- Email: [email protected]
Nanomedicine and Drug Delivery
Med Clin N Am 91 (2007) 863–870
Nanomedicine and Drug Delivery Chiming Wei, MD, PhD, FACC, FAHA, FAANa,*, Wenchi Weia, Michael Morrisa, Eisaku Kondo, MD, PhDb, Mikhail Gorbounovb, Donald A. Tomalia, PhDc a
Department of Surgery, Johns Hopkins University School of Medicine, 600 N. Wolfe Street/Harvey 606, Baltimore, MD 21205, USA b Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan c Dendritic Nanotechnologies, Inc., 2625 Denison Drive, Suite B, Mt. Pleasant, MI 48858, USA
Nanotechnology will be very useful in drug delivery approaches. Magnetic nanotechnology is finding wide applications in medicine, most notably in MRI and magnetic separation. The impedance biosensor is expected to find applications in monitoring cytokines in cancer, bone turnover markers in osteoporosis, and understanding neural-degenerative diseases. Nanomedicine and drug delivery in cancer Prostate cancer is the most common cancer in men in the Unites States and is the second leading cause of cancer mortality in men over age 40 years. In human prostate cancer, a multistage process involves progression from small latent carcinomas of low histologic grade to high-grade metastatic cancer [1]. During the past decade, substantial improvements in diagnosis and staging of the disease have been made with the combined use of digital rectal examination, measurement of serum prostate-specific antigen levels, and transrectal ultrasound [2,3]. In North America, almost 90% of men diagnosed as having prostate cancer present with localized disease [4]. Early diagnosis and early intervention would allow these patients to be treated with the appropriate, least invasive local treatment. Furthermore, local therapy could be useful in patients who have recurrence after critical prostatectomy to decrease the risk of local and/or metastatic progression of the disease. To enhance the * Corresponding author. E-mail address: [email protected] (C. Wei). 0025-7125/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2007.05.005 medical.theclinics.com
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therapeutic efficacy of anticancer agents in general, a tumor-specific treatment has been advocated. In this regard, polymeric-, misceller- and liposome-based delivery systems conjugated to tumor-specific ligands have been studied [5–7]. Because most tumor cells overexpress transferring receptors, ligand transferring has been investigated extensively for targeting drug to tumors. This approach, however, has resulted in moderate improvement in the therapy because transferring receptors are normal tissues [8]. An alternative approach to the systemic administration of drugs for the treatment of a localized prostate tumor could be direct intertumoral delivery of controlled-release biodegradable nanoparticles. Nanoparticles are colloidal carrier systems and improve the efficacy of the encapsulated drug by overcoming drug resistance as well as by providing sustained drug effect [9]. Biodegradable (poly)hydroxyl acid, such as the copolymers of (poly)lactic acid and (poly)lactic-co-glycolic acid (PLGA), are being used extensively in biomedical applications because of their biocompatibility, ability to encapsulate various drug molecules, and sustained release properties. Drug-loaded nanoparticles that can deliver the pharmacologically effective dose of the drug to the tumor for a sustained period of time could avoid the systemic toxicity and the hypersensitive reactions caused by the Cremophor EL (BASF Aktiengesellschaft, Ludwigshafen, Germany) formulation. Therefore, nanoparticles conjugated ligand to transferring could further enhance the therapeutic efficacy of the encapsulated drug and thus could be more effective in promoting tumor regression than the drug dissolved in the Cremophor EL formulation [10]. Dendrimer-based nanomedicine: its impact on biology, drug delivery, and polyvalent/targeted therapies Dendrimers now are referred to as ‘‘artificial proteins’’ based on the close scaling and mimicry of their dimensions, shapes, and surface chemistries to these biologic nanostructures [11,12]. These important nanoscaffolding/nanocontainer nanochemistry features have allowed the development of wellrecognized commercial products such as nanodiagnostics (Stratus, Dade Behring, Deerfield, Illinois), nanoscaffolding/gene vectors (Superfect, Qiagen), and small interfering RNA vectors (PrioFect, Dendritic Nanotechnologies, Inc., Mt. Pleasant, Michigan) [13] and also portend the development of many new dendrimer-based nanodevices and prototypes in the future. Considering the importance of nanoscale structures in dimensions associated with proteins, DNA, antibody-antigen complexes, viral particles, to mention a few issues, it is safe to make the following statement: ‘‘The positive management of human health, disease, and longevity probably will be determined and controlled by a deeper understanding of critical parameters in the nano-length scale, namely: nanomedicine.’’ This section presents the use of precise, synthetic nanostructures (ie, dendrimers) as critical nanoscale building blocks in a variety of nanodiagnostic, drug delivery and nanopharmacologic applications [14,15].
