Using chitosan-coated magnetite nanoparticles as a drug carrier for opioid delivery against breast cancer.

Over the past decades, opium derivatives have been discovered as new anticancer agents. In our study, Fe3O4 superparamagnetic nanoparticles (SPIONs) decorated with chitosan were loaded with papaverine or noscapine to surmount drug delivery-related obstacles. Modifying the magnetic nanoparticles (MNP) surface with polymeric materials such as chitosan prevents oxidation and provides a site for drug linkage, which renders them a great drug carrier. The obtained systems were characterized by DLS (20-40 nm were achieved for MNPs and drug- loaded MNPs), TEM (spherical with average size of 11-20 nm) FTIR, XRD, and VSM (71.3 - 42.8 emu/g). Contrary to noscapine, papaverine-MNPs attenuated 4T1 murine breast cancer cell proliferation (11.50 ± 1.74 µg/mL) effectively compared to the free drug (62.35 ± 2.88 µg/mL) while sparing L-929 fibroblast cells (138.14 ± 4.38 µg/mL). Furthermore, SPION and SPION-chitosan displayed no cytotoxic activity. Colony-formation assay confirmed the long-term cytotoxicity of nanostructures. Both developed formulations promoted ROS production accompanied by late apoptotic cell death. The biocompatible nanoparticle exerted an augmenting effect to deliver papaverine to metastatic breast cancer cells.

Combination therapy for cerebral ischemia: do progesterone and noscapine provide better neuroprotection than either alone in the treatment?

Ischemic stroke presents multifaceted pathological outcomes with overlapping mechanisms of cerebral injury. High mortality and disability with stroke warrant a novel multi-targeted therapeutic approach. The neuroprotection with progesterone (PG) and noscapine (NOS) on cerebral ischemia-reperfusion (I-R) injury was demonstrated individually, but the outcome of combination treatment to alleviate cerebral damage is still unexplored. Randomly divided groups of rats (n = 6) were Sham-operated, I-R, PG (8 mg/kg), NOS (10 mg/kg), and PG + NOS (8 mg/kg + 10 mg/kg). The rats were exposed to bilateral common carotid artery occlusion, except Sham-operated, to investigate the therapeutic outcome of PG and NOS alone and in combination on I-R injury. Besides the alterations in cognitive and motor abilities, we estimated infarct area, oxidative stress, blood-brain barrier (BBB) permeability, and histology after treatment. Pharmacokinetic parameters like Cmax, Tmax, half-life, and AUC0-t were estimated in biological samples to substantiate the therapeutic outcomes of the combination treatment. We report PG and NOS prevent loss of motor ability and improve spatial memory after cerebral I-R injury. Combination treatment significantly reduced inflammation and restricted infarction; it attenuated oxidative stress and BBB damage and improved grip strength. Histopathological analysis demonstrated a significant reduction in leukocyte infiltration with the most profound effect in the combination group. Simultaneous analysis of PG and NOS in plasma revealed enhanced peak drug concentration, improved AUC, and prolonged half-life; the drug levels in the brain have increased significantly for both. We conclude that PG and NOS have beneficial effects against brain damage and the co-administration further reinforced neuroprotection in the cerebral ischemia-reperfusion injury.

Immunomodifying and neuroprotective effects of noscapine: Implications for multiple sclerosis, neurodegenerative, and psychiatric disorders.

Noscapine is a phthalide isoquinoline alkaloid with antitussive activity. Noscapine protects oligodendroglia from ischemic and chemical injury, binds to bitter taste receptors, antagonizes the bradykinin and histaminergic systems, which may be of benefit in treatment of multiple sclerosis. Noscapine normalizes axonal transport and exerts significant therapeutic efficacy in animal models of Parkinson's Disease and Amyotrophic Lateral Sclerosis. Noscapine exerts neuroprotective effects on oxygen- and glucose-deprived fetal cortical neuronal cells and reduces ischemic brain damage in neonatal rat pups. Pilot clinical studies indicated some beneficial effects of noscapine in stroke. Noscapine harbours anxiolytic activity and methyl-noscapine blocks small conductance SK channels, which is beneficial in alleviating anxiety and depression. Noscapine exerts anticholinesterase activity and acts inhibitory on the inflammatory transcription factor NF-κB, which may be harnessed in treatment of Alzheimer's Disease. With its blood-brain barrier traversing features and versatile actions, noscapine may be a promising agent in the armamentarium against neurodegenerative and psychiatric diseases.

