®) development is solvent free and based on albumin which is naturally circulating in the blood. Therefore, the risk of hypersensitivity reaction is drastically reduced which remarkably occurs with cremophor-based paclitaxel [89,102,103]. A phase II studies described a significant potential action of Abraxane® against PTX resistant ovarian cancer cell [86,104]. These results may be ascribed to the delivery of high concentration of PTX to the ovarian cancerous tissue with much more enhanced efficacy and reduced toxicity profile compared to Taxol®. Another study investigated the development of polyethylene glycol-dendritic block copolymer, referred to as telodendrimer, for the delivery of the paclitaxel for ovarian cancer therapy. Polymeric micelles established in this study composed of the PEG and unique amphiphilic molecule (cholic acid). Such PEG-CA telodendrimer based micellar nanoparticle (PTX-PEG5kCA8 NPs) resulted in high loading of the hydrophobic PTX that led to prolonging of the circulation time, accumulation in ovarian tumor tissue, sustained release profile. Consequently, it maximizes therapeutic efficiency and significantly decrease the nonspecific toxicities compared to Taxol or Abraxane alone [105]. A novel Nano-block copolymer system (PTX-PEG-PLA-FA-NP) was recently prepared by Yao et al. and

2.3. Route of administration Some of the researchers were not only focusing on developing of novel nanocarrier for PTX delivery but also on studying of the best route of administration of this drug loaded nanoparticle. Peritoneal metastasis remain the main cause of high mortality and morbidity rate in ovarian cancer [94]. It was proven by clinical trials that intraperitoneal paclitaxel administration is more beneficial and advantageous regarding its efficacy than intravenous [35,36]. One of the most recently completed phase III trial showed 16 months survival extension when comparing IP chemotherapy by IV chemotherapy which was considered one of the most important privileges in ovarian cancer research [95,96]. Despite of the significant survival advantage, intraperitoneal chemotherapy is hindered by the extended use of indwelling catheter that may result in infections as well as occurrence of local toxicity and by the non-targeted nature of the intraperitoneal chemotherapy. However, this can be circumvented by using sustained release formulations for the sake of IP route of administration 129

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of carboxylic functional domain in order to encapsulate both PTX and cisplatin. In vitro studies reported a synergism in the antitumor activity that led to death of ovarian cancer cell line. In addition, high stability of such nanocarrier led to prolongation of the systemic circulation time that eliminated especially cisplatin toxicity in SKOV-3 ovarian cancer xenograft model. Finally, it was detected that the combination loadedtelodendrimer possessed an efficient tumor-targeted ability with high effective concentration in the ovarian cancerous tissues in comparison with free drug combination or single loaded formulations [117]. Under other conditions, the same combination of drugs was studied to be delivered through a polymer-based micellar system composed of amphiphilic block copolymer called poly (2- methyl-2-oxazoline-2-butyl-2oxazoline-block-2-methyl-2-oxazoline). Such delivery system was assessed using cisplatin-resistant human ovarian cancer (A2780/CisR) xenograft model. Conclusively, the results showed an improvement of the pharmacokinetic parameters, enhanced accumulation of both drugs in tumor site with synergistic antineoplastic activity, and lower side effects [30]. One of the promising cross-linked polymer-based drug delivery systems is called “Nanogels”. It is characterized by its high drug loading, high stability which in return prolongs its blood circulation. Besides it possesses a capability to cross most of the biological barriers while protecting the encapsulated drugs and its surface can be easily decorated by targeting ligand to enhance active targeting [118]. Based on the previously mentioned facts about nanogels, S.S. Desale et al. formulated a biodegradable polypeptide-based nanogel to co-deliver paclitaxel and cisplatin to ovarian cancerous tissue. It was prepared from amphiphilic copolymers such as PEG-b-poly L-glutamic acid-b-poly L-phenylalanine. Besides, the nanogel surface was decorated by folic acid to enable the active targeting to the ovarian tumor tissues. They recorded that after IP administration; nanogel demonstrated a sustained release profile of the drugs owing to the crosslinking architecture of the synthesize nanogel. In addition, it inhibited cancerous cells proliferation, extended the survival time and reduced the toxicity profile [119]. On the other hand, chitosan-based nanoparticle has been deeply investigated in many research papers for cancer treatment for the sake of enhancement of targeting ability, sustained delivery and augmented therapeutic efficacy [112,120–122]. For instance, J. Emami et al. recently had formulated polymeric micelles based on chitosan and loaded with paclitaxel and α-tocopherol succinate for ovarian cancer treatment. Co-delivery of PTX and α-TS resulted in a significant synergistic effect that in return led to the use of low dose of PTX. This new combinatory approach delivered in such nanocarrier resulted in enhanced micellar stability that control the rate of paclitaxel release, high capacity of drug loading, reduced toxicity profile of PTX and much higher cytotoxic effect [112]. A unique potential of concurrent delivery of cytotoxic agent and targeting agents loaded in nanoplatforms was extensively investigated for the treatment of metastatic ovarian cancer. Such multi-drug combination used polyethylene glycol-block-poly ε-caprolactone micelles to be loaded with paclitaxel, Bcl-2 inhibitor (gossypol), and cyclopamine (hedgehog inhibitor). IP delivery of such combination nano-plateform for ovarian cancer treatment achieved several major requirements for combination drug delivery. These include: biocompatibility, stability, multiple-drug solubilization and sustained drug release. Results demonstrated a significant reduction in the tumor volume, suppression of the proliferation of cancerous cells and extended survival time compared to therapy with paclitaxel alone [123]. Curcumin is a pivotal phytomedicine that has an anticancer potential through inhibiting proliferation, apoptosis induction and its capability to inhibit the MDR [6,124,125]. A.H. Abouzeid et al. prepared a delivery system of PTX and curcumin combination through encapsulating both in mixed micelles of polyethylene glycol-phosphatidylethanolamine (PEG-PE) and vitamin E. Results suggested that, these combination micelles have a remarkable efficacy in vitro as well as in vivo; most importantly a synergistic effect was recorded at 10 μM curcumin. Besides it demonstrated 3-folds elevation in growth

