Very low oral bioavailability due to extensive pre-systemic metabolism and P-gp efflux has constrained the oral metronomic chemotherapy of docetaxel (DTX). There is tremendous need of compounds facilitating oral delivery of DTX. The research was aimed to investigate the effect of piperlongumine (PPL) on human liver microsomal metabolism, Caco-2 permeability and cytotoxicity of DTX in triple negative breast cancer (TNBC) cell lines. Reduction in testosterone and DTX metabolism (2-fold increase in half-life) by piperlongumine was comparable to the standard CYP3A4 inhibitor, Cyclosporine A. P-gp efflux ratio of DTX across caco-2 monolayer was reduced from 2.37 to 1.52 on co-incubation with piperlongumine. The IC50 value of DTX was reduced 3-5 times and combination index values in all the cell lines were below 0.6. PPL at non-cytotoxic concentration showed significant enhancement of the anti-migration effect of DTX. Expression of tumor markers such as survivin, bcl2, C-myc and cyclin D1 were down regulated to a great extent with enhanced p53 expression when treated with combination instead of individual drug. Co-treatment with PPL led to 1.68 fold enhancement in DTX bioavailability in SD rats. Piperlongumine could be a potential candidate in overcoming the obstacles associated with oral docetaxel delivery with synergistic anticancer activity.

In this study, we demonstrate for the first time the concurrent transdermal delivery of erlotinib and IL36α siRNA as a potential dual therapy for psoriasis. The objectives were to develop and evaluate lipid nanocarriers (CYnLIP) using a novel pyrrolidinium lipid to disrupt the skin barrier for enhanced transdermal delivery. CYnLIP (132.00±6.23nm) had encapsulation efficiency of 49.04±2.54% for erlotinib. DSC confirmed encapsulation of erlotinib within CYnLIP. Atomic Force Microscopy demonstrated notable topographical changes in the stratum corneum of skin permeated with CYnLIP that were absent in skin hydrated with water. Peak force distance curves also exhibited a more permeable membrane for CYnLIP-incubated skin than hydrated skin. Permeation studies showed enhanced (p<0.01) skin retention of erlotinib by CYnLIP (40.76-fold) than solution and more pronounced fluorescence at deeper layers of the skin for fluorescein-labeled siRNA-CYnLIP than solution. The enhanced co-transdermal delivery of erlotinib and IL36α siRNA by CYnLIP efficaciously treated psoriatic-like plaques in C57BL/6 mice (PASI score of 1) compared to imiquimod-only treatment (PASI score of 4). IHC and western blotting revealed reduction in epidermal hyperplasia (Ki67) and in the dermal infiltration of inflammatory cytokines (IL36α, pSTAT3, TNFα, NFκB, IL23 and IL17) for erlotinib/IL36α siRNA-CYnLIP (p<0.05) comparable to Tacrolimus but markedly less than imiquimod-only treatment.

AimThe objective of this study was to formulate and evaluate a unique matrix mixture (nanomiemgel) of nanomicelle and nanoemulsion containing aceclofenac and capsaicin using in vitro and in vivo analyses and to compare it to a marketed formulation (Aceproxyvon).MethodsNanomicelles were prepared using Vitamin E TPGS by solvent evaporation method and nanoemulsion was prepared by high-pressure homogenization method. In vitro drug release and human skin permeation studies were performed and analyzed using HPLC. The efficiency of nanomiemgel as a delivery system was investigated using an imiquimod-induced psoriatic like plaque model developed in C57BL/6 mice.ResultsAtomic Force Microscopy images of the samples exhibited a globular morphology with an average diameter of 200, 250 and 220 nm for NMI, NEM and NMG, respectively. Nanomiemgel demonstrated a controlled release drug pattern and induced 2.02 and 1.97-fold more permeation of aceclofenac and capsaicin, respectively than Aceproxyvon through dermatomed human skin. Nanomiemgel also showed 2.94 and 2.09-fold greater Cmax of aceclofenac and capsaicin, respectively than Aceproxyvon in skin microdialysis study in rats. The PASI score, ear thickness and spleen weight of the imiquimod-induced psoriatic-like plaque model were significantly (p<0.05) reduced in NMG treated mice compared to free drug, NEM, NMI & Aceproxyvon.ConclusionUsing a new combination of two different drug delivery systems (NEM+NMI), the absorption of the combined system (NMG) was found to be better than either of the individual drug delivery systems due to the utilization of the maximum possible paths of absorption available for that particular drug.