Reversal of drug-resistance by noscapine chemo-sensitization in docetaxel resistant triple negative breast cancer.

Multidrug resistance (MDR) is a major impediment to cancer treatment. Here, for the first time, we investigated the chemo-sensitizing effect of Noscapine (Nos) at low concentrations in conjunction with docetaxel (DTX) to overcome drug resistance of triple negative breast cancer (TNBC). In vitro experiments showed that Nos significantly inhibited proliferation of TNBC wild type (p < 0.01) and drug resistant (p < 0.05) TNBC cells. Nos followed by DTX treatment notably increased the cell viability (~1.3 fold) markedly (p < 0.05) in 3D models compared to conventional 2D systems. In vivo oral administration of Nos (100 mg/kg) followed by intravenous DTX (5 mg/kg) liposome treatment revealed regression of xenograft tumors in both wild type (p < 0.001) and drug-resistant (p < 0.05) xenografts. In wild type xenografts, combination of Nos plus DTX group showed 5.49 and 3.25 fold reduction in tumor volume compared to Nos and DTX alone groups, respectively. In drug-resistant xenografts, tumor volume was decreased 2.33 and 1.41 fold in xenografts treated with Nos plus DTX significantly (p < 0.05) compared to Nos and DTX alone respectively and downregulated the expression of anti-apoptotic factors and multidrug resistance proteins. Collectively, chemo-sensitizing effect of Nos followed by DTX regime provide a promising chemotherapeutic strategy and its significant role for the treatment of drug-resistant TNBC.

Nanoparticles Based on Linear and Star-Shaped Poly(Ethylene Glycol)-Poly(ε-Caprolactone) Copolymers for the Delivery of Antitubulin Drug.

PURPOSE: Biodegradable polymeric nanoparticles of different architectures based on polyethylene glycol-co-poly(ε-caprolactone) block copolymers have been loaded with noscapine (NOS) to study their effect on its anticancer activity. It was intended to use solubility of NOS in an acidic environment and ability of the nanoparticles to passively target drugs into cancer tissue to modify the NOS pharmacokinetic properties and reduce the requirement for frequent injections. METHODS: Linear and star-shaped copolymers were synthetized and used to formulate NOS loaded nanoparticles. Cytotoxicity was performed using a sulforhodamine B method on MCF-7 cells, while biocompatibility was determined on rats followed by hematological and histopathological investigations. RESULTS: Formulae with the smallest particle sizes and adequate entrapment efficiency revealed that NOS loaded nanoparticles showed higher extent of release at pH 4.5. Colloidal stability suggested that nanoparticles would be stable in blood when injected into the systemic circulation. Loaded nanoparticles had IC50 values lower than free drug. Hematological and histopathological studies showed no difference between treated and control groups. Pharmacokinetic analysis revealed that formulation P1 had a prolonged half-life and better bioavailability compared to drug solution. CONCLUSIONS: Formulation of NOS into biodegradable polymeric nanoparticles has increased its efficacy and residence on cancer cells while passively avoiding normal body tissues. Graphical Abstract ᅟ.

Formulation, Pharmacokinetic, and Efficacy Studies of Mannosylated Self-Emulsifying Solid Dispersions of Noscapine.