they investigated its efficacy in SKOV-3 cells and in tumor mice models. The problem of poor hydrophilicity and anaphylactic response was resolved by eliminating the use of cremophore EL. Interestingly, the results showed longer half-life, perfect slow release effect, improved tumor-targeting characteristics and enhanced antineoplastic activity [106]. Diversely, different from the traditional lipid-based nanoparticles, lipocore a spherical lipid core coated drug, can incorporate in its solid core only poorly water-soluble drugs and its surface surrounded by poly ethylene glycol. W.R. Perkins et al. formulated lipocores loaded with PTX as a therapeutic delivery vehicle for ovarian cancer treatment to be investigated in OvCar3 human ovarian carcinoma in SCID mice. They showed that this lipocore is very efficient delivery system with high drug: lipid molar ratio in addition to pegylation that imparted stability and prevented particle growth/adhesion. Moreover, the survival time of treated mice was prolonged and the toxicity profile was dramatically reduced [107] Recently, polymer-lipid hybrid systems are being developed to combine the beneficial properties of both polymeric and lipid based nanoplatforms. In this regard, B.K. Kang et al. formulated and investigated paclitaxel microemulsion prepared by selfmicro emulsifying drug delivery system (SMEDDS) containing PLGA to offer the desirable release profile of paclitaxel. The droplets of microemulsion containing PLGA were characterized by spherical shape, smooth surface and there was no agglomeration or stickiness among them. Moreover, the PTX antineoplastic activity was appraised by both in vivo and in vitro methods for microemulsion with or without PLGA. Results revealed that, that PLGA containing microemulsion released PTX slowly in a sustained release profile compared to microemulsion without PLGA. In addition, PLGA presence offered a significant enhancement of the antitumor activity, extend the circulation time and hence led to remarkable tumor size reduction [108]. Another hybrid formulation for paclitaxel delivery was recently investigated by joining lipids and dendrimers to formulate lipid-dendrimer hybrid (LDH) Nano system. This study aimed to benefit from the unique features of both liposomes and dendrimers as DDS for ovarian cancer treatment. It was reported that PTX-LDH Nano system could be loaded by a high quantity of the hydrophobic paclitaxel in comparison to the use of either liposomes or dendrimer separately. In addition, results revealed improved PTX potency by 37 folds due to the synergistic cancer cell killing of PTX-LDH compared to the free PTX [109]. Consequently, the dose of PTX could be reduced about10-folds leading to lowering the incidence of side effects. 3. Nanocarrier-based combination therapy for PTX Concurrent delivery of multiple actives using Nano-formulations was proven by many previous preclinical as well as clinical trials to improve outcomes of ovarian cancer treatments [110–113]. As mentioned previously, the first line benchmark treatment for ovarian cancer is combination of taxane and platinum-based compounds. Consequently, a lot of researchers' attention was grabbed towards the codelivery of taxanes and platinum in diverse types of nanoparticle as a delivery system. However, PTX suffers from poor pharmacokinetic parameters that limit its in vivo efficacy leading to the use of high PTX doses compared to cisplatin and hence higher side effects [114,115]. Diversely, cisplatin binds to blood circulating proteins, moreover its metabolism and elimination in vivo is slower than that of paclitaxel as well. Consequently, the normal as well as the cancerous tissue became in long term drug exposure which in return led to cisplatin associated significant acute and chronic ototoxicity, nephrotoxicity and peripheral neurotoxicity [116]. Therefore, the most important rational of encapsulating both drugs in nanoparticle based DDS is to improve PTX bioavailability, enhance its exposure and accumulation in the tumor tissues while eliminating the toxicity of both cisplatin and paclitaxel through modification of pharmacokinetic and pharmacodynamics profile [117]. In this regard, S Cai, Xu et al., had efficiently designed a copolymer system (telodendrimer) that was modified through addition 130