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Dendrimers are synthesized routinely as tunable nanostructures that may be designed and regulated as a function of their size, shape, surface chemistry, and interior void space. Their structural control approaches that of traditional biomacromolecules such as DNA/RNA or proteins, and they are distinguished by their precise nanoscale scaffolding and nanocontainer properties. These important properties are expected to play an important role in the emerging field of nanomedicine. Recent efforts have focused on the synthesis and preclinical evaluation of the multipurpose dendrimer prototype polyamidoamine that exhibits properties suitable for use as a targeted, diagnostic MRI/near–infra red contrast agent and for controlled delivery of cancer therapies. This dendritic nanostructure (w 5.0 nm in diameter) was selected because of its very favorable biocompatibility profile, the expectation that it will exhibit desirable mammalian kidney excretion properties, and demonstrated targeting features.
Nanoparticles for drug delivery of paclitaxel Paclitaxel is one of the best antineoplastic drugs found in nature in the past decades. It is effective in treating a wide spectrum of cancers including breast cancer, ovarian cancer, colon cancer, small cell and non-small cell lung cancer, head and neck cancer, multiple myeloma, melanoma, and Kaposi’s sarcoma. Like many other anticancer drugs, its poor solubility in water creates difficulties in clinical administration. In its current clinical applications, it can create many serious side effects. Nanoparticles of biodegradable polymers could be an ideal solution to such problems and could achieve controlled and targeted delivery of the drug with better efficacy and fewer side effects. With further developments, such as optimization of particle size and surface coating, a nanoparticle formulation of paclitaxel could improve the efficacy and quality of chemotherapy, making possible personalized chemotherapy, local chemotherapies, sustained chemotherapy, oral chemotherapy, chemotherapy across the blood–brain barrier, chemotherapy across the microcirculation barrier, and other advances. The nanoparticles composed of various agents and manufactured under various conditions were characterized by X-ray photoelectron spectroscopy and Fourier transformation infrared spectroscopy for surface chemistry, by scanning electron microscopy and atomic force microscopy for morphologic properties, by laser light scattering for size and size distribution, by zeta-potential for surface charge, and by differential scanning calorimetry for the thermographic properties. These natural emulsifiers have great advantages for nanoparticle formulation of paclitaxel over the traditional macromolecular emulsifiers, such as polyvinyl alcohol. Nanoparticles of desired small size and narrow size distribution can be developed. The efficacy of drug encapsulation can be as high as 100%. Nanoparticles allow control of the release kinetics of the drugs administered. A previous study involving the
866
WEI
et al
HT-29 cancer cell line showed that after 24 hours of incubation the cell mortality caused by the drug delivered by such nanoparticle formulation could be more than 13 times higher than the mortality caused by the free drug under similar conditions.
Paclitaxel-loaded nanoparticles in anticancer activity A previous study demonstrated a new method for an intravenously administered polymeric drug-delivery system for paclitaxel that was intended to be capable of improving the therapeutic index of the drug and devoid of the adverse effects of Chromophor EL. Paclitaxel-loaded PLGA nanoparticles were prepared by the interfacial deposition method. The influence of different experimental parameters on the efficacy with which paclitaxel was incorporated in the nanoparticles was investigated. The efficacy of paclitaxel incorporation in nanoparticles was affected mostly by the method of preparation in the organic phase and also by the ratio of the organic phase to the aqueous phase. The preparation methodology allowed the formation of spherical, nanometric (! 200 nm), homogeneous, negatively charged particles that are suitable for intravenous administration. The release behavior of paclitaxel from the developed nanoparticles exhibited a biphasic pattern characterized by initial fast release during the first 24 hours followed by slower and continuous release. The in vitro antitumor activity of paclitaxel-loaded PLGA developed in previous work was assessed using a human small cell lung cancer cell line and was compared with the in vitro antitumoral activity of a proprietary formulation of paclitaxel.