PURPOSE: To formulate hydroxypropyl methylcellulose-stabilized self-emulsifying solid dispersible carriers of noscapine to enhance oral bioavailability. METHODS: Formulation of noscapine (Nos) self-emulsifying solid dispersible microparticles (SESDs) was afforded by emulsification using an optimized formula of Labrafil M1944, Tween-80, and Labrasol followed by spray-drying with hydroxypropyl methylcellulose (HPMC), with and without mannosamine (Mann-Nos_SESDs and Nos_SESDs respectively); self-microemulsifying liquid dispersions (SMEDDs) with and without mannosamine (Mann-Nos_SMEDDs and Nos_SMEDDs respectively) were also prepared. SMEDDs and SESDs were characterized for size, polydispersity, surface charge, entrapment efficiency, in vitro permeability, in vitro release kinetics, and oral pharmacokinetics in Sprague-Dawley rats (10 mg/kg p.o). The antitumor efficacy of Mann-Nos_SESDs on the basis of chemosensitization to cisplatin (2.0 mg/kg, i.v.) was investigated in a chemorefractory lung tumor Nu/Nu mouse model up to a maximal oral dose of 300 mg/kg. RESULTS: The oil/surfactant/co-surfactant mixture of Labrafil M1944, Tween-80, and Labrasol optimized at weight ratios of 62.8:9.30:27.90% produced stable self-microemulsifying dispersions (SMEDDs) at a SMEDD to water ratio of 1-3:7-9 parts by weight. SMEDDs had hydrodynamic diameters between 231 and 246 nm; surface charges ranged from -16.50 to -18.7 mV; and entrapment efficiencies were between 32 and 35%. SESDs ranged in size between 5.84 and 6.60 µm with surface charges from -10.62 to -12.40 mV and entrapment efficiencies of 30.96±4.66 and 32.05±3.72% (Nos_SESDs and Mann-Nos_SESDs respectively). Mann-Nos_SESDs exhibited saturating uptake across Caco-2 monolayers (Papp = 4.94±0.18 × 10(-6) cm/s), with controlled release of 50% of Nos in 6 hr at pH 6.8 following Higuchi kinetics. Mann-Nos_ SESDs was 40% more bioavailable compared to Nos_SESDs; and was effective in sensitizing H1650 SP cells to Cisplatin in vitro and in an orthotopic lung tumor model of H1650 SP origin. CONCLUSIONS: Mannosylated noscapine self-emulsifying solid dispersions (Mann-Nos_SESDs) are bioavailable and potentiate the antineoplastic effect of cisplatin-based chemotherapy in cisplatin-resistant NSCLC.

Metabolic pathway profiling of the derivative of important herbal component noscapine.

The present study aims to investigate the influence of metabolic behavior by the introduction of bromo atom into the structure of noscapine. Oral gavage of 50 mg/kg bromo-noscapine for 6- to 8-week-old male mice with C57BL/6 background resulted in the detection of the metabolite undergoing cleavage of methylenedioxy group (II), demethylated bromo-noscapine (III, IV), meconine (V), bromo-cotarnine (VI), bisdemethylated bromo-noscapine (VII), and their corresponding glucuronides (G1-G4) in urine, feces, and serum (24 h). In vitro human liver microsomes or mice liver microsomes incubation system can also give the formation of phase I metabolites. Furthermore, the phase I drug-metabolizing enzymes involved in the metabolism of bromo-noscapine was screened. Many CYP isoforms were involved in the formation of metabolite II, and CYP3A4, CYP1A1, CYP2C19, and CYP2D6 were major CYP isoforms. All the determined CYP isoforms showed the catalytic activity towards the formation of metabolites III, V, and VI. The major CYP isoforms involved in the catalytic formation of metabolite IV were CYP2C19, CYP2D6, and CYP2E1. In conclusion, to date, many structural derivatives of noscapine have been synthesized based on the efficiency. However, the metabolic behavior remains to be elucidated, and the present study gave an example through the investigation of metabolic pathway of bromo-noscapine. The introduction of bromo atom into the structure of noscapine did not alter the metabolites profile, but changed the drug-metabolizing enzyme profiles.

Inhalable nanostructured lipid particles of 9-bromo-noscapine, a tubulin-binding cytotoxic agent: in vitro and in vivo studies.