Our observations demonstrate that F-NALPs can efficiently carry siSTAT3 and siTNF-α into the dermis and combination of the two nucleic acids can synergistically treat psoriatic-like plaques.

Aim: Therapeutic efficacy of anticancer nanomedicine is compromised by tumor stromal barriers. The present study deals with the development of docetaxel loaded PEGylated liposomes (DTXPL) and to investigate the effect of tumor stroma disrupting agent, telmisartan, on anticancer efficacy of DTXPL. Methods: DTXPL was prepared using proprietary modified hydration method. Effect of oral telmisartan treatment on tumor uptake of coumarin-6 liposomes and anticancer efficacy of DTXPL was evaluated in orthotopic xenograft lung tumor bearing mice. Results: DTXPL (105.7 ± 3.8 nm) showed very high physical stability, negligible hemolysis, 428% enhancement in bioavailability with significantly higher intratumoral uptake. Marked reduction in collagen-I, MMP2/9 and lung tumor weight were observed in DTXPL+telmisartan group. Conclusion: Combination of DTXPL with telmisartan could significantly enhance clinical outcome in lung cancer. Lung cancer is by far the most common cause of cancer related mortality in both men and women. Non-small-cell lung cancer (NSCLC) accounts for 87% of total cases of lung cancer with overall 5-year survival rate less than 18.2% [1,2]. Depending on the stage of lung cancer and condition of patients, the chemotherapeutic regimen for lung cancer includes following drugs: Cisplatin/carboplatin or paclitaxel/docetaxel, etoposide, vinorelbine, erlotinib or other tyrosine kinase inhibitors, gemcitabine and pemetrexed. Despite recent advances in diagnosis and treatment, the clinical outcome amongst NSCLC patients is still not impressive. Docetaxel (DTX) is one the most widely used for drug for the treatment of various types of solid tumor including ovarian, breast, lung and head/neck cancers. Docetaxel has extremely poor water solubility and rapid precipitation tendency, which necessitates very high concentration of ethanol and surfactant for its intravenous injection. Tween 80 in Taxotere ® formulation is responsible for severe life threatening hypersensitivity and peripheral neuropathy [3,4]. A safer formulation to enhance patient compliance and therapeutic efficacy of DTX is always in demand. As a result, current research is mainly focused on developing nanomedicinal formulation such as liposomes, polymeric micelles, albumin nanoparticles, polymer drug conjugates, etc. Liposomes are the most versatile nanocarrier with superior biocompatibility and large scale manufacturing feasibility compared to other types of nanocarrier. Abraxane ® ,

In the present study, we designed and developed novel lipids that include (Z)-1-(Octadec-9-en-1-yl)-pyrrolidine (Cy5T), 1, 1-Di-((Z)-octadec-9-en-1-yl)pyrrolidin-1-ium iodide (Cy5), (Z)-1-(Octadec-9-en-1-yl)-piperidine (Cy6T), and 1, 1-Di-((Z)-octadec-9-en-1-yl) piperidin-1-ium iodide (Cy6) to enhance the transdermal permeation of some selected drugs. Firstly, we evaluated the transdermal permeation efficacies of these lipids as chemical permeation enhancers in vehicle formulations for melatonin, ß-estradiol, caffeine, α-MSH, and spantide using franz diffusion cells. Among them Cy5 lipid was determined to be the most efficient by increasing the transdermal permeation of melatonin, ß-estradiol, caffeine, α-MSH, and spantide by 1.5 to 3.26-fold more at the epidermal layer and 1.3 to 2.5-fold more at the dermal layer, in comparison to either NMP or OA. Hence we developed a nanoparticle system (cy5 lipid ethanol drug nanoparticles) to evaluate any further improvement in the drug penetration. Cy5 lipid formed uniformly sized nanoparticles ranging from 150–200 nm depending on the type of drug. Further, Cy5 based nanoparticle system significantly (p<0.05) increased the permeation of all the drugs in comparison to the lipid solution and standard permeation enhancers. There were about 1.54 to 22-fold more of drug retained in the dermis for the Cy5 based nanoparticles compared to OA/NMP standard enhancers and 3.87 to 66.67-fold more than lipid solution. In addition, epifluorescent microscopic analysis in rhodamine-PE permeation studies confirmed the superior permeation enhancement of LEDs (detection of fluorescence up to skin depth of 340 μm) more than lipid solution, which revealed fluorescence up to skin depth of only 260 μm. In summary the present findings demonstrate that i) cationic lipid with 5 membered amine heterocyclic ring has higher permeating efficacy than the 6 membered amine hertocyclic ring. ii) The nanoparticle system prepared with Cy5 showed significant (p<0.05) increase in the permeation of the drugs than the control penetration enhancers, oleic acid and NMP.