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treatment of ovarian carcinoma.

inhibition and improved pharmacokinetic parameters such as prolonged blood circulation. Thus, it was recommended for further clinical investigation in resistant ovarian cancer [126]. Another recent research paper studied the same combination (PTX and curcumin) encapsulated in nanoparticles of PLGA/phospholipid/PEG for ovarian cancer therapy. The efficacy of this chemotherapeutic combination incorporated in such NP was investigated in human ovarian cancer cell line (A2780) and resistant cells (A2780/ADM). Conclusively, this approach reversed the MDR, prolonged the circulation time, increased PTX accumulation in tumor cells and hence improved antitumor activity [124]. Another delivery system was discussed by Gawde, Sau et al., who formulated bovine serum albumin nanocarriers loaded with PTX and synthetic difluorinated curcumin (CDF). Both formulations were decorated with folic acid as an active targeting ligand to ovarian cancer tissue. Such combination therapy was assessed through administration of (FA-BSA-CDF) and (FA-BSA-PTX) in SKOV3 ovarian cancer cell lines. The result of in vitro folate blockade assay demonstrated superior targeting ability besides augmented cancer cell killing effect. In addition, results suggested the use of a lower dose of PTX than that of marketed product (Abraxane), so side effects could be greatly reduced [6]. Regarding the fact of MDR, one of the major barriers that handicap PTX delivery and efficacy, several studies intensively have investigated the use of paclitaxel combined with other drugs to overcome PTX chemoresistance. One study in 2011 studied the combination of PTX and lapatinib, a double tyrosine kinase inhibitor which interrupts the epidermal growth factor receptor pathway and hence inhibits the Pglycoprotein transporters. D. Vergara et al. aimed to investigate the efficiency of PTX-lapatinib (LBL)-loaded nanocolloid (PTX/chitosan/ alginic acid/chitosan/ lapatinib/chitosan/alginic acid) in resistant ovarian cancer cell line OVCAR-3. The dual drugs have been delivered through a nanocapsule where PTX was located in the core while lapatinib was on the shell periphery. Conclusively, they witnessed a significant clinical advantages include; remarkable reduction of side effects, overcoming PTX resistance, synergistic potential, and improvement of the anti-proliferative effect. Lastly, LBL-PTX nanocolloids were found to reduce the minimum dose required to achieve a remarkable reduction in cell viability. Therefore, this dual DDS is of great importance to be investigated and applied in vivo to avoid the adverse events of PTX [127]. Combination of PTX with borneol (P-gp inhibitior) was successfully prepared and co-loaded in PEG-PAMAM Polyamidoamine dendrimer nanoparticle. This DDS is considered as a promising approach to overwhelm MDR in ovarian cancer. Furthermore, it was found that this combination led to high cellular uptake with controlled release profile and significant decrease in tumor growth in A2780/PTX cells [16]. Combination delivery of PTX and Tanespimycin-loaded in biocompatible PEG-DSPE/TPGS mixed micelles was investigated for ovarian cancer treatment. Tanespimycin is an inhibitor of Heat shock protein 90 (Hsp90) which is considered as an important therapeutic target that important for tumor cell survival. This DDS was investigated in human ovarian carcinoma SKOV-3 cells that were implanted in mice model. The vital outcomes of this approach were the elimination of toxic effect of organic solubilizers that used to solubilize the two hydrophobic drugs separately. In addition results revealed prolongation of circulation time, enhanced drug accumulation in tumor tissue and Improved anticancer efficacy [128]. One more combination strategy that involved PTX with apoptotic signaling molecule (C6-ceramide) was deeply discussed by Devalapally, Duan et al. Such combination was successfully loaded in a compatible and biodegradable poly(ethylene oxide)-modified poly-(epsilon-caprolactone) for ovarian cancer therapy. It was appraised in vitro using wild-type SKOV-3 and multidrug resistant SKOV3TR models to prove the rational of overcoming MDR. Moreover, the results showed high drug loading, sustained release profile, prolonged systemic circulation and high drug concentration in the tumor cells [129]. The following Table 2 illustrated the nanocarriers-mediated combination therapy of paclitaxel for