9-Bromo-noscapine (9-Br-Nos) alters tubulin polymerization in non-small cell lung cancer cells differently from noscapine. However, clinical applications of 9-Br-Nos are limited owing to poor aqueous solubility and high lipophilicity that eventually lead to suboptimal therapeutic efficacy at the site of action. Hence, 9-Br-Nos loaded nanostructured lipid particles (9-Br-Nos-NLPs) were prepared by nanoemulsion method to reduce the particle size below 100 nm. To impart the inhalable and rapid release (RR) attributes, 9-Br-Nos-NLPs were treated with spray dried lactose and effervescent excipients to generate, 9-Br-Nos-RR-NLPs. The mean particle and aerodynamic size of 9-Br-Nos-NLPs were measured to be 13.4±3.2 nm and 2.3±1.5 µm, significantly (P<0.05) lower than 19.4±6.1 nm and 3.1±1.8 µm of 9-Br-Nos-RR-NLPs. In addition, zeta-potential of 9-Br-Nos-NLPs was examined to be -9.54±0.16 mV, significantly (P<0.05) lower than -7.23±0.10 mV of 9-Br-Nos-RR-NLPs. Hence, both formulations were found to be optimum for pulmonary delivery through inhalation route of administration. Next, 9-Br-Nos-RR-NLPs exhibited enhanced cytotoxicity, apoptosis and cellular uptake in A549, lung cancer cells, as compared to 9-Br-Nos-NLPs and 9-Br-Nos suspension. This may be attributed to enhanced drug delivery and internalization character of 9-Br-Nos-RR-NLPs by energy-dependent endocytosis and passive diffusion mechanism. Pharmacokinetic and distribution analysis demonstrated the superiority of 9-Br-Nos-RR-NLPs that exhibited ∼1.12 and ∼1.75-folds enhancement in half-life of the drug as compared to 9-Br-Nos-NLPs and 9-Br-Nos powder following inhalation route. Continuation to this, 9-Br-Nos-RR-NLPs also displayed ∼3.75-fold increment in half-life of the drug in lungs, as compared to 9-Br-Nos suspension following intravenous route of administration. Furthermore, enhanced drug exposure was measured in terms of AUC(last) in lungs following administration of 9-Br-Nos-RR-NLPs, as compared to 9-Br-Nos-NLPs, 9-Br-Nos powder and 9-Br-Nos suspension. This may be attributed to rapid dispersion, enhanced dissolution and deep lung deposition of nanoparticles following inhalation route. Therefore, inhalable 9-Br-Nos-RR-NLPs claims further in depth in vivo tumor regression study to scale up the technology for clinical applications.

Formulation approaches to improving the delivery of an antiviral drug with activity against seasonal flu.

The main objective of the present study was to develop formulations of noscapine hydrochloride hydrate with enhanced solubility and bioavailability using co-solvent- and cyclodextrin-based approaches. Different combinations of co-solvents, which were selected on the basis of high-throughput solubility screening, were subjected to in vitro intestinal drug permeability studies conducted with Ussing chambers. Vitamin E tocopherol polyethylene glycol succinate and propylene glycol based co-solvent formulations provided the maximum permeability coefficient for the drug. Inclusion complexes of the drug were prepared using hydroxypropyl-ß-cyclodextrin and sulphobutylether cyclodextrins. Pharmacokinetic studies were carried out in male Sprague-Dawley rats for the selected formulations. The relative bioavailabilities of the drug with the co-solvent- and cyclodextrin-based formulations were found to be similar.

Molecular insight of isotypes specific ß-tubulin interaction of tubulin heterodimer with noscapinoids.

Noscapine and its derivatives bind stoichiometrically to tubulin, alter its dynamic instability and thus effectively inhibit the cellular proliferation of a wide variety of cancer cells including many drug-resistant variants. The tubulin molecule is composed of α- and ß-tubulin, which exist as various isotypes whose distribution and drug-binding properties are significantly different. Although the noscapinoids bind to a site overlapping with colchicine, their interaction is more biased towards ß-tubulin. In fact, their precise interaction and binding affinity with specific isotypes of ß-tubulin in the αß-heterodimer has never been addressed. In this study, the binding affinity of a panel of noscapinoids with each type of tubulin was investigated computationally. We found that the binding score of a specific noscapinoid with each type of tubulin isotype is different. Specifically, amino-noscapine has the highest binding score of -6.4, -7.2, -7.4 and -7.3 kcal/mol with αßI, αßII, αßIII and αßIV isotypes, respectively. Similarly 10 showed higher binding affinity of -6.8 kcal/mol with αßV, whereas 8 had the highest binding affinity of -7.2, -7.1 and -7.2 kcal/mol, respectively with αßVI, αßVII and αßVIII isotypes. More importantly, both amino-noscapine and its clinical derivative, bromo-noscapine have the highest binding affinity of -46.2 and -38.1 kcal/mol against αßIII (overexpression of αßIII has been associated with resistance to a wide range of chemotherapeutic drugs for several human malignancies) as measured using MM-PBSA. Knowledge of the isotype specificity of the noscapinoids may allow for development of novel therapeutic agents based on this class of drugs.

