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Current Drug Metabolism, 2012, 13, 1476-1483
Implications of Nanoscale Based Drug Delivery Systems in Delivery and Targeting Tubulin Binding Agent, Noscapine in Cancer Cells Ramesh Chandra1*, Jitender Madan1, Prashant Singh1, Ankush Chandra1,3, Pradeep Kumar1, Vartika Tomar1 and Sujata K. Dass2 1
Dr. B.R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi-110007, India; 2V.P. Chest Institute, University of Delhi, Delhi-110007, India; 3Boston University, Boston, MA 02215, USA Abstract: Noscapine, a tubulin binding anticancer agent undergoing Phase I/II clinical trials, inhibits tumor growth in nude mice bearing human xenografts of breast, lung, ovarian, brain, and prostrate origin. The analogues of noscapine like 9-bromonoscapine (EM011) are 5 to 10-fold more active than parent compound, noscapine. Noscapinoids inhibit the proliferation of cancer cells that are resistant to paclitaxel and epothilone. Noscapine also potentiated the anticancer activity of doxorubicin in a synergistic manner against triple negative breast cancer (TNBC). However, physicochemical and pharmacokinetic (ED50~300-600 mg/kg bodyweight) limitations of noscapine present hurdle in development of commercial anticancer formulations. Therefore, objectives of the present review are to summarize the chemotherapeutic potential of noscapine and implications of nanoscale based drug delivery systems in enhancing the therapeutic efficacy of noscapine in cancer cells. We have constructed noscapine-enveloped gelatin nanoparticles, NPs and poly (ethylene glycol) grafted gelatin NPs as well as inclusion complex of noscapine in -cyclodextrin (-CD) and evaluated their physicochemical characteristics. The Fe3O4 NPs were also used to incorporate noscapine in its polymeric nanomatrix system where molecular weight of the polymer governed the encapsulation efficiency of drug. The enhanced noscapine delivery using PAR-targeted optical-MR imaging trackable NPs offer a great potential for image directed targeted delivery of noscapine. Human Serum Albumin NPs (150-300 nm) as efficient noscapine drug delivery systems have also been developed for potential use in breast cancer.
Keywords: Cancer, noscapine, 9-bromonoscapine, pharmacokinetic, drug delivery. INTRODUCTION Noscapine is a novel tubulin binding, antiangiogenic, anticancer drug that causes cell cycle arrest and induces apoptosis in cancer cells both in-vitro and in-vivo (Fig. 1A) [1-4]. Moreover, noscapine has been also investigated for use in the treatment of hypoxic ischemia in stroke patients [5]. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. The bioactive compounds are emerging as potential future drugs in addition to those already under research and development, and a major challenge for efficient drugs delivery and targeting. Thus, Newman and Cragg [6] have shown that 63% of anticancer drugs introduced over the last 25 years are natural products or can be traced back to a natural products source, and similar observations have been made by many others. A recent review by Butler lists 79 natural products or natural product analogs that entered clinical trial as anticancer agents in the 2005-2007 timeframe [7]. The very slow progress in the efficacy of the treatment of severe diseases, suggested a need for multidisciplinary approach to the delivery of therapeutic drugs to the targeted tissues. A new idea on controlling the pharmacokinetics, pharmacodynamics, non specific toxicity, immunogenicity, bio-recognition and efficacy of drugs is being generated. These new strategies are called as drug *Address correspondence to this author at the Dr. B.R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi-110007, India; Tel: +9111-27667593; Fax: +91-27666272; E-mail:
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delivery systems (DDS), and based on interdisciplinary approaches that combined bio-conjugate chemistry, pharmaceutics, polymer science and molecular biology. Targeting is the ability to direct the drug-loaded system to the site of interest. Two major mechanisms can be distinguished for addressing the desired sites for drug release: (i) passive and (ii) active targeting. An example of passive targeting is the preferential accumulation of chemotherapeutic agents in solid tumors as a result of the enhanced vascular permeability of tumor tissues compared with healthy tissue. A strategy that could allow active targeting involves the surface functionalization of drug carriers with ligands that are selectively recognized by receptors on the surface of the cells of interest. Since ligand– receptor interactions can be highly selective, this could allow a more precise targeting of the site of interest. When developing these formulations, the goal is to obtain systems with optimized drug loading and release properties, long shelf-life and low toxicity. The incorporated drug participates in the microstructure of the system, and may even influence it due to molecular interactions, especially if the drug possesses amphiphilic and/or mesogenic properties. Noscapine, a phthalide isoquinoline alkaloid derived from opium, has been used as an oral antitussive agent and has shown minimal toxic effects in animals and humans. It is a naturally