Efficient growth inhibition of intractable malignancies by delivery of antitumor peptides by means of the peptide transporter system Aa novel medical approach, molecular targeting technology using various biologic and chemical tools recently has received attention as a way to overcome obstacles or defects in conventional cancer therapies. Smallmolecule inhibitors and humanized antibody drugs have found an active role in clinical practice. Therefore, molecular targeting can be approached from various perspectives. Conventional DNA/RNA transfection methods using chemical reagents (eg, lipocation) have limited use in vivo and in vitro because of low efficiency in transmission and cellular toxicity, especially in hematopoietic malignancies including intractable leukemia/lymphomas. A recent study established a highly efficient system for delivery of a functional peptide into human cells by using a peptide/protein transporter (peptide/ protein vector, Wr-T),which forms a cell-permeable complex with cargo peptides [16,17]. This study performed fundamental in vitro and in vivo investigations for the development of growth-suppression systems for use
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against intractable human malignancies including high-grade glioblastomas and lymphomas. With this novel peptide transporter system, the delivery of intracellular peptide is more than 10 times as efficient as with previous methods. The transporter, peptide/protein vector, has an enlarged, repeated hydrophobic pocket motif consisting of triple tryptophan-rich domains fused with nine D-enantiomer polyarginines by means of a Gly-Pro-Gly spacer, which serves to augment delivery of a cargo peptide. The peptide/ protein vector–mediated transport of p16INK4a functional tumor suppressor peptide efficiently inhibits growth of highly aggressive leukemia/lymphomas by 80% to 90% through restoration of p16 function with a nanomol dose of the peptides. Moreover, the peptide/protein vector delivery system enabled multiple molecular targeting against tumor suppressor–defected human glioblastomas by simultaneously introducing p14ARF, p16INK4a, and p21CIP antitumor peptides, resulting in potent growth suppression in studies of in vitro cell lines and in vivo mouse brain tumor models. The peptide/protein vector system thus represents a highly effective approach to the delivery of cargo peptides with the potential for developing antitumor peptide–based therapy for various intractable human malignancies (Fig. 1).
Nanomedicine and drug delivery in heart disease In the near future, nanotechnology will play an increasingly significant role in cardiovascular practice. Nanotechnology is a product of research and development that uses nanoscale (ie, ! 100 nm) structures, devices, and systems having novel properties and functions associated with the size and structure. Recent rapid advances in nanotechnology and nanoscience provide many
Fig. 1. Molecular targeting by delivery of functional peptides by the peptide/protein vector. FITC, fluorescein isothiocyanate. Abbreviations: PTD, protein transduction domain; Wr-T, peptide/protein vector.
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opportunities for treatment of cardiovascular disease. Nanotechnology and nanoscience focus on materials at the atomic, molecular, and supermolecular levels, producing novel molecular assemblies and designing systems of self-assembly for individual cells. Nanosize components also will be important in microscale devices, which are included in the category of nanotherapeutics. The current generation of drugs is based largely on small molecules with a mass of 1000 d or less that circulate throughout the system. The methods mentioned previously increase their biologic availability and allow continuous release. Previous studies demonstrated that drugs can be encapsulated in nanospheres [18] or erodible self-assembled structures [19] or conjugated to well-defined multivalent macromolecules such as dendrimers (highly branched polymers) [20]. Treatment targets include, but are not limited to, proliferating smooth muscle cells, inflammatory mediators, neoplastic cells, proteins expressed in viral infections, and mitochondria and other organelles. Such advances control the initial dose, improve the effectiveness, and increase the diversity of possible treatments of diseases. A recent study demonstrated that the locally controlled intramyocardial delivery of platelet-derived growth factor (PDGF)-BB with self-assembling peptide nanofibers improves postinfarction ventricular function without pulmonary toxicity [21]. After experimental infarction, intramyocardial delivery of PDGF by self-assembling peptide nanofibers leads to long-term improvement in cardiac performance without apparent pulmonary toxicity. Drug targeting should reduce systemic toxicity. Encapsulation and conjugation to nanocarriers protect drugs from the metabolism and from excretion. Another advantage of using nano particles and macromolecular targeting systems is the ability to trigger release in response to a number of signals, including, pH, ultrasound, infrared light, magnetic fields, and radio waves.
Nanomedicine and drug delivery in vascular disease A mechanism that involves drug diffusion through pores (whose diameter is in the nanometer range) offers novel methods of administering antiangiogenic and antioxidant drugs. These treatment methods have clinical application in the treatment of proliferative vascular disease. There are three types of molecules that have various mechanisms for action in different phases in the development of proliferative disease. One of those molecules is catalase, a hydrogen peroxide–degrading enzyme that results from free radicals present during the initiating phase of some cardiovascular diseases. The second molecule, ascorbic acid, interferes with formation of free radicals and the angiogenic process. The third molecule, endostatin, a potent antiangiogenic molecule, has applicability in the treatment of angiogenic-dependent diseases. Because oxidative stress mediates the formation of reactive oxygen
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869
species in cardiovascular diseases, treatment with vitamin C, vitamin E, or other antioxidants has been suggested as therapy. The drug-delivery method based on the administration of antioxidant agents across an inorganic aluminum oxide nanoporous filter passed critical in vitro tests for diffusibility and biocompatibility, allowing new treatments for vascular diseases. Nanotechnologies promise a new means of drug application. A good example is intracellular adhesion molecule 1 (ICAM-1). This drug protects endothelial cells from oxidative damage by reactive oxygen species particles. ICAM-1 also is a good target for vascular immunotargeting of nanoparticles to the disturbed endothelium. A recent study demonstrated the unique trafficking pathway followed by internalized anti-ICAM-1 nanoparticles; this targeting mechanism seems well suited for targeted delivery of therapeutic enzymes to endothelial cells and may provide a basis for the treatment of acute vascular oxidative stress [22].