Clinical efficacy of Spasmofen® suppository in the emergency treatment of renal colic: a randomized, double-blind, double-dummy comparative trial.

BACKGROUND: Renal colic is typically characterized by the sudden onset of severe pain radiating from the flank to the groin and its acute management in emergency departments essentially aims at rapid pain relief. Spasmofen(®) is a brand of Amriya Pharmaceutical Industries in the form of rectal suppositories containing ketoprofen 100 mg and hyoscine butylbromide 10 mg. This combination is intended for the rapid relief of severe colicky pain in the renal system, hepatobiliary system, or gastrointestinal tract. This trial aims to compare a single-dose of Spasmofen rectal suppository to a single intravenous (IV) ketorolac tromethamine 30 mg/2 mL dose in patients with acute renal colic. METHODS: A total of 80 eligible consecutive patients presenting to the emergency departments of two medical centers with acute renal colic were included in the study. Eligible patients who signed the informed consent were randomly assigned into two treatment groups: an experimental group (Spasmofen group) who received one Spasmofen rectal suppository plus an IV injection of 2 mL of normal saline solution; and a control group (ketorolac group) who received one ketorolac 30 mg/2 mL ampoule IV plus one placebo suppository. Treatment success, defined as a change in the verbal rating score from severe or moderate pain to none or mild at 60 minutes after the dose, was compared between groups using the chi-square/Fisher's exact test. Percentage reductions in visual pain analog scale (VPAS) scores at 15 and 60 minutes after the dose were compared between groups using the Z-test for proportions. RESULTS: Successful treatment at 60 minutes occurred in 35 of 40 (87.5%) of Spasmofen-treated patients and in 33 of 40 (82.5%) of ketorolac-treated patients. The difference was not statistically significant by Fisher's exact test (P=0.755). The mean percentage reduction of VPAS after 15 minutes was 61.82% in the Spasmofen-treated group and 64.76% in the ketorolac-treated group. The difference was also not statistically significant by the Z-test for proportions (P=0.795). Sixty minutes after being treated, Spasmofen was associated with a statistically significant greater reduction in VPAS (mean% reduction =92.36%) than ketorolac (75.06%; P=0.0466). CONCLUSION: Single-dose Spasmofen rectal suppository might be a safe and effective first-aid treatment for the emergency department relief of acute renal colic.

Enhanced noscapine delivery using estrogen-receptor-targeted nanoparticles for breast cancer therapy.

Noscapine (Nos), an orally available plant-derived antitussive alkaloid, is in phase II clinical trials for cancer chemotherapy. It has extensively been shown to inhibit tumor growth in nude mice bearing human xenografts of hematopoietic, breast, lung, ovarian, brain, and prostate origin. However, high tumor-suppressive Nos dosages encumber the development of oral controlled-release formulations because of a short biological half-life (<2 h), poor absorption, low aqueous solubility, and extensive first-pass metabolism. Here, we present the design, fabrication, optimization, characterization, and biological evaluation of estrone-conjugated noscapine-loaded gelatin nanoparticles (Nos-ES-GN) for targeting estrogen-receptor-positive breast cancer MCF-7 cells. Gelatin nanoparticles (GN) were a uniformly compact size, stable at physiological pH, and showed a drug entrapment efficiency of 66.1±5.9 and 65.2±5.6% for Nos-GN and Nos-ES-GN, respectively. The secondary structure of gelatin nanocoacervates was predicted using circular dichroism and in-silico molecular modeling. Our data suggest that ethanol-fabricated GN retained the α-helical content of gelatin, whereas acetone favored the formation of random coils. The conjugation of estrone to Nos-GN did not affect the release rate of the drug, and both formulations followed first-order release kinetics with an initial burst, followed by a slow release. The IC50 value of Nos-ES-GN was 21.2 µmol/l, which was ∼50% lower than the free drug (43.3 µmol/l), suggesting targeted drug delivery. Our cell uptake study carried out in an estrogen-receptor-positive (MCF-7) and negative (MDA-MB-231) cancer cell lines showed greater accumulation of Nos-ES-GN in MCF-7 cells instead of MDA-MB-231 cells. Our data indicated that estrone-conjugated nanoparticles may potentially be used for targeting breast cancer cells.