occurring tubulin-binding agent currently undergoing clinical trials for anticancer therapy. During last 25 years, researchers have appreciated the potential benefits of nanotechnology in providing vast improvements in drug delivery and drug targeting. Improving delivery techniques that minimize toxicity and improve efficacy offers great potential benefits to patients, and opens up new markets for pharmaceutical and drug delivery companies. Other approaches to drug delivery are focused on crossing particular physical barriers, such as the blood brain barrier, in order to better target the drug and improve its effectiveness; or on finding alternative and acceptable routes for the delivery of protein drugs other than via the gastrointestinal tract, where degradation can occur. Microtubule inhibitors based chemotherapy is a major therapeutic approach for the treatment of cancer which may be used alone or combined with other forms of therapy. In this series, our group is
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continuously working on noscapine and its derivatives for better future prospects [2,3]. However, low aqueous solubility, short oral and plasma half-life, low oral bioavailability, and high therapeutic dose produce hurdles in their extensive commercialization. Nanotherapeutics is rapidly progressing aimed to solve several limitations of conventional drug delivery systems. Nonspecific targeting of cancer chemotherapy leads to damage rapidly proliferating normal cells. Hydrophobic nature of chemotherapeutics leads to poor aqueous solubility and low bioavailability which can be overcome by colloidal drug delivery systems. Currently available chemotherapeutic drugs induce side effects in therapeutic dose-dosage regimen and cause severe toxicity to normal tissues. Scaling novel drug delivery systems of anticancer drugs have the potential to selectively accumulate in the tumor cells while escaping the normal tissues is the most intense area of investigation in cancer science. Several different possibilities have been explored to reduce the toxicity and increased anti-tumor efficacy of anti-cancer drugs using nano-devices. Encapsulating Noscapine in NPs will help to increase its efficacy and lowers any side effects. In this manuscript, we have discussed the work done in our and collaborating labs, various types of NPs of noscapine and their efficacy when used to target various types of tumors [8-10]. MECHANISM OF ACTION OF NOSCAPINE Among the various mechanisms of action of natural products, that of interaction with the cellular protein tubulin is one of the most important, and over 25% of the new clinical candidates listed by Butler operate by this general mechanism. Two major classes of anticancer drugs owe their effectiveness to this mechanism; the first class is that of the tubulin polymerization inhibitors, and the second is that of tubulin polymerization promoters. The cellular protein tubulin is a crucial protein for cellular replication. The cell cycle involves the replication of DNA and the packaging of the resulting replicated chromosomes into two daughter cells. The separation of the daughter chromosomes in mitosis is brought about by microtubules, which are formed by the polymerization of - and tubulin. The microtubules radiate in cells from centrosomes and from the poles of mitotic spindles, and are formed by attachment of GTP-tubulin to the growing end of an existing microtubule. Microtubules undergo rapid assembly and disassembly in cells, and this property enables those associated with the mitotic spindle to generate a large collection of structures and thus to produce those structures which will interact constructively with the centromeres of daughter chromosomes and generate the necessary aligned chromosomes at metaphase. The normal functioning of tubulin assembly and disassembly is thus crucial to cell division, and any interference with this process will disrupt cell division and cause cell death by apoptosis. Although the most dramatic effect of the tubulin-interactive drugs is that of changing the extent of microtubule polymer mass, either decreasing it for the tubulin polymerization inhibitors, or increasing it for the tubulin polymerization promoters, cancer cell growth can be inhibited at concentrations significantly lower than those necessary to exert these macroscopic effects. This fact can be explained by the observation that cell growth inhibition at low concentrations is caused by the suppression of microtubule dynamics. The structure of the tubulin heterodimer has been solved by electron diffraction. Both the vinca alkaloids and the taxane drugs bind to -tubulin, but at different locations on the protein; the vinca alkaloids bind to -tubulin between amino acids 175 and 213, while paclitaxel binds both to an N-terminal unit of -tubulin14 as well as to the region bounded by amino acids 217-231 [11, 12]. Colchicine, which is not a clinically used drug for cancer but which has been studied extensively, binds between the two subunits [13]. The epothilones also bind at the paclitaxel site [14]. Noscapine attenuates micro-tubule dynamics just enough to activate the mitotic checkpoints to stop cell cycle and do not alter the steady state monomer/polymer ratio of tubulin [15].