4. Novel strategies of gene silencing RNA is a biogenetic polymer that has been extensively investigated as a diagnostic and therapeutic tool for a diversity of human diseases. Many types of RNA with different biological functions have been discovered, including mRNA, transfer RNA, small interfering RNA (siRNA) and microRNAs (miRNA). Regarding chemoresistance, recent studies have identified a number of genes to be targeted associated with the resistance to chemotherapy in the MDR ovarian tumor tissues. RNA interference (RNAi) was first discovered by Fire et al. and was predicted to be the next generation medicine for the therapy of refractory diseases mainly cancer [131,132]. Moreover, small interfering RNAs (siRNAs) have grabbed considerable attention for their potential applications [133]. As an anticancer strategy siRNAs silence the oncogenes expression and specialized targets that promote the proliferation of tumor cells [134]. Several studies investigate the efficacy of siRNA by silencing focal adhesion kinase (FAK), MDR-1, BCL2, survivin and so on to circumvent PTX resistance [135,136]. On the other hand, miRNA is a small non-coding RNAs (22 nucleotides) that present in exosomes in several biofluids including; plasma, serum, urine and ascetic fluid. In addition, it plays an essential role in many biological processes such as proliferation, differentiation and death, and is also incorporated in diverse pathologies [137]. In ovarian cancer, miR-135a-3p is probably associated with ascites, chemoresistance, and tumorigenesis. Accordingly, the miR-135a-3p expression indicator is appropriate for application as a biological marker in ovarian cancer progression. In addition, it was reported that, the amount of miR-135a-3p was greatly decreased in patients diagnosed with ovarian carcinoma in comparison with normal patients. Therefore, subcutaneous or intravenous administration of miR-135a-3p analogues are very encouraging agents for ovarian tumor treatment. This strategy can be achieved through different pathways mainly; sensitizing MDR ovarian cancerous cells to chemotherapy or reducing of ascites [138]. Many reports confirmed the previous findings where Zhou X et al., found that miRNAs (especially miR-152 and miR-148a) were down-regulated in ovarian cancer tissues that led to carcinogenesis and more proliferation of OC. In other words, their up regulation suppress the growth of ovarian cancer [139]. Regarding combinations with taxanes, Zhao et al. recently have studied a combination therapy between PTX and miR-148a for ovarian cancer treatment to investigate whether it will sensitize the ovarian cancerous tissues to PTX or not. The results demonstrated that miR-148a promoted the inhibition of proliferation, mediated the sensitivity of OC cancer cells to PTX, and hence enhanced PTX induced apoptosis [140]. Although siRNAs and miRNAs possess a pivotal role in gene regulation that makes them novel targets for discovery and development of drugs. However, for clinical application, both types of small RNA molecules confer a similar set of hurdles. Such as: poor stability in systemic circulation, renal elimination, off-target effects, and poor tumor celluptake [132,141,142]. Consequently, in order to circumvent these severe limitations and to apply in vivo settings an adequate delivery strategies that permits the siRNA to be stabilized and reach the cytosol of the target cells is needed [143–147]. Such approach includes the use of new drug delivery systems which can extremely protect siRNA from degradation. This can be performed through masking it from various enzymes which will affect the biodistribution and pharmacokinetics of siRNA and hence extend the half-lives of siRNA in plasma [148]. For example: co-delivery of MDR1 and BCL2 siRNA in PLGA nanoparticles for reversing the resistance towards PTX was investigated for treatment of recurrent ovarian cancer. This dual siRNA suppression system resulted in a substantial cytotoxic effect of PTX on the paclitaxel-resistant SKOV3-TR OC cells. This could be illustrated through the efficient simultaneous suppression of both genes which resulted in reversal of the drug-resistance. Moreover, the IC50 of paclitaxel markedly decreased about 7 times [15]. Another approach included the study of the co131