References [1] Bosland MC, Dreef-Van Der Meulen HC, Sukumar S, et al. Multistage prostate carcinogenesis: the role of hormones. Princess Takamatsu Symp 1991;22:109–23. [2] Caplan A, Kratz A. Prostate-specific antigen and the early diagnosis of prostate cancer. Am J Clin Pathol 2002;117(Suppl):S104–8. [3] Garzotto M, Park Y, Mongoue-Tchokote S, et al. Recursive partitioning for risk stratification in men undergoing repeat prostate biopsies. Cancer 2005;104:1911–7. [4] Gleave M, Evans CP. What’s hot in the prostate? Prostate Cancer Prostatic Dis 2003;6: 200–3. [5] Gade TP, Hassen W, Santos E, et al. Targeted elimination of prostate cancer by genetically directed human T lymphocytes. Cancer Res 2005;65:9080–8. [6] Bucur O, Ray S, Bucur MC, et al. APO2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in prostate cancer therapy. Front Biosci 2006;11:1549–68. [7] Wolf S, Mertens D, Pscherer A, et al. Ala228 variant of trail receptor 1 affecting the ligand binding site is associated with chronic lymphocytic leukemia, mantle cell lymphoma, prostate cancer, head and neck squamous cell carcinoma and bladder cancer. Int J Cancer 2006;118:1831–5. [8] Carraway RE, Hassan S, Cochrane DE. Polyphenolic antioxidants mimic the effects of 1,4-dihydropyridines on neurotensin receptor function in PC3 cells. J Pharmacol Exp Ther 2004;309:92–101. [9] Bondi ML, Craparo EF, Giammona G, et al. Nanostructured lipid carriers-containing anticancer compounds: preparation, characterization, and cytotoxicity studies. Drug Deliv 2007;14:61–7. [10] Sahoo SK, Ma W, Labhasetwar V. Related Articles, Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. Int J Cancer 2004;112:335–40. [11] Svenson S, Tomalia DA. Dendrimers in biomedical applicationsdreflections on the field. Adv Drug Deliv Rev 2005. [12] Tomalia DA, Reyna LA, Svenson S. Dendrimers as multi-purpose nanodevices for oncology drug delivery and diagnostic imaging. Biochem Soc Trans 2007;35:61–7. [13] Tomalia DA. Supramolecular chemistry: fluorine makes a difference. Nat Mater 2003;2: 711–2. [14] Svenson S, Tomalia DA. Dendrimers in biomedical applicationsdreflections on the field. Adv Drug Deliv Rev 2005;57(15):2106–29.
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[15] Tomalia DA, Reyna LA, Svenson S. Dendrimers as multi-purpose nanodevices for oncology drug delivery and diagnostic imaging. Biochem Soc Trans 2007;35(1):61–7. [16] Kondo E, Seto M, Yoshikawa K, et al. Highly efficient delivery of p16 antitumor peptide into aggressive leukemia/lymphoma cells using a novel transporter system. Mol Cancer Ther 2004;3:1623–30. [17] Patent #3748561 (E. Kondo et al.), Japan Patent Office. [18] Kolodgie FD, Petrov A, Virmani R, et al. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation 2003;108:3134–9. [19] Elder AC, Gelein R, Oberdorster G, et al. Efficient depletion of alveolar macrophages using intratracheally inhaled aerosols of liposome-encapsulated clodronate. Exp Lung Res 2004; 30:105–20. [20] Kolodgie FD, John M, Khurana C, et al. Sustained reduction of in-stent neointimal growth with the use of a novel systemic nanoparticle paclitaxel. Circulation 2002;106:1195–8. [21] Hsieh PC, MacGillivray C, Gannon J, et al. Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicity. Circulation 2006;114:637–44. [22] Muro S, Cui X, Gajewski C, et al. Slow intracellular trafficking of catalase nanoparticles targeted to ICAM-1 protects endothelial cells from oxidative stress. Am J Physiol Cell Physiol 2003;285:C1339–47.