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ANTIANGIOGENIC EFFECT OF NOSCAPINE Angiogenesis, necessary for tumor growth involves cell proliferation and directed migration. Thus, there is [unreadable] clearly a crucial role of cytoskeletal microtubule (MT) dynamics in angiogenesis; linking perturbations of MT [unreadable] dynamics to Inhibition of tumor angiogenesis. The process includes the action of various growth factors and cytokines, in particular vascular endothelial growth factor (VEGF). For example- Nitric oxide causes local vasodilation and metalloproteinases, a kind of protease degrade the local basement membrane and the local matrix, and also mobilize further growth factors from the matrix. Further, endothelial cells migrate out, forming a solid capillary sprout followed by stabilization of the endothelial layer through cell to cell binding by adherence proteins and integrin binding of cells to the matrix [16]. Over expression of hypoxia-inducible factor-1 (HIF-1) is a common feature in solid malignancies, thus HIF-1 and its signaling pathway are well known targets for cancer chemotherapy [17]. Noscapine down regulated hypoxia mediated HIF-1 expression in human glioma cells, concomitantly with reduced secretion of the potent angiogenic cytokine, VEGF. [18]. PHYSICOCHEMICAL, PHARMACOKINETIC AND PHARMACODYNAMIC LIMITATIONS OF NOSCAPINE Beside the major benefits of noscapine as a novel resistance free anticancer drug, it also associated with several limitations as like other cancer chemotherapeutic drugs. (a) Limited aqueous solubility: Noscapine being an alkaloid is hydrophobic in nature and possess limited solubility in aqueous phase; [8] (b) Ionization at acidic pH: Noscapine ionizes at acidic pH in stomach which may lead to low bioavailability due to slow absorption from the intestine; (c) Lack of selectivity of anticancer drugs: Most chemotherapeutics lack selectivity toward cancerous cells cause significant damage to rapidly proliferating normal cells; (d) Limited oral bioavailability: Noscapine is reported to have low oral bioavailability both in humans and mice below 44%; [8, 19] (e) Short oral and plasma half-life: Noscapine presents short oral and plasma half life of below 2 h, which poses hurdles in designing of controlled release formulations [8] (f) Rapid elimination from body tissues: Noscapine rapidly eliminates from body tissues with first order kinetic, therefore requires multiple injections for successive chemotherapy [20]. NOVEL POTENT ANALOGUES OF NOSCAPINE Our group has synthesized and reported various potent analogues of noscapine. We showed that 9-chloronoscapine (Fig. 1C) is more potent than 9-bromonoscapine (Fig. 1B), when tested on U87 glioma cells, however, it did not show significant difference at low concentration [21]. Moreover, 9-bromonoscapine was also tested on various cancer cell lines and possesses 5-to10-fold higher anticancer activity in comparison to parent compound, noscapine in preclinical testing [22-24]. Moreover, a cyclic ether fluorinated noscapine analog showed potent antiproliferative and anticancer activity in both hormone-responsive (MCF-7) and hormone nonresponsive (MDA-MB-231) breast cancer cells [25]. 9-aminonoscapine (Fig. 1E) also showed promising results and it binds to tubulin at a site overlapping with colchicine-binding site or close to it. Thus, 9-aminonoscapine has better anti-tumor activity than noscapine [26]. Researchers now validated more potent antitumor noscapinoid, 9-azido-noscapine, and reduced 9-azido-noscapine with IC50 value of 1.2 to 56.0 M in human acute lymphoblastic leukemia cells [27]. Moreover, 9-bromonoscapine is potently effective against vinblastine sensitive line CEM [28]. NOSCAPINE: COMBINATION THERAPY Current approach in cancer chemotherapy involves a mixture of drugs and techniques that designed to target selectively cancer cells.