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Table 2 Nanoplatforms-based approaches of PTX in combination to other chemotherapeutic agent for ovarian cancer therapy. Drug combination

Type of nano-carrier

Paclitaxel and Cisplatin

Polypeptide-based nanogel from amphiphilic copolymers, polyethylene glycol-b-poly L-glutamic acid-b-poly L-phenylalanine

Paclitaxel and Cisplatin

Amphiphilic block copolymer Poly(2-oxazoline) Polymeric micelles Folic acid-Bovine Serum Albumin (FA-BSA) nanoparticle

Paclitaxel and Difluorinated curcumin (CDF) Paclitaxel and Tanespimycin (17-AAG) Paclitaxel and α-tocopherol succinate. Paclitaxel and Gemcitabine Paclitaxel, gossypol and cyclopamine Paclitaxel and Curcumin

Method of assessments

Biocompatible and biodegradable amphiphilic copolymer PEG-DSPE/ TPGS mixed micelles Mixed micelles of Chitosan derivative Di-block copolymer of N-hydroxypropyl methacrylamide Polyethylene glycol-block-poly ε-caprolactone micelles Polyethylene glycol-phosphatidylethanolamine/ vitamin E micelles

Paclitaxel and Curcumin

PLGA-phospholipid-PEG nanoparticles

PTX and lapatinib Paclitaxel and Cisplatin

Nano colloids Telodendrimer micelles (III) PEG5K (COOH)8-L-CA8

Paclitaxel and Borneol Paclitaxel and C6-ceramide

PEG-PAMAM Polyamidoamine dendrimer nanoparticle poly (ethylene oxide)-modified poly (epsilon-caprolactone (PEOPCL) NP

human ovarian tumor xenograft-bearing • A2780/Luc female immunocompromised mice. human ovarian tumor cells. • A2780 • A2780 cells • SKOV-3 Cell line • Human ovarian cancer mouse model (SKOV-3 cells)

• SKOV3 ovarian cancer cells human ovarian tumor models. • A2780 cells • SKOV3 xenograft models • SKOV3 cells • SK-OV-3-paclitaxel-resistant mice bearing SK-OV-3 paclitaxel sensitive tumors • Nude and paclitaxel resistant tumors. ovarian cancer cell line A2780 cell line treated • Human with ADM to establish A2780/ADM resistant cells. cell lines. • OVCAR-3 ovarian cancer cell lines. • SKOV-3 ovarian cancer xenograft model • SKOV-3 cells • A2780/PTX SKOV-3 and multidrug resistant SKOV3TR • Wild-type ovarian adenocarcinoma models

References [119]

[30] [6] [128]

[112] [130] [123] [126]

[124] [127] [117] [16] [129]

Table 3 Different nanoplatforms of novel gene silencing combination with paclitaxel for ovarian cancer treatment. Drug combination Paclitaxel and focal adhesion kinase (FAK) siRNA Paclitaxel and Akt siRNA

Paclitaxel and TLR4 siRNA

Survivin shRNA and PTX

Nano-carrier type - Hyaluronic - acid-labeled poly(d,L-lactide-co-glycolide) nanoparticle - TEA-core PAMAM dendrimer triethanolamine-core poly(amidoamine) dendrimer - (PEI-g-PCL-b-PEG-Fol) Tri-block copolymer that consists of polyethyleneimine graftpolycaprolactone-block poly (ethylene glycol) - Supramolecular micellar assembly

Paclitaxel and anti-survivin siRNA Paclitaxel and siRNA targeted to CD44 mRNA

- Polyethylene glycol2000-phosphatidyl ethanolamine (PEG2000-PE)-based polymeric micelles - LHRH-targeted–PPI–(polypropylenimine) PEG dendrimers

Paclitaxel and MDR-1 siRNA

- Poly (ethylene oxide)-modified poly (β-amino ester) nanoparticles - Poly (ethylene oxide)-modified poly(Ɛ-caprolactone) nanoparticles