Nanomedicine and Drug Delivery Chiming Wei, MD, PhD, FACC, FAHA, FAANa,*, Wenchi Weia, Michael Morrisa, Eisaku Kondo, MD, PhDb, Mikhail Gorbounovb, Donald A. Tomalia, PhDc a
Department of Surgery, Johns Hopkins University School of Medicine, 600 N. Wolfe Street/Harvey 606, Baltimore, MD 21205, USA b Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan c Dendritic Nanotechnologies, Inc., 2625 Denison Drive, Suite B, Mt. Pleasant, MI 48858, USA
Nanotechnology will be very useful in drug delivery approaches. Magnetic nanotechnology is finding wide applications in medicine, most notably in MRI and magnetic separation. The impedance biosensor is expected to find applications in monitoring cytokines in cancer, bone turnover markers in osteoporosis, and understanding neural-degenerative diseases. Nanomedicine and drug delivery in cancer Prostate cancer is the most common cancer in men in the Unites States and is the second leading cause of cancer mortality in men over age 40 years. In human prostate cancer, a multistage process involves progression from small latent carcinomas of low histologic grade to high-grade metastatic cancer [1]. During the past decade, substantial improvements in diagnosis and staging of the disease have been made with the combined use of digital rectal examination, measurement of serum prostate-specific antigen levels, and transrectal ultrasound [2,3]. In North America, almost 90% of men diagnosed as having prostate cancer present with localized disease [4]. Early diagnosis and early intervention would allow these patients to be treated with the appropriate, least invasive local treatment. Furthermore, local therapy could be useful in patients who have recurrence after critical prostatectomy to decrease the risk of local and/or metastatic progression of the disease. To enhance the * Corresponding author. E-mail address: [email protected] (C. Wei). 0025-7125/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2007.05.005 medical.theclinics.com
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et al
therapeutic efficacy of anticancer agents in general, a tumor-specific treatment has been advocated. In this regard, polymeric-, misceller- and liposome-based delivery systems conjugated to tumor-specific ligands have been studied [5–7]. Because most tumor cells overexpress transferring receptors, ligand transferring has been investigated extensively for targeting drug to tumors. This approach, however, has resulted in moderate improvement in the therapy because transferring receptors are normal tissues [8]. An alternative approach to the systemic administration of drugs for the treatment of a localized prostate tumor could be direct intertumoral delivery of controlled-release biodegradable nanoparticles. Nanoparticles are colloidal carrier systems and improve the efficacy of the encapsulated drug by overcoming drug resistance as well as by providing sustained drug effect [9]. Biodegradable (poly)hydroxyl acid, such as the copolymers of (poly)lactic acid and (poly)lactic-co-glycolic acid (PLGA), are being used extensively in biomedical applications because of their biocompatibility, ability to encapsulate various drug molecules, and sustained release properties. Drug-loaded nanoparticles that can deliver the pharmacologically effective dose of the drug to the tumor for a sustained period of time could avoid the systemic toxicity and the hypersensitive reactions caused by the Cremophor EL (BASF Aktiengesellschaft, Ludwigshafen, Germany) formulation. Therefore, nanoparticles conjugated ligand to transferring could further enhance the therapeutic efficacy of the encapsulated drug and thus could be more effective in promoting tumor regression than the drug dissolved in the Cremophor EL formulation [10]. Dendrimer-based nanomedicine: its impact on biology, drug delivery, and polyvalent/targeted therapies Dendrimers now are referred to as ‘‘artificial proteins’’ based on the close scaling and mimicry of their dimensions, shapes, and surface chemistries to these biologic nanostructures [11,12]. These important nanoscaffolding/nanocontainer nanochemistry features have allowed the development of wellrecognized commercial products such as nanodiagnostics (Stratus, Dade Behring, Deerfield, Illinois), nanoscaffolding/gene vectors (Superfect, Qiagen), and small interfering RNA vectors (PrioFect, Dendritic Nanotechnologies, Inc., Mt. Pleasant, Michigan) [13] and also portend the development of many new dendrimer-based nanodevices and prototypes in the future. Considering the importance of nanoscale structures in dimensions associated with proteins, DNA, antibody-antigen complexes, viral particles, to mention a few issues, it is safe to make the following statement: ‘‘The positive management of human health, disease, and longevity probably will be determined and controlled by a deeper understanding of critical parameters in the nano-length scale, namely: nanomedicine.’’ This section presents the use of precise, synthetic nanostructures (ie, dendrimers) as critical nanoscale building blocks in a variety of nanodiagnostic, drug delivery and nanopharmacologic applications [14,15].