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Fig. (1). Schematic representation of chemical structures of a) Noscapine b) 9-Bromonoscapine c) 9-Chloronoscapine d) 9-Nitronoscapine e) 9Aminonoscapine.
Therefore, noscapine, being a novel anticancer drug was also investigated with a number of drugs for better cancer chemotherapy. Researchers showed that noscapine and doxorubicin combination treatment significantly increase the extent of apoptosis in breast cancer cells [29]. This combination showed decreased expression of NF-KB pathway proteins, VEGF, cell survival, and increased expression of apoptotic and growth inhibitory proteins compared to single-agent treatment and control groups. These findings indicated the potential use of oral noscapine and doxorubicin combination therapy for treatment of more aggressive tumors. Further, noscapine was combined with cisplatin and tested on A549 and H460 lung cancer cells and in vivo in murine xenograft model [30]. The combination showed the higher percentage of apoptotic non-small cell lung cancer cells and increased expression of p53, p21, caspase-3, cleaved caspase-3, cleaved-PARP, Bax, and decreased expression of Bcl-2 and surviving proteins compared with treatment with either agent. Moreover, docetaxel (25nM) in combination with 9bromonoscapine caused an additive increase in proapoptotic activity in prostate cancer cells [31]. But the researchers did not observe the synergistic effect in all combinations. Combination of noscapine with imatinib mesylate showed antagonist effect in T98G human GBM cells in vitro [32]. NANOSCALE BASED DRUG DELIVERY SYSTEMS FOR CANCER CHEMOTHERAPEUTICS Nanotechnology literally means technology performed on a nanoscale. The nanoscale/ nanocavities are ultrafine vesicles in the size of nanometre from 1 nm to 1000 nm. Nanomedicine is an important area in nanotechnology which refers to highly specific medical intervention at the molecular scale for diagnosis, prevention and treatment of diseases. Nanotherapeutics are rapidly progressing field which are utilized to solve several limitations of conventional drug delivery system such as nonspecific bio
distribution, lack of targeting, lack of aqueous solubility, poor oral bioavailability, and low therapeutic indices [33]. For exampleNanotherapeutics acquired two cancer treatment drugs that are in late stage development. Cloretazine, formerly known as Onrigen for the treatment of relapsed acute AML and Triapine for solid tumors such as cervical and vaginal cancers. Some important technological advantages of nanotherapeutic drug delivery systems (NDDS) are (a) NDDS provides longer shelf-life, (b) Both hydrophilic and hydrophobic substances can be incorporated in NDDS (c) NDDS can be administrated through oral, nasal, parenteral, intraocular etc. (d) NDDS improve the bio distribution of cancer drugs. Whereas optimal size and surface characteristics of NPs increases the circulation time of the drug, (e) NDDS provides control and sustain release of the drug both during the transportation and at the site of action and NDDS increases the intercellular concentration of drug either by enhanced permeability and retention effect (EPR) or by endocytosis mechanism [34]. Therefore targeting NDDS is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. Generally, these NDDS carries the chemotherapeutic drug in tumor vasculature by two mechanisms i.e passive targeting and active targeting. PASSIVE TARGETING Size of nanovesicles and behaviour of tumor tissue vasculature plays a significant role in passive targeting. Solid tumor consists of tumor parenchyma and stroma, which in turn consist of vasculature and other supporting cells. Due to increased metabolic requirements of growing tumor cells, pre-existing blood vessels are subjected to angiogenic pressure and leads to the development of new capillaries to the tumor in a process called angiogenesis. Scanning electron microscopic studies revealed that the formed tumor capillaries are highly irregular and showed gross architectural changes. Normal tissue vasculatures are lined by tight endothelial cells thereby preventing entry of nanovesicles whereas tumor tissue vasculatures are leaky (gaps as large as 200 to 2000 nm between adjacent endothelial cells) and hyper permeable. This defective vascular architecture