Synergistic suppression of noscapine and conventional chemotherapeutics on human glioblastoma cell growth.

AIM: Noscapine (NOS) is a non-narcotic opium alkaloid with anti-tumor activity. The aim of this study was to investigate the effects of the combination of NOS with conventional chemotherapeutics temozolamide (TMZ), bis-chloroethylnitrosourea (BCNU), or cisplatin (CIS)on human glioblastoma cells. METHODS: U87MG human glioblastoma cells were examined. Cell proliferation was quantified using MTT assay. Western blotting and flow cytometry were used to examine apoptosis and the expression of active caspase-3 and cleaved PARP. Mouse tumor xenograft model bearing U87MG cells was treated with TMZ (2 mg·kg(-1)·d(-1), ip) or CIS (2 mg/kg, ip 3 times a week) alone or in combination with NOS (200 mg·kg(-1)·d(-1), ig) for 3 weeks. Immunohistochemistry was used to investigate the expression of active caspase-3 and Ki67 following treatment in vivo. The safety of the combined treatments was evaluated based on the body weight and histological studies of the animal's organs. RESULTS: NOS (10 or 20 mol/L) markedly increased the anti-proliferation effects of TMZ, BCNU, and CIS on U87MG cells in vitro. The calculated combination index (CI) values of NOS-CIS, NOS-TMZ, and NOS-BCNU (20 µmol/L) were 0.45, 0.51, and 0.57, respectively, demonstrating synergistic inhibition of the drug combinations. In tumor xenograft models, combined treatment with NOS robustly augmented the anti-cancer actions of TMZ and CIS, and showed no detectable toxicity. The combined treatments significantly enhanced the apoptosis, the activated caspase-3 and PARP levels in U87MG cells in vitro, and reduced Ki67 staining and increased the activated caspase-3 level in the shrinking xenografts in vivo. CONCLUSION: NOS synergistically potentiated the efficacy of FDA-approved anti-cancer drugs against human glioblastoma cells, thereby allowing them to be used at lower doses and hence minimizing their toxic side effects.

Sterically stabilized gelatin microassemblies of noscapine enhance cytotoxicity, apoptosis and drug delivery in lung cancer cells.

Noscapine, recently identified as anticancer due to its microtubule-modulating properties. It is presently in Phase I/II clinical trials. The therapeutic efficacy of noscapine has been established in several xenograft models. Its pharmacokinetic limitations such as low bioavailability and high ED50 impede development of clinically relevant treatment regimens. Here we present design, synthesis, in vitro and in vivo characterization of sterically stabilized gelatin microassemblies of noscapine (SSGMS) for targeting human non-small cell lung cancer A549 cells. The average size of the sterically stabilized gelatin microassemblies of noscapine, SSGMS was 10.0±5.1 µm in comparison to noscapine-loaded gelatin microassemblies, GMS that was 8.3±5.5 µm. The noscapine entrapment efficiency of SSGMS and GMS was 23.99±4.5% and 24.23±2.6%, respectively. Prepared microassemblies were spherical in shape and did not show any drug and polymer interaction as examined by FTIR, DSC and PXRD. In vitro release data indicated that SSGMS and GMS follow first-order release kinetics and exhibited an initial burst followed by slow release of the drug. In vitro cytotoxicity evaluated using A549 cells showed a low IC50 value of SSGMS (15.5 µM) compared to GMS (30.1 µM) and free noscapine (47.2 µM). The SSGMS can facilitate a sustained therapeutic effect in terms of prolonged release of noscapine as evident by caspase-3 activity in A549 cells. Concomitantly, pharmacokinetic and biodistribution analysis showed that SSGMS increased the plasma half-life of noscapine by ~9.57-fold with an accumulation of ~48% drug in the lungs. Our data provides evidence for the potential usefulness of SSGMS for noscapine delivery in lung cancer.