NANOMEDICINE AND DRUG DELIVERY
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Dendrimers are synthesized routinely as tunable nanostructures that may be designed and regulated as a function of their size, shape, surface chemistry, and interior void space. Their structural control approaches that of traditional biomacromolecules such as DNA/RNA or proteins, and they are distinguished by their precise nanoscale scaffolding and nanocontainer properties. These important properties are expected to play an important role in the emerging field of nanomedicine. Recent efforts have focused on the synthesis and preclinical evaluation of the multipurpose dendrimer prototype polyamidoamine that exhibits properties suitable for use as a targeted, diagnostic MRI/near–infra red contrast agent and for controlled delivery of cancer therapies. This dendritic nanostructure (w 5.0 nm in diameter) was selected because of its very favorable biocompatibility profile, the expectation that it will exhibit desirable mammalian kidney excretion properties, and demonstrated targeting features.
Nanoparticles for drug delivery of paclitaxel Paclitaxel is one of the best antineoplastic drugs found in nature in the past decades. It is effective in treating a wide spectrum of cancers including breast cancer, ovarian cancer, colon cancer, small cell and non-small cell lung cancer, head and neck cancer, multiple myeloma, melanoma, and Kaposi’s sarcoma. Like many other anticancer drugs, its poor solubility in water creates difficulties in clinical administration. In its current clinical applications, it can create many serious side effects. Nanoparticles of biodegradable polymers could be an ideal solution to such problems and could achieve controlled and targeted delivery of the drug with better efficacy and fewer side effects. With further developments, such as optimization of particle size and surface coating, a nanoparticle formulation of paclitaxel could improve the efficacy and quality of chemotherapy, making possible personalized chemotherapy, local chemotherapies, sustained chemotherapy, oral chemotherapy, chemotherapy across the blood–brain barrier, chemotherapy across the microcirculation barrier, and other advances. The nanoparticles composed of various agents and manufactured under various conditions were characterized by X-ray photoelectron spectroscopy and Fourier transformation infrared spectroscopy for surface chemistry, by scanning electron microscopy and atomic force microscopy for morphologic properties, by laser light scattering for size and size distribution, by zeta-potential for surface charge, and by differential scanning calorimetry for the thermographic properties. These natural emulsifiers have great advantages for nanoparticle formulation of paclitaxel over the traditional macromolecular emulsifiers, such as polyvinyl alcohol. Nanoparticles of desired small size and narrow size distribution can be developed. The efficacy of drug encapsulation can be as high as 100%. Nanoparticles allow control of the release kinetics of the drugs administered. A previous study involving the
866
WEI
et al
HT-29 cancer cell line showed that after 24 hours of incubation the cell mortality caused by the drug delivered by such nanoparticle formulation could be more than 13 times higher than the mortality caused by the free drug under similar conditions.
Paclitaxel-loaded nanoparticles in anticancer activity A previous study demonstrated a new method for an intravenously administered polymeric drug-delivery system for paclitaxel that was intended to be capable of improving the therapeutic index of the drug and devoid of the adverse effects of Chromophor EL. Paclitaxel-loaded PLGA nanoparticles were prepared by the interfacial deposition method. The influence of different experimental parameters on the efficacy with which paclitaxel was incorporated in the nanoparticles was investigated. The efficacy of paclitaxel incorporation in nanoparticles was affected mostly by the method of preparation in the organic phase and also by the ratio of the organic phase to the aqueous phase. The preparation methodology allowed the formation of spherical, nanometric (! 200 nm), homogeneous, negatively charged particles that are suitable for intravenous administration. The release behavior of paclitaxel from the developed nanoparticles exhibited a biphasic pattern characterized by initial fast release during the first 24 hours followed by slower and continuous release. The in vitro antitumor activity of paclitaxel-loaded PLGA developed in previous work was assessed using a human small cell lung cancer cell line and was compared with the in vitro antitumoral activity of a proprietary formulation of paclitaxel.