induces an EPR and permits accumulation of nanovesicles in the tumor interstitial space. Accumulation of nanovesicles in tumor tissues depends on interstitial fluid pressure which is higher in tumor tissues than in benign tumor and normal tissues. In particular, interstitial pressure would be higher at the centre diminishing towards the periphery which is responsible for induction of drugs outflow from the cells that may leads to drug redistribution in some portions of the cancer tissue. Accumulation of nanovesicles in tumor tissues are also depends on size, surface character, circulation half-life of the nanovesicles and the degree of angiogenesis of the tumor. Selected delivery systems to achieve passive targeting are liposomes, polymeric NPs, nanocrystals, inorganic NPs, micelles, and dendrimers etc. ACTIVE TARGETING Paul Ehrlich coined the term “magic bullet” which is an idealized package that would target and deliver drugs to a specific place in the body and this idea of active targeting was proposed even before a rational targeting ligand was discovered. Active targeting involves conjugation of targeting molecules (like antibodies, ligands, peptides, nucleic acids etc.) on the surface of nanovesicles with receptors over expressed on a tumor cell surface. Tumor targeting molecules on the nanovesicles bind to cell through an endosome-dependent mechanism which bypasses the drug efflux pump leading to high intracellular concentration [35, 36]. NANOPARTICLES (NPS) FOR DRUG DELIVERY IN CANCER NPs hold great promise for improving cancer treatment. For example, they can guide drugs directly to tumors, increasing
Nanotherapeutics of Noscapine
effectiveness and reducing side effects. However, significant challenges need to be overcome before these engineering marvels make it to the clinic. On the engineering side, it’s difficult to make anything that small, around 100 nanometers (a nanometer is one billionth of a meter). Researchers also must generate particles that are uniform in size and shape and, once they’ve done their job, these particles must break down safely in the body. On the treatment side, NPs share the same obstacles as all potential treatments—cancer is wily. Because the disease evolves so rapidly, it finds ways to escape treatments, leading to drug resistance. So even the perfect nanoparticle containing a single treatment might not be effective in the long run. NPs, by using passive and active targeting strategies, can enhance the intracellular concentration of drugs on cancer cells while avoiding toxicity in normal cells. Furthermore, when NPs bind to specific receptors and then enter the cell, they are usually enveloped by endosomes via receptor mediated endocytosis, thereby bypassing the recognition of P-glycoproteins one of the main drug resistance mechanisms. Although NPs offer many advantage as drug carrier system, there are still many limitation to be solved such as poor oral bioavailability, instability in circulation, inadequate tissue distribution and toxicity. NPs applied as drug delivery systems are sub-micron sized particles (3-200 nm), devices or systems that can be made using variety of material including polymers (Polymeric NPs, micelles or dendrimers) and even oganometallic compounds (nanotubes) [37]. TWO-FACED NPS AND CANCER Named for the Roman god with two faces, Janus particles are spherical and have two very different sides—one that loves water and one that hates it. This conflicted relationship with water comes into play when attaching therapies. The two distinct sides can hold different agents. “These particles give us a lot of versatility,” according to Dr. Jeffrey Smith, whose lab is working to perfect Janus particles. “For example, they can create a theranostic, a particle with a therapy on one side and a diagnostic imaging agent on the other.” Janus particles have been around for a few years, but they have been difficult to make in the quantity and uniformity needed for clinical trials. The Smith laboratory may have solved these problems. “These particles are stunningly uniform,” according to Dr. Smith. In addition, the particles are made of a polymer called PLGA, which is already approved by the Food and Drug Administration and breaks down into harmless glycolic acid and lactic acid in the bloodstream. Janus particles could be a great