Method of assessment

Reference

- HEOC model: HeyA8-MDR and SKOV3-TR Drug-resistant (PDX) model - In Vitro cell culture model: SKOV-3 cells - In Vivo Tumor Model: female immunocompromised mice - SKOV-3 cells

[151]

[148]

[152]

- SKOV-3 cells - BALB/c nude mice bearing SKOV-3 ovarian tumors - Mice xenografted with SKOV3-tr

[149]

- Human ascetic cells line - Murine xenograft model of human ovarian carcinoma - SKOV3-TR cells - SKOV3 xenografts

[153]

[150]

[135]

was investigated in mice xenograft with SKOV3-tr ovarian cancer cells and the results revealed reversed chemoresistance, high cytotoxicity against SKOV3-tr cells and marked inhibition in growth of tumor tissues [150]. Several previous research papers investigated the efficacy of siRNA by silencing FAK in combination of PTX in diverse DDS for treatment of ovarian carcinoma. Focal adhesion kinase (FAK) is considered as a novel therapeutic target to reverse the MDR, thus a combination of PTX and (FAK) siRNA and its incorporation in HA-PLGANPs was designed and studied by Byeon et al. This study resulted in significant silencing of targeted oncogenes, reversed drug resistance in advanced epithelial ovarian tumor and potent antitumor efficacy. Moreover, reduction of off target toxicity because of the enhanced accumulation of high drug concentration in the tumor site only [151]. Yadav, van Vlerken et al. formulated delivery system of combination therapy (paclitaxel and MDR-1 siRNA) for ovarian cancer therapy through Poly (ethylene oxide)-modified poly (β-amino ester) (PEOPbAE) and PEO-modified poly(Ɛ-caprolactone) NPs. The efficacy was

delivery of PTX with surviving-siRNA. Survivin is one of the IAP (inhibitors of apoptosis protein) and it is considered to be absent in normal adult tissues, however it is overexpressed in ovarian cancerous cells. It was found that survivin worsened the cancer prognosis as it plays a critical role in inhibition of apoptosis, metastasis and MDR [18]. Consequently, based on this fact, polymeric micellar self-assembly were designed to co-deliver survivin shRNA and PTX in vitro to SKOV-3 cells and in vivo to ovarian cancer animal model. It was concluded that a remarkable knockdown in the expression of survivin that resulted in increased chemotherapeutic sensitivity towards PTX. In addition to the prolonged circulation time, reduced toxicity profile, synergistic apoptotic effect and the inhibition of growth of tumor tissues was observed [149]. The same therapeutic combination (Paclitaxel and anti-survivin siRNA) have been formulated and encapsulated in polyethylene glycol 2000-phosphatidyl ethanolamine based polymeric micelles. It was clear that anti-survivin siRNA significantly reduced the survivin expression in cancer tissues. Furthermore, such novel DDS (survivin siRNA/PTX PM) 132

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Drug-resistant sublines of A2780, which are derived by in vitro selection with stepwise exposure to increasing doses of cisplatin, include CP70, C30 and C200. Another chemo resistant cell lines that also available are named adriamycin resistant A2780 cell line, A2780ADR that are also cross resistant to melphalan and vinblastine [163]. So far, to our knowledge, there are no ovarian tumor cell lines that have been derived from patients previously treated with paclitaxel. However, many ovarian tumor cell lines that are resistant to paclitaxel have been developed in-vitro such as, A2780 paclitaxel-resistant subclasses PTX10 and PTX22 [164]. As well as SKOV3TR, a paclitaxel resistant subline of SKOV3 cells [165,166]. Another common method for evaluating OC growth, proliferation, and response of the treatment is animal xenograft tumor models. Animal xenograft tumor models are efficient at evaluating tumor growth in response to expression of an exogenous gene. In addition, it also can summarize aspects of ovarian cancer metastasis. The use of animal models allows testing various factors that affect tumor growth, dissemination, and biological response in vivo. These elements cannot be entirely summarized in in-vitro. To study the growth of tumor tissue in mice, human OC cells are inserted into mice. Cells from various genetic backgrounds are injected into immune-deficient mice such as Nude NOD/SCID thus the OC cells are able to engraft without being cleared by the immune system. Moreover, cells are either injected subcutaneously (SC), intraperitoneally (IP), or intrabursally (IB) as described in Table 4 [167].