Efficient growth inhibition of intractable malignancies by delivery of antitumor peptides by means of the peptide transporter system Aa novel medical approach, molecular targeting technology using various biologic and chemical tools recently has received attention as a way to overcome obstacles or defects in conventional cancer therapies. Smallmolecule inhibitors and humanized antibody drugs have found an active role in clinical practice. Therefore, molecular targeting can be approached from various perspectives. Conventional DNA/RNA transfection methods using chemical reagents (eg, lipocation) have limited use in vivo and in vitro because of low efficiency in transmission and cellular toxicity, especially in hematopoietic malignancies including intractable leukemia/lymphomas. A recent study established a highly efficient system for delivery of a functional peptide into human cells by using a peptide/protein transporter (peptide/ protein vector, Wr-T),which forms a cell-permeable complex with cargo peptides [16,17]. This study performed fundamental in vitro and in vivo investigations for the development of growth-suppression systems for use
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867
against intractable human malignancies including high-grade glioblastomas and lymphomas. With this novel peptide transporter system, the delivery of intracellular peptide is more than 10 times as efficient as with previous methods. The transporter, peptide/protein vector, has an enlarged, repeated hydrophobic pocket motif consisting of triple tryptophan-rich domains fused with nine D-enantiomer polyarginines by means of a Gly-Pro-Gly spacer, which serves to augment delivery of a cargo peptide. The peptide/ protein vector–mediated transport of p16INK4a functional tumor suppressor peptide efficiently inhibits growth of highly aggressive leukemia/lymphomas by 80% to 90% through restoration of p16 function with a nanomol dose of the peptides. Moreover, the peptide/protein vector delivery system enabled multiple molecular targeting against tumor suppressor–defected human glioblastomas by simultaneously introducing p14ARF, p16INK4a, and p21CIP antitumor peptides, resulting in potent growth suppression in studies of in vitro cell lines and in vivo mouse brain tumor models. The peptide/protein vector system thus represents a highly effective approach to the delivery of cargo peptides with the potential for developing antitumor peptide–based therapy for various intractable human malignancies (Fig. 1).
Nanomedicine and drug delivery in heart disease In the near future, nanotechnology will play an increasingly significant role in cardiovascular practice. Nanotechnology is a product of research and development that uses nanoscale (ie, ! 100 nm) structures, devices, and systems having novel properties and functions associated with the size and structure. Recent rapid advances in nanotechnology and nanoscience provide many
Fig. 1. Molecular targeting by delivery of functional peptides by the peptide/protein vector. FITC, fluorescein isothiocyanate. Abbreviations: PTD, protein transduction domain; Wr-T, peptide/protein vector.
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opportunities for treatment of cardiovascular disease. Nanotechnology and nanoscience focus on materials at the atomic, molecular, and supermolecular levels, producing novel molecular assemblies and designing systems of self-assembly for individual cells. Nanosize components also will be important in microscale devices, which are included in the category of nanotherapeutics. The current generation of drugs is based largely on small molecules with a mass of 1000 d or less that circulate throughout the system. The methods mentioned previously increase their biologic availability and allow continuous release. Previous studies demonstrated that drugs can be encapsulated in nanospheres [18] or erodible self-assembled structures [19] or conjugated to well-defined multivalent macromolecules such as dendrimers (highly branched polymers) [20]. Treatment targets include, but are not limited to, proliferating smooth muscle cells, inflammatory mediators, neoplastic cells, proteins expressed in viral infections, and mitochondria and other organelles. Such advances control the initial dose, improve the effectiveness, and increase the diversity of possible treatments of diseases. A recent study demonstrated that the locally controlled intramyocardial delivery of platelet-derived growth factor (PDGF)-BB with self-assembling peptide nanofibers improves postinfarction ventricular function without pulmonary toxicity [21]. After experimental infarction, intramyocardial delivery of PDGF by self-assembling peptide nanofibers leads to long-term improvement in cardiac performance without apparent pulmonary toxicity. Drug targeting should reduce systemic toxicity. Encapsulation and conjugation to nanocarriers protect drugs from the metabolism and from excretion. Another advantage of using nano particles and macromolecular targeting systems is the ability to trigger release in response to a number of signals, including, pH, ultrasound, infrared light, magnetic fields, and radio waves.
Nanomedicine and drug delivery in vascular disease A mechanism that involves drug diffusion through pores (whose diameter is in the nanometer range) offers novel methods of administering antiangiogenic and antioxidant drugs. These treatment methods have clinical application in the treatment of proliferative vascular disease. There are three types of molecules that have various mechanisms for action in different phases in the development of proliferative disease. One of those molecules is catalase, a hydrogen peroxide–degrading enzyme that results from free radicals present during the initiating phase of some cardiovascular diseases. The second molecule, ascorbic acid, interferes with formation of free radicals and the angiogenic process. The third molecule, endostatin, a potent antiangiogenic molecule, has applicability in the treatment of angiogenic-dependent diseases. Because oxidative stress mediates the formation of reactive oxygen
NANOMEDICINE AND DRUG DELIVERY
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species in cardiovascular diseases, treatment with vitamin C, vitamin E, or other antioxidants has been suggested as therapy. The drug-delivery method based on the administration of antioxidant agents across an inorganic aluminum oxide nanoporous filter passed critical in vitro tests for diffusibility and biocompatibility, allowing new treatments for vascular diseases. Nanotechnologies promise a new means of drug application. A good example is intracellular adhesion molecule 1 (ICAM-1). This drug protects endothelial cells from oxidative damage by reactive oxygen species particles. ICAM-1 also is a good target for vascular immunotargeting of nanoparticles to the disturbed endothelium. A recent study demonstrated the unique trafficking pathway followed by internalized anti-ICAM-1 nanoparticles; this targeting mechanism seems well suited for targeted delivery of therapeutic enzymes to endothelial cells and may provide a basis for the treatment of acute vascular oxidative stress [22].