boon to cancer treatment. For example, clinicians could create particles with chemically different treatments on each face, allowing them to combine treatments that normally could not be combined. In addition, some treatments known for their toxicity are significantly less toxic when delivered by NPs. Dr. Smith is also creating particles with a treatment on one side and a gene or piece of RNA on the other. The genetic material would make the cancer cell more vulnerable to the treatment. Ultimately, Dr. Smith would like to make particles with multiple faces, allowing him to create a nanococktail to attack cancer. “You just cannot be effective without attacking from multiple angles”. “More faces mean more therapeutics and hopefully more success” [38]. Drug substances are considered highly soluble when the largest dose of drug is soluble in < 250 mL water throughout the physiological pH range from 1–8 but most of the anticancer drugs show poor aqueous solubility. Poor aqueous solubility chemotherapeutics both from plant source and synthetic often demonstrate decreased bioavailability, increased chance of food effect, more frequent incomplete release from the dosage form and higher interpatient variability. However, administration of poor watersoluble drugs through systemic route requires solvents like Cremophor EL, Tween (polysorbate)-80, etc. which in turn, lead to severe adverse effects, including acute hypersensitivity reactions, fluid retention, and peripheral neuropathy. There are two basic approaches to overcome the poor water solubility and poor
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bioavailability problems (a) Increase of saturation solubility (by complex formation) and (b) Increase of dissolution velocity (Dissolution velocity can be increased by increasing the surface area of the drug powder, i.e. nanonisation). NOSCAPINE LOADED MAGNETIC POLYMERIC NPS Targeting chemotherapeutic drugs to cancer cells using magnetic NPs is one of the most promising techniques in drug targeting [39,40]. Here, we encapsulate the chemotherapeutic drug in nanomatrix system of magnetic NPs that layered with a polymeric coat. Further this technology enables the magnetic NPs to escape from reticulo-endothelial system and multiple drug resistance pumps that contribute poor therapeutic efficacy of the drug. Therefore, researchers have focused on design and development of magnetic NPs for drug delivery and diagnosis [41-45]. Generally, NPs are endocytosed or phagocytosed by either dendritic cells or macrophages and enter into the cytoplasmic membrane or nuclear membrane. Moreover, NPs deliver the drug either by passive targeting or active targeting process. In passive targeting, NPs are retained by tumor cells due to their leaky nature which further enhances the permeability of NPs in tumor cells. This process is called enhanced permeation and retention (EPR) effect [43]. The coating of magnetic NPs with a polymeric coat also offers sustained drug release for a long period of time. Therefore one can also achieve the desired release profile of drug by altering either the composition of polymeric coat or molecular weight of the polymer. Super paramagnetic iron oxide NPs (Fe3O4 NPs) The magnetic property of iron oxide NPs not only offers drug delivery to cancer cells but can be also used for diagnostic purposes by applying magnetic resonance imaging (MRI) technique. Noscapine has recently been found to bind to tubulin and alter its conformation, assembly properties, and microtubule dynamics [46]. The analog EM105 (chloro) is more potent and regresses breast cancer xenografts in nude mice without significant toxicity. Noscapine and its analogues are thus interesting lead compounds. Thus targeting noscapine at the site of action would not only improve therapeutic index of the drug but will also enhance drug retention time in vivo. Therefore, noscapine loaded polymeric magnetic NPs were constructed of about 252 nm for targeting tumor cells. Further, presence of noscapine in the polymeric layer was confirmed by FTIR spectroscopy, elemental analysis and mass spectroscopy. Moreover, the effect of molecular weight of polylactide acid (PLLA) and poly (lactide-co-glycolide) (PLGA) on encapsulation efficiency of noscapine was also studied. It was demonstrated that molecular weight of the