Enhanced anti-tumor efficacy of paclitaxel with PEGylated lipidic nanocapsules in presence of curcumin and poloxamer: In vitro and in vivo studies.

Cancer chemotherapeutic drug containing PEGylated lipidic nanocapsules (D-LNCs) were formulated by the controlled addition of organic phase (combined solution of paclitaxel and curcumin in a mixture of oleic acid and MPEG2000-DSPE (90:2.5 molar ratio) in acetone) to the aqueous phase (consist of Poloxamer 407 as emulsifying agents and glycerol as a co-solvent) at a temperature of 55-60°C followed by evaporation of organic solvent. The obtained pre-colloidal dispersion of D-LNCs was processed through high pressure homogenization to get more uniformly and nano-sized particles. Effect of concentration of emulsifying agent and process variables of high pressure homogenization (pressure and number of cycles) on average particle size and entrapment efficiency was further investigated by constructing Box-Behnken experimental design to achieve the optimum manufacturing process. D-LNCs were characterized by dynamic light scattering, scanning and transmission electron microscopy, Fourier transform infrared spectroscopy, and differential scanning calorimetry. In vitro release studies showed a sustained release pattern of drug from the PEGylated D-LNCs, whereas in vivo pharmacokinetic studies after a single-dose intravenous (i.v.) administration of paclitaxel (15mg/kg) in Ehrlich ascites tumor (EAT)-bearing female Swiss albino mice showed a prolonged circulation time and slower elimination of paclitaxel from D-LNCs as compared with marketed formulation (Paclitec®). From the plasma concentration vs. time profile, i.v. bioavailability (AUC0-∞) of paclitaxel from D-LNCs was found to be increased approximately 2.91-fold (P<0.001) as compared to Paclitec®. In vitro cell viability assay against MCF-7 and MCF-7/ADR cell lines, in vivo biodistribution studies and tumor inhibition study in EAT-bearing mice, all together prove its significantly improved potency towards cancer therapy.

Chondroitin sulfate-capped super-paramagnetic iron oxide nanoparticles as potential carriers of doxorubicin hydrochloride.

Chondroitin-4-sulfate (CS), a glycosaminoglycan, was used to prepare CS-capped super-paramagnetic iron oxide nanoparticles, which were further employed for loading a water-soluble chemotherapeutic agent (doxorubicin hydrochloride, DOX). CS-capped SPIONs have potential biomedical application in cancer targeting. The optimized formulation had a hydrodynamic size of 91.2±0.8nm (PDI; 0.228±0.004) and zeta potential of -49.1±1.66mV. DOX was loaded onto the formulation up to 2% (w/w) by physical interaction with CS. TEM showed nano-sized particles having a core-shell structure. XRD confirmed crystal phase of iron oxide. FT-IR conceived the interaction of iron oxide with CS as bidentate chelation and also confirmed DOX loading. Vibration sample magnetometry confirmed super-paramagnetic nature of nanoparticles, with saturation magnetization of 0.238emug(-1). In vitro release profile at pH 7.4 showed that 96.67% of DOX was released within 24h (first order kinetics). MTT assay in MCF7 cells showed significantly higher (p<0.0001) cytotoxicity for DOX in SPIONs than DOX solution (IC50 values 6.294±0.4169 and 11.316±0.1102µgmL(-1), respectively).

A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives.

In the modern world, a number of therapeutic proteins such as vaccines, antigens, and hormones are being developed utilizing different sophisticated biotechnological techniques like recombinant DNA technology and protein purification. However, the major glitches in the optimal utilization of therapeutic proteins and peptides by the oral route are their extensive hepatic first-pass metabolism, degradation in the gastrointestinal tract (presence of enzymes and pH-dependent factors), large molecular size and poor permeation. These problems can be overcome by adopting techniques such as chemical transformation of protein structures, enzyme inhibitors, mucoadhesive polymers and permeation enhancers. Being invasive, parenteral route is inconvenient for the administration of protein and peptides, several research endeavors have been undertaken to formulate a better delivery system for proteins and peptides with major emphasis on non-invasive routes such as oral, transdermal, vaginal, rectal, pulmonary and intrauterine. This review article emphasizes on the recent advancements made in the delivery of protein and peptides by a non-invasive (peroral) route into the body.

Transungual Delivery of Ketoconazole Nanoemulgel for the Effective Management of Onychomycosis.