Nanosolvated microtubule-modulating chemotherapeutics: a case-to-case study.

About 10% of the drugs in the preclinical stage are poorly soluble, 40% of the drugs in the pipeline have poor solubility, and even 60% of drugs coming directly from synthesis have aqueous solubility below 0.1 mg/ml. Out of the research around, 40% of lipophilic drug candidates fail to reach the market despite having potential pharmacodynamic activities. Microtubule-modulating chemotherapeutics is an important class of cancer chemotherapy. Most chemotherapeutics that belong to this category are plant-derived active constituents, such as vincristine, vinblastine, colchicine, docetaxel, paclitaxel, and noscapinoids. The pKa of a drug considerably affects its solubility in physiological fluids and consequently bioavailability. It usually ranges from 5 to 12 for microtubule-modulating drugs. Hence, the solubility of these drugs in physiological fluids is considerably affected by a change in pH. However, because of unpredictable parameters involved in poor solubility and the low oral bioavailability of these chemotherapeutics during the early phases of drug development, they often have an unusual pharmacokinetic profile. This makes the development process of novel chemotherapeutics slow, inefficient, patient-unfriendly, and very costly, emphasizing a need for more rational approaches on the basis of preclinical concepts. Nanosolvation is a process of increasing the polarity of a hydrophobic molecule either by solvation or cavitization in a hydrophilic macrocycle. The present review therefore focuses on the techniques applied in nanosolvation of microtubule-modulating chemotherapeutics to enhance solubility and bioavailability. The methodologies described will be highly beneficial for anticancer researchers to follow a trend of rational drug development.

Poly (ethylene)-glycol conjugated solid lipid nanoparticles of noscapine improve biological half-life, brain delivery and efficacy in glioblastoma cells.

Noscapine crosses blood-brain-barrier and inhibits proliferation of glioblastoma cells. However, short plasma half-life and rapid elimination necessitate the administration of multiple injections for successive chemotherapy. Noscapine bearing solid lipid nanoparticles, Nos-SLN and poly (ethylene)-glycol conjugated solid lipid nanoparticles of noscapine, Nos-PEG-SLN of 61.3 ± 9.3-nm and 80.5 ± 8.9-nm containing 80.4 ± 3.2% and 83.6 ± 1.2% of Nos, were constructed. First order kinetic and Higuchi equation were followed to release the Nos at intracellular pH~4.5. Further, a decrease in IC50 (Nos; 40.5 µM>Nos-SLN; 27.2 µM>20.8 µM) and enhanced subG1 population were observed in U87cells. Plasma half-life was enhanced up to ~11-fold and ~5-fold by Nos-PEG-SLN and Nos-SLN which significantly (P<0.05) deposits 400.7 µg/g and 313.1 µg/g of Nos in comparison to 233.2 µg/g by drug solution. This is first report demonstrating a workable approach to regulate the administration of multiple injections of Nos, warranting further in vivo tumor regression study for superior management of brain cancer. FROM THE CLINICAL EDITOR: This report describes a possible approach to regulate the administration of multiple injections of Noscapine using solid lipid nanoparticles. The data warrant further in vivo tumor regression studies for optimal management of glioblastoma, a generally very poorly treatable brain cancer.

Implications of nanoscale based drug delivery systems in delivery and targeting tubulin binding agent, noscapine in cancer cells.

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 ß-cyclodextrin (ß-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 µPAR-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.