investigated in SKOV3-TR ovarian cancer cell line and (SKOV3) xenografts models. The results showed that MDR-1 silencing enhanced PTX accumulation in tumor tissues (SKOV3-TR), controlled intracellular delivery profile and improved cytotoxic effect as well as potent therapeutic effect [135]. As shown in Table 3, a recent research paper investigated the capability of a tri-block copolymer decorated by folic acid for the effective delivery of both anti-TLR4 (Toll-like Receptor 4) siRNA and PTX. Results showed that a significant and continuous knockdown of TLR4 receptor which in turn reversed PTX resistance and reduced off target toxicity. As well as, enhancement of the pharmacokinetic profile such as marked prolongation of the circulation time and so on [152]. Shah et al. prepared a novel combination of PTX and siRNA against CD44 through LHRH-targeted polypropylenimine-PEG dendrimers. The efficacy of this novel DDS was appraised, and results showed inhibition of CD44 which led to suppression of MDR1 gene. Consequently, a successful accumulation of drugs in OC cells with high targeting efficiency was observed. [153]. Kala, Mak et al. formulated triethanolamine-core poly (amidoamine) dendrimer and loaded it with paclitaxel and Akt siRNA for their delivery to SKOV-3 ovarian cancerous cells in vitro and in vivo. Conclusively, potent gene silencing (Akt Knockdown), reduced tumorigenicity, enhanced PTX induced cytotoxic effect and potentiation of antitumor activity was revealed [148]. Talekar, Ouyang et al. postulated that co-silencing of both genes which play pivotal role in aerobic glycolysis, altered metabolic state of cancer cells, and multi drug resistance would result in synergistic antineoplastic effect, sensitizing MDR ovarian tumor cells to PTX, therefore much more efficacy. In their study they use dual siRNA (siPKM-2) as well as (siMDR-1) against MDR gene-1 and pyruvate kinase M2, respectively. Those siRNA duplexes were loaded in hyaluronic acid (HA)based self-assembling nanocarrier for the sake of targeting behavior. In this concern, active targeting is achieved through modifying the surface of the nanoparticle with peptide targeted to epidermal growth factor receptor (EGFR) which is highly expressed over the membrane of SKOV-3 ovarian tumor cells. This drug loaded nanoparticle was investigated in vitro (SKOV-3) and in in vivo murine model that were developed to be PTX resistant to evaluate whether dual silencing of PKM-2 and MDR-1 genes sensitizes MDR ovarian cancer cells to PTX at cellular and tissue levels. Conclusively, the results showed notable down-regulation of gene expression in return led to an increase in cellular PTX concentration therefore, high antitumor efficacy with minimal toxicity profile following combined therapy of double siRNA and PTX [154].

6. Conclusion and future perspective Nanotechnology application in the area of cancer therapy has formerly borne many breakthroughs and is continuing to flourish towards becoming a pivotal component of the health care system. In the current review different strategies based on nanomedicine were described as Nano-platforms for PTX and its combinations in combat of ovarian cancer. A lot of challenges have encountered the conventional delivery of PTX in addition to the occurrence of the severe toxicity profile. One of the main hindrances that leads to OC recurrence is MDR. Thus, incorporation of PTX solely or in combination to other drug in nanocarrier systems such as polymeric nanoparticles, nanomicelle, proteinbased nanoparticles, nanoemulsions, nanogels, dendrimers, nanocapsules, has been depicted in detail regarding OC therapy. Moreover, hybrid nanocarrier systems should gain a lot of researchers' attention because they can comprise the advantages of the combined nanoparticles and avoid their drawbacks. A closer inspection of the literature indicates that nanotechnology application is of major importance in the field of cancer therapy. As a result, the science of nanotoxicology should be well investigated focusing on the long as well as the short-term toxicity profile following the administration. Finally, much work should be dedicated towards the early diagnosis of OC through the application of efficient Nanostrategies for the sake of prolonging survival time.