polymer critically affects the loading efficiency of noscapine. Both low molecular weight PLLA and PLGA have shown significantly enhanced loading efficiency of noscapine. Therefore, magnetically guided polymeric NPs bearing noscapine has shown the promising results and warrant a further preclinical study. Clinical data of prostate cancer therapy (available on pcref.com) has shown that 1000 mg/day of noscapine is required to suppress the prostate specific antigens while this dose did not exhibit any toxicity in normal tissues. Thus magnetically guided NPs of noscapine may potentially be used to discriminate the deposition of drug in non-targeting organs. Hence the tailored system allows pre and post administration visualization that lead to more therapeutically effective treatment [10]. CYCLODEXTRIN BASED NANOMICELLES TO ENHANCE AQUEOUS SOLUBILITY AND BIOAVAILABILITY Cyclodextrins were used to enhance aqueous solubility and stability of anticancer drugs in dissolution medium. Researchers studied the inclusion complexation behavior of paclitaxel with a series of oligo (ethylenediamino) bridged bis (-cyclodextrin) possessing bridge chains in different length of 1 - 4 to improve the
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water solubility and bioavailability of paclitaxel. [47, 48] Cyclodextrin inclusion complex of anticancer drug alters the solubility and bioavailability and can be utilized to deliver cancer therapeutics with low solubility and bioavailability. Noscapine, due to short half-life and low bioavailability requires high therapeutic doses of drug (ED50~300 mg/kg bodyweight) for induction of anticancer activity. Therefore, we synthesized the noscapine--cyclodextrin inclusion complex in 1:1 ratio as shown by AL type curve in phase solubility analysis [8] with Kc value of 0.454 mM-1 at pH 7.4, indicating the formation of a stable complex with low affinity. We also explored the molecular mechanism in the inclusion mode with spectroscopic techniques and correlated with the molecular modeling. Our data proved that O-CH 2-O moiety of noscapine entered in the -cyclodextrin cavity and formed the inclusion complex in 1:1 ratio (Fig. 2A). Noscapine requires basic environment to remain in unionized form and also for its absorption. The dissolution profile of noscapine and noscapine--cyclodextrin inclusion complex demonstrated that noscapine rapidly released from the inclusion complex in comparison with noscapine. Results show that noscapine--cyclodextrin inclusion complex release high percentage of noscapine at pH 7.4 in comparison with noscapine base and physical mixture [8]. Moreover, noscapine--cyclodextrin inclusion complex gave shorter tmax and higher AUC and Cmax than did noscapine. Pharmacokinetic analysis disclosed the enhanced bioavailability of 1.87-fold in absolute bioavailability indicating that the enhanced oral bioavailability of noscapine in the inclusion complex might be due to increased absorption rate of noscapine through intestinal pH. However, t1/2 value of noscapine was not significantly changed in inclusion complex indicated that inclusion complex allowed fast absorption in the initial phase, thereby improved bioavailability. [8] NOSCAPINE NANOTHERAPEUTICS ENHANCE PLASMA HALF-LIFE AND THERAPEUTIC INDEX Nanoparticles mediated anticancer drug delivery to solid tumors can be an effective approach to enhance therapeutic concentration of drug in tumor cells, usually have a permeability cut-off less than 600 nm. However, intravenously injected nanoparticles are rapidly cleared from the circulation by a process of opsonization, which is initiated by complement activation and preferential uptake of the nanoparticles by the organs of RES. Therefore, we designed and synthesized noscapine encapsulated poly (ethylene glycol) grafted gelatin nanoparticles and gelatin nanoparticles. The data of Transmission electron microscopy (TEM) state that both gelatin nanoparticles and PEGylated gelatin nanoparticles were below 200 nm and freeze drying factors did not affect the nanoparticle texture (Fig. 2B, C) [9]. Moreover, in vitro release of noscapine from optimized formulations documented that PEGylated gelatin nanoparticles release 97.28±1.1% of noscapine whereas gelatin nanoparticles release 85.1±4.2% of noscapine at pH 4.5. The release was significantly (P