Purpose In this study, we developed cationic ultra-flexible nanocarriers (UltraFLEX-Nano) to surmount the skin barrier structure and to potentiate the topical delivery of a highly lipophilic antioxidative diindolylmethane derivative (DIM-D) for the inhibition of UV-induced DNA damage and skin carcinogenesis. Methods UltraFLEX-Nano was prepared with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-3-trimethylammonium-propane, cholesterol and tween-80 by ethanolic injection method; was characterized by Differential Scanning Calorimetric (DSC), Fourier Transform Infrared (FT-IR) and Atomic Force Microscopic (phase-imaging) analyses and permeation studies were performed in dermatomed human skin. The efficacy of DIM-D-UltraFLEX-Nano for skin cancer chemoprevention was evaluated in UVB-induced skin cancer model in vivo. Results DIM-D-UltraFLEX-Nano formed a stable mono-dispersion (110.50±0.71nm) with >90% encapsulation of DIM-D that was supported by HPLC, DSC, FT-IR and AFM phase imaging. The blank formulation was non-toxic to human embryonic kidney cells. UltraFLEX-Nano was vastly deformable and highly permeable across the stratum corneum; there was significant (p<0.01) skin deposition of DIM-D for UltraFLEX-Nano that was superior to PEG solution (13.83-fold). DIM-D-UltraFLEX-Nano pretreatment delayed the onset of UVB-induced tumorigenesis (2 weeks) and reduced (p<0.05) the number of tumors observed in SKH-1 mice (3.33-fold), which was comparable to pretreatment with sunscreen (SPF30). Also, DIM-D-UltraFLEX-Nano caused decrease (p<0.05) in UV-induced DNA damage (8-hydroxydeoxyguanosine), skin inflammation (PCNA), epidermal hyperplasia (c-myc, CyclinD1), immunosuppression (IL10), cell survival (AKT), metastasis (Vimentin, MMP-9, TIMP1) but increase in apoptosis (p53 and p21). Conclusion UltraFLEX-Nano was efficient in enhancing the topical delivery of DIM-D. DIM-D-UltraFLEX-Nano was efficacious in delaying skin tumor incidence and multiplicity in SKH mice comparable to sunscreen (SPF30).

The objectives of this study were to develop an innovative investigative model using doxorubicin as a fluorophore to evaluate the skin permeation of nanocarriers and the impact of size and surface characteristics on their permeability. Different doxorubicin-loaded liposomes with mean particle size <130nm and different surface chemistry were prepared by ammonium acetate gradient method using DPPC, DOPE, Cholesterol, DSPE-PEG 2000 and 1,1-Di-((Z)-octadec-9-en-1-yl)pyrrolidin-1-ium chloride (CY5)/DOTAP/1,2-dioleoyl-sn-glycero-3-phosphate (DOPA) as the charge modifier. There was minimal release of doxorubicin from the liposomes up to 8 h; indicating that fluorescence observed within the skin layers was due to the intact liposomes. Liposomes with particle sizes >600nm were restricted within the stratum corneum. DOTAP (p<0.01) and CY5 (p<0.05) liposomes demonstrated significant permeation into the skin than DOPA and PEG liposomes. Tape stripping significantly (p<0.01) enhanced the skin permeation of doxorubicin liposomes but TAT-decorated doxorubicin liposomes permeated better (p<0.005). Blockage of the hair follicles resulted in significant reduction in the extent and intensity of fluorescence observed within the skin layers. Overall, doxorubicin liposomes proved to be an ideal fluorophore-based model. The hair follicles were the major route utilized by the liposomes to permeate skin. Surface charge and particle size played vital roles in the extent of permeation.