Long-circulating poly(ethylene glycol)-grafted gelatin nanoparticles customized for intracellular delivery of noscapine: preparation, in-vitro characterization, structure elucidation, pharmacokinetics, and cytotoxicity analyses.

Noscapine, the tubulin-binding anticancer agent, when administered orally, requires high ED(50) (300-600 mg/kg), whereas intravenous administration (10 mg/kg) results in rapid elimination of the drug with a half-life of 0.39 h. Hence, the development of long-circulating injectable nanoparticles can be an interesting option for designing a viable formulation of noscapine for anticancer activity. Noscapine-enveloped gelatin nanoparticles and poly(ethylene glycol)-grafted gelatin nanoparticles were constructed and characterized. Data indicate that smooth and spherical shaped nanoparticles of 127 ± 15 nm were engineered with maximum entrapment efficiency of 65.32 ± 3.81%. Circular dichroism confirms that nanocoacervates retained the α-helical content of gelatin in ethanol whereas acetone favored the formation of a random coil. Moreover, the Fourier transform infrared and powder X-ray diffraction pattern prevents any significant change in the noscapine-loaded gelatin nanoparticles in comparison with individual components. In-vitro release kinetic data suggest a first-order release of noscapine (85.1%) from gelatin nanoparticles with a release rate constant of 7.611×10(-3). It is to be noted that there is a 1.43-fold increase in the area under the curve up to the last sampling point for the noscapine-loaded poly(ethylene glycol)-grafted gelatin nanoparticles over the noscapine-loaded gelatin nanoparticles and a 13.09-fold increase over noscapine. Cytotoxicity analysis of the MCF-7 cell line indicated that the IC(50) value of the noscapine-loaded poly(ethylene glycol)-grafted gelatin nanoparticles was equivalent to 20.8 µmol/l, which was significantly (P<0.05) lower than the IC(50) value of the noscapine-loaded gelatin nanoparticles (26.3 µmol/l) and noscapine (40.5 µmol/l).Noscapine-loaded poly(ethylene glycol)-grafted gelatin nanoparticles can be developed as a promising therapeutic agent for the management of breast cancer.

Enhanced noscapine delivery using uPAR-targeted optical-MR imaging trackable nanoparticles for prostate cancer therapy.

The tubulin-binding anticancer activity of noscapine, an orally available plant-derived anti-tussive alkaloid, has been recently identified. Noscapine inhibits tumor growth in nude mice bearing human xenografts of hematopoietic, breast, lung, ovarian, brain and prostate origin. Despite its nontoxic attributes, significant elimination of the disease has not been achieved, perhaps since the bioavailability of noscapine to tumors saturates at an oral dose of 300 mg/kg body weight. To enable the selective and specific delivery of noscapine to prostate cancer cells, we have engineered a multifunctional nanoscale delivery vehicle that takes advantage of urokinase plasminogen activator receptor (uPAR) overexpression in prostate cancer compared to normal prostate epithelia and can be tracked by magnetic resonance imaging (MRI) and near-infrared (NIR) imaging. Specifically, we employed the human-type 135 amino-acid amino-terminal fragment (hATF) of urokinase plasminogen activator (uPA), a high-affinity natural ligand for uPAR. Noscapine (Nos) was efficiently adsorbed onto the amphiphilic polymer coating of uPAR-targeted nanoparticles (NPs). Nos-loaded NPs were uniformly compact-sized, stable at physiological pH and efficiently released the drug at pH 4 to 5 within a span of 4h. Our results demonstrate that these uPAR-targeted NPs were capable of binding to the receptor and were internalized by PC-3 cells. uPAR-targeted Nos-loaded NPs enhanced intracellular noscapine accumulation as evident by the ~6-fold stronger inhibitory effect on PC-3 growth compared to free noscapine. In addition, Nos-loaded iron oxide NPs maintained their T2 MRI contrast effect upon internalization into tumor cells owing to their significant susceptibility effect in cells. Thus, our data provide compelling evidence that these optically and magnetic resonance imaging (MRI)-trackable uPAR-targeted NPs may offer a great potential for image-directed targeted delivery of noscapine for the management of prostate cancer.