Cabazitaxel-Loaded Nanocarriers for Cancer Therapy with Reduced Side Effects.

Jevtana® is a micellar cabazitaxel (CBZ) solution that was approved for prostate cancer in 2010, and recently, this drug has been reported for breast cancer. The purpose of this study is to evaluate the mediated delivery of CBZ via liposomes and nanoparticles (NPs) for the treatment of breast cancer and compare these with a micellar formulation that is currently in clinical use. CBZ-loaded nanocarriers were prepared with particle sizes between 70⁻110 nm, and with the sustained in vitro release of CBZ for more than 28 days. Cytotoxicity studies on MCF-7 and MDA-MB-231 cells demonstrated the toxic potential of these nanocarriers. Cellular internalization revealed that NPs and liposomes have better permeability than micelles. Cell cycle analysis and apoptosis studies on MCF-7 and MDA-MB-231 cells confirmed G2/M phase arrest as well as cell death due to apoptosis and necrosis, where formulations were found to be effective compared to a micellar CBZ solution. Results from pharmacokinetic studies revealed that there is an increased circulation half-life and mean residence time for CBZ liposomes and NPs in comparison with a micellar CBZ solution. CBZ liposomes and NPs showed a reduction in hemolysis and neutropenia in comparison with a micellar CBZ solution in rats.

Dendrimer mediated targeting of siRNA against polo-like kinase for the treatment of triple negative breast cancer.

Irresponsiveness of triple negative breast cancer (TNBC) toward conventional therapies has drawn attention toward siRNA therapeutics. In gene delivery, dendrimers are gaining significant attention due to their characteristic features and polo-like kinase (PLK1) is reported as a potential target for TNBC. In this work, phosphorus and polyamidoamine dendrimer (generation 3 and 4 of each type) are explored to address delivery challenges of PLK1 siRNA (siPLK1). Dendriplexes were formed and complexation was found at 3:1 N/P ratio for all dendrimers by gel electrophoresis. Complexation was also supported by zeta potential, circular dichroism and intercalation assay. Dendriplexes were found to be stable in presence of ribonuclease and serum. Dendriplexes resulted in enhanced cell uptake of siPLK1 compared to siPLK1 solution in MDA-MB-231 and MCF-7 cells. Dendriplexes caused increased cell arrest in sub-G1 phase compared to solution. These observations suggested phosphorus and polyamidoamine dendrimers as potential carriers for siPLK1 delivery to treat TNBC.

Cabazitaxel and silibinin co-encapsulated cationic liposomes for CD44 targeted delivery: A new insight into nanomedicine based combinational chemotherapy for prostate cancer.

Cancer stem cells (CSCs) are the promising targets for cancer chemotherapy that cannot be eliminated by conventional chemotherapy. In this study cationic liposomes of cabazitaxel (CBX) and silibinin (SIL) were prepared with an aim to kill cancer cells and CSCs for prostate cancer. CBX act as cancer cell inhibitor and SIL as CSC inhibitor. Hyaluronic acid (HA), an endogenous anionic polysaccharide was coated on cationic liposomes for targeting CD44 receptors over expressed on CSCs. Liposomes were prepared by ethanol injection method with particle size below 100 nm and entrapment efficiency of more than 90% at 10% w/w drug loading. Liposomes were characterized by dynamic light scattering, transmission electron microscopy, 1H nuclear magnetic resonance and scanning electron microscopy-energy dispersive x-ray spectroscopy. Liposomes were evaluated for their anticancer action in androgen independent human prostate cancer cell lines (PC-3 and DU-145). HA coated liposomes showed potential cytotoxicity over other groups with low IC50, significantly inhibited cell migration and induced apoptosis. Synergistic cytotoxic effect was also observed with HA coated liposomes that resulted in colony formation inhibition and G2/M phase arrest. Proficient cytotoxicity against CD44+ cells (14.87 ± 0.41% in PC-3 and 33.95 ± 0.68% in DU-145 cells) indicated the efficiency of HA coated liposomes towards CSC targeting. Hence, the outcome of this combinational therapy with CD44 targeting indicates the suitability of HA coated CBX and SIL co-loaded liposomes as a potential approach for eradicating prostate cancer and herein might provide a insight for future studies.

Development and in vitro assessment of psoralen and resveratrol co-loaded ultradeformable liposomes for the treatment of vitiligo.

Vitiligo is a de-pigmenting skin disorder characterized by white patches on skin due to partial or complete loss of melanocytes. Psoralen in combination with ultraviolet-A (PUVA) acts by stimulation of melanin content and tyrosinase activity in melanocytes. Resveratrol, a sirtuin activator and a potential anti-oxidant reduce oxidative stress which is one of the triggering factors for initiation of vitiligo. Despite their therapeutic activity, weak percutaneous permeability of psoralen and poor solubility of resveratrol hinders their effective topical administration. The aim of present study is to formulate ultradeformable liposomes (UDL) co-loaded with psoralen and resveratrol for evaluation of PUVA and anti-oxidant combination in vitiligo treatment. For this purpose, UDL composed of DC-Chol, cholesterol and sodium deoxy cholate were prepared for their co-delivery. Liposomal carriers were characterized and evaluated for their efficacy using B16F10 cell line. Free radical scavenging potential was also determined for these carriers by in vitro anti-oxidant assays. Optimal co-loaded UDL with particle size ranging from 120 to 130nm, zeta potential of +46.2mV, entrapment efficiency of 74.09% (psoralen) and 76.91% (resveratrol) were obtained. Compared to control, co-loaded UDL showed significant stimulation of melanin and tyrosinase activity with major contribution of psoralen. Further, co-loaded UDL also exhibited potential free radical scavenging activity where resveratrol played a key role. Hence, psoralen and resveratrol co-loaded UDL acts in vitiligo through dual mechanisms of action viz., stimulation of melanin and tyrosinase activity as well as by anti-oxidant activity. These findings indicate that psoralen and resveratrol co-loaded UDL has the promising therapeutic potential for the treatment of vitiligo.