References [1] Bosland MC, Dreef-Van Der Meulen HC, Sukumar S, et al. Multistage prostate carcinogenesis: the role of hormones. Princess Takamatsu Symp 1991;22:109–23. [2] Caplan A, Kratz A. Prostate-specific antigen and the early diagnosis of prostate cancer. Am J Clin Pathol 2002;117(Suppl):S104–8. [3] Garzotto M, Park Y, Mongoue-Tchokote S, et al. Recursive partitioning for risk stratification in men undergoing repeat prostate biopsies. Cancer 2005;104:1911–7. [4] Gleave M, Evans CP. What’s hot in the prostate? Prostate Cancer Prostatic Dis 2003;6: 200–3. [5] Gade TP, Hassen W, Santos E, et al. Targeted elimination of prostate cancer by genetically directed human T lymphocytes. Cancer Res 2005;65:9080–8. [6] Bucur O, Ray S, Bucur MC, et al. APO2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in prostate cancer therapy. Front Biosci 2006;11:1549–68. [7] Wolf S, Mertens D, Pscherer A, et al. Ala228 variant of trail receptor 1 affecting the ligand binding site is associated with chronic lymphocytic leukemia, mantle cell lymphoma, prostate cancer, head and neck squamous cell carcinoma and bladder cancer. Int J Cancer 2006;118:1831–5. [8] Carraway RE, Hassan S, Cochrane DE. Polyphenolic antioxidants mimic the effects of 1,4-dihydropyridines on neurotensin receptor function in PC3 cells. J Pharmacol Exp Ther 2004;309:92–101. [9] Bondi ML, Craparo EF, Giammona G, et al. Nanostructured lipid carriers-containing anticancer compounds: preparation, characterization, and cytotoxicity studies. Drug Deliv 2007;14:61–7. [10] Sahoo SK, Ma W, Labhasetwar V. Related Articles, Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. Int J Cancer 2004;112:335–40. [11] Svenson S, Tomalia DA. Dendrimers in biomedical applicationsdreflections on the field. Adv Drug Deliv Rev 2005. [12] Tomalia DA, Reyna LA, Svenson S. Dendrimers as multi-purpose nanodevices for oncology drug delivery and diagnostic imaging. Biochem Soc Trans 2007;35:61–7. [13] Tomalia DA. Supramolecular chemistry: fluorine makes a difference. Nat Mater 2003;2: 711–2. [14] Svenson S, Tomalia DA. Dendrimers in biomedical applicationsdreflections on the field. Adv Drug Deliv Rev 2005;57(15):2106–29.
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[15] Tomalia DA, Reyna LA, Svenson S. Dendrimers as multi-purpose nanodevices for oncology drug delivery and diagnostic imaging. Biochem Soc Trans 2007;35(1):61–7. [16] Kondo E, Seto M, Yoshikawa K, et al. Highly efficient delivery of p16 antitumor peptide into aggressive leukemia/lymphoma cells using a novel transporter system. Mol Cancer Ther 2004;3:1623–30. [17] Patent #3748561 (E. Kondo et al.), Japan Patent Office. [18] Kolodgie FD, Petrov A, Virmani R, et al. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation 2003;108:3134–9. [19] Elder AC, Gelein R, Oberdorster G, et al. Efficient depletion of alveolar macrophages using intratracheally inhaled aerosols of liposome-encapsulated clodronate. Exp Lung Res 2004; 30:105–20. [20] Kolodgie FD, John M, Khurana C, et al. Sustained reduction of in-stent neointimal growth with the use of a novel systemic nanoparticle paclitaxel. Circulation 2002;106:1195–8. [21] Hsieh PC, MacGillivray C, Gannon J, et al. Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicity. Circulation 2006;114:637–44. [22] Muro S, Cui X, Gajewski C, et al. Slow intracellular trafficking of catalase nanoparticles targeted to ICAM-1 protects endothelial cells from oxidative stress. Am J Physiol Cell Physiol 2003;285:C1339–47.