Ketoconazole (KCZ) nanoemulgel containing permeation enhancer was formulated as a vehicle for transungual drug delivery, and its efficacy to inhibit the growth of onychomycotic dermatophytes was investigated in vitro. Different components of oil-in-water nanoemulsions were moderately agitated by classical titration method and passed through a high-pressure homogenizer to formulate various nanoemulsions, which were further identified by constructing pseudo-ternary phase diagrams. Stress-stability testing was carried out for the nanoemulsions, and those that passed these tests were characterized for mean droplet size, zeta potential, morphology, pH, refractive index, viscosity and transmittance. Mean droplet size and zeta potential of the optimized nanoemulsion (NE3) were found to be 77.52 ± 0.92 nm (polydispersity index (PDI) = 0.128 ± 0.035) and -5.44 ± 0.67 mV, respectively. Optimized nanoemulsion was converted into nanoemulgel (NEG1) with 1% (w/w) of gelling agent (Carbopol® Ultrez 21) and 1%-2% (v/v) thioglycolic acid as permeation enhancer, and evaluated for pH, viscosity, spreadability, extrudability, tensile strength and bio-adhesion measurement. In vitro cumulative drug released at the end of 24 h from NE3, NEG1 and drug suspension were found to be 98.87 ± 1.29, 84.42 ± 2.78% and 54.86 ± 2.19%, respectively. Ex vivo transungual permeation values for KCZ through goat hooves from NE3, NEG1 and drug suspension were found to be 62.49 ± 2.98, 77.54 ± 2.88% and 38.54 ± 2.54%, respectively, in 24 h. The antifungal effect of NEG1 on Trichophyton rubrum and Candida albicans showed a significant (p < 0.05) zone of inhibition as compared to drug solution. Skin irritation and histopathology studies on rat skin showed the safe topical use and enhanced permeation of formulated nanoemulgel.

Role of nanomedicines in delivery of anti-acetylcholinesterase compounds to the brain in Alzheimer's disease.

Alzheimer's disease (AD) is a multifarious progressive neuro-degenerative state among elders. Potentiation of central cholinergic activity by using acetylcholinesterase inhibitors (AChEI) is considered as one of the major pharmacological means for the management of AD. Investigation in the past and the rest decades revealed that many drugs with anti-AD activity, including the AChEI have been discovered from natural and synthetic origin but getting success in their brain delivery is still limited. However, barriers like blood-brain barrier, blood-cerebrospinal fluid barrier and p-glycoproteins restrict the effective and safe drug delivery to the brain in patients with AD. Advancement in nanotechnology-based drug delivery systems over the last decade exemplifies the effective drug delivery and targeting to the brain with controlled rate in various diseases including AD. Till recently, diverse kinds of nanomedicines for targeting of the anti-AD drugs in brain are being studied. In this review, we have highlighted the recent progress in AChEI, challenges in their effective brain delivery (physicochemical properties and biological barriers) and possible nanotechnology-based strategies that can deliver drugs across the CNS barriers during AD.

Transformation of curcumin from food additive to multifunctional medicine: nanotechnology bridging the gap.

Curcumin (CUR) is a yellow-coloured polyphenolic compound obtained from the rhizomes of Curcuma longa. In-depth pharmacological screening of curcumin has given the evidence that CUR persuades shielding and curative effects against various cancers, cardiovascular, wound healing effect and neuro disorders etc owning to anti-oxidant, antiproliferative, anti-inflammatory, anti-angiogenic and antimicrobial activities. However, miserable bioavailability due to poor aqueous solubility limits the application of CUR in various ailments. Different methodologies including the nanoparticle technology have been reported for the bioavailability enhancement of CUR. Nanoparticles exhibit not only the improvement in the solubility of CUR and alike lipophilic molecules (resulted in improved bioavailability) but also giving the opportunity for the disease specific cellular and organ targeting. Improved bioavailability and disease based site specific delivery of CUR is more likely to bring it as a safe multifunctional medicine.

Enhanced bioavailability of nano-sized chitosan-atorvastatin conjugate after oral administration to rats.

A novel approach to improve the bioavailability and stability of atorvastatin (AT) was developed by constructing a nano-sized polymer-atorvastatin conjugate. Firstly, a novel chitosan-atorvastatin (CH-AT) conjugate was efficiently synthesized through amide coupling reaction. The formation of conjugate was confirmed by (1)H NMR and FT-IR spectrometry. Nano-sized conjugate with a mean size of 215.3±14.2 nm was prepared by the process of high pressure homogenization (HPH). Scanning electron microscopy (SEM) revealed that CH-AT nano-conjugate possess smooth surface whereas X-ray diffraction (XRD) spectra demonstrated amorphous nature of nano-conjugate. Further, CH-AT nano-conjugate showed solubility enhancement of nearly 4-fold and 100-fold compared to CH-AT conjugate and pure AT, respectively. In vitro drug release studies in simulated gastric fluid and simulated intestinal fluid suggested sustained release of AT from the conjugate. Additionally, the nano-conjugate significantly reduced the acidic degradation of AT. The plasma-concentration time profile of AT after oral administration of CH-AT nano-conjugate (2574±95.4 ng/mL) to rat exhibited nearly 5-fold increase in bioavailability compared with AT suspension (583±55.5 ng/mL). Finally, variable bioavailability, as observed for AT suspension was also reduced when AT was administered in form of CH-AT nano-conjugate. Taken together these data demonstrate that chitosan conjugate nano-prodrugs may be used as sustained polymeric prodrugs for enhancing bioavailability.