5. Appropriate in-vitro and in-vivo ovarian cancer models for pharmaceutical appraisal of nanocarriers Various cell line techniques gained recently an enormous interest in the field of drug delivery screening and pharmaceutical assessment. This includes permeability tests, in vitro cytotoxicity studies, evaluation of targeting efficiency [155]. Worldwide, around 150 ovarian tumor cell lines are available as described in literature. Approximately 100 are human cell lines originated from ovarian cancer or human ovarian surface epithelium, while about 50 are non-human cell line originated from the ovary. In this regards some of the OC cell lines were investigated in the literature namely; CAOV3, CAOV4, SKOV3, OVCAR3, OVCAR2, OVCAR4, OVCAR5, OVCAR8 TOV-112D, TOV-21G, 59 M, A2780, IGROV1, HO8910 and others [10,156]. Although several studies report that SK-OV-3, A2780, OVCAR-3, CAOV3 and IGROV1 do not represent a good approximation of the HGSOC genotype. Despite that, these cells are the most commonly cited ovarian cancer cell line and widely assumed to be a good model of HGSOC [157–160]. Regarding the chemo-sensitivity, some cell lines were originally derived from the ascites of patients with platinum resistant epithelial ovarian cancer such as OVCAR3, OVCAR4, OVCAR8, and SKOV3 [161,162]. From another point of view, other cancerous cell lines that have been treated with chemotherapy to produce resistant sublines [161]. For instance,

7. Expert opinion Ovarian carcinoma is one of the major leading causes of death among women all over the world. It is characterized by high mortality rate because of the lack of early diagnosis or most probably diagnosed at advanced stages.

• Foremost the first approach for OC therapy is primary surgical resection of the cancerous tissue followed by auxiliary chemotherapy. • The benchmark treatment is PTX in combination to platinum-based • 133

drugs. In most of cases disease relapse occurs within six months despite the initial success of this chemotherapeutic combination. Regarding the route of administration, intraperitoneal administration of PTX is more beneficial and advantageous than the intravenous route because of peritoneum metastasis and ascites that

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Table 4 Pros and cons of different xenograft ovarian cancer mouse models. Type of OC models Subcutaneous xenografts

Intraperitoneal xenografts

Intrabursal xenografts

Patient derived xenografts (PDXs)

Pros

Cons

- A straightforward, easy to handle injection technique, and tumor volume can be easily monitored by using simple caliper measurement. - Appropriate particularly for evaluating imaging techniques. - Can mimic the characteristics of metastatic dissemination. - IP injection of OC cell lines leads to the development of intraperitoneal carcinomatosis with consequent development of ascites, thus photocopying the clinical progression of OC observed in patients. IP-injected tumor cells such as SKOV3, A2780, OVCAR3, OVCAR4, OVCAR5, and OVCAR8 metastasize to the ovary, peritoneal wall, diaphragm, and form ascites fluid similar to human disease - Capable of mimicking the first steps of metastasis in addition to all features of metastatic dissemination. Thus, ovarian metastasis studies can be evaluated in IB models. - Ovarian tumors are isolated from patients, and then surgically implanted into mice. - Tumor tissues from various genetic sources can be injected and its growth can be evaluated. - PDXs covers the features of OC basically metastasis and ascites. Therefore, it could be used to examine tumor development and metastasis. - Individual patient's response to therapy can be feasibly and accurately predicted

- Ovarian metastasis studies cannot be investigated in SC model as the tumors do not normally metastasize as well as the tumor is not positioned in the right anatomic location or microenvironment. - Mice with short life span, No primary tumors and high rate of metastases. - IP xenograft tumors are very deep thus cannot be used in imaging techniques in contrast to SC models. - Cancer initiation and dissemination cannot be evaluated through this model as they are not able to mimic the initial steps in metastasis. Because of the depth of the tumor of IB models investigation of imaging modalities cannot be performed. Cancer initiation and dissemination cannot be evaluated through this model. - One major hurdle of PDXs application is the lack of ease access to patient samples.

accompanied with ovarian cancer.

• Common delivery of PTX suffers from many obstacles. One major

•

•

[9]

problem is through solubility improvement in Cremophor EL which resulted in hypersensitivity side effects. Accordingly, application of nanotechnology has grabbed attention of researchers as it circumvents all these hurdles via its tailored design as well as passive and active targeting. It is clear that PTX in combination to other chemotherapeutic drugs is more advantageous through circumventing the MDR, synergistic effect, improvement of the progression free survival, etc. Nanocarriers for instance; polymeric nanoparticles, nanomicelle, protein based nanoparticles, nanoemulsions, nanogels, microemulsion, nanostructured lipid carriers, dendrimers, nanocapsules or hybrid systems are investigated for OC therapy. Gene silencing approach has attracted considerable research attention for their potential therapeutic applications. Thus, incorporation of PTX in combination to siRNAs or miRNA to target certain gene is strongly recommended.

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