Unravelling the anticancer efficacy of 10-oxo-7-epidocetaxel: in vitro and in vivo results.

PURPOSE: To prepare 7-epidocetaxel (7ED) and 10-oxo-7-epidocetaxel (10-O-7ED) formulations as like marketed Taxotere® (TXT) injection and to screen them for in vitro and in vivo anticancer efficacy including their in vivo toxicity behavior. METHODS: The 7ED and 10-O-7ED formulations were screened for in vitro anti-proliferative, anti-metastatic and cell cycle arresting behaviors. Further, in vivo acute toxicity of TXT injection containing 10% of 7ED and 10-O-7ED separately and the therapeutic study of 10-O-7ED alone were studied in B16F10 experimental metastasis mouse model. RESULTS: 10-O-7ED caused significantly higher cytotoxicity after 48 and 72 h than 22 h study. 10-O-7ED showed significantly increased in vitro anti-metastatic activity than TXT. The TXT caused more arrest of cells at S phase, whereas 10-O-7ED arrested more at G2-M phase and vice versa at higher concentration. In vivo acute toxicity study revealed better therapeutic effect with reduced toxicity of TXT containing 10% 10-O-7ED than TXT alone. Similarly, the therapeutic study revealed significantly less number of surface metastatic nodules formation with 10-O-7ED treated group (107 ± 49) (***p < .0001) than control group (348 ± 56). Also, the control group showed significant weight loss at the end (20th day) of the experiment (*p < .05, p = .041) than 10-O-7ED treated group which showed about 4% increased mean group weight. CONCLUSION: Our study revealed the significantly higher in vivo anti-metastatic behavior, with no toxicity, of 10-O-7ED. However, it is a preliminary observation being noticed but further investigations are needed to address the potential of 10-O-7ED in cancer treatment with mechanisms behind the improved therapeutic efficacy with no toxicity.

Acylated chitosan anchored paclitaxel loaded liposomes: Pharmacokinetic and biodistribution study in Ehrlich ascites tumor bearing mice.

Acylated chitosan (Myristoyl and Octanoyl) coated paclitaxel-loaded liposomal formulation was developed with an aim to overcome the cremophor EL related toxicities. They were evaluated for drug entrapment, in vitro drug release, and cytotoxicity and cell uptake behavior using A549 cells. The 99mTc radio-labeled formulations were also evaluated in vivo in Ehrlich Ascites Tumor (EAT) bearing mice for biodistribution and tumor uptake. The mean particle size of both coated and uncoated liposomal formulations was found to be in the range of 180-200 nm with high drug entrapment efficiency (>90% in case of uncoated liposomes and 80 ±â€¯5% in case of coated liposomes). The uncoated liposomes displayed negative zeta potential (-10.5 ±â€¯4.9 mV) whereas coated liposomes displayed positive zeta potential in the range of +21 to +27 mV. Slower drug release was observed in case of liposomes coated with acylated chitosans as compared to uncoated and native chitosan coated liposomes. All liposomal formulations were found less cytotoxic than paclitaxel injection (Celtax™, Celon Labs, India). In vitro cell uptake and intracellular distribution studies confirmed the cytosolic delivery of uncoated and coated liposomes. The myristoyl chitosan coated liposomal system (LMC) exhibited improved pharmacokinetic, biodistribution and tumor uptake characteristics over other formulations. These obtained results confirmed the potential application of acylated chitosn coated liposomal delivery systems (LMC) in tumor targeting of paclitaxel and other drugs.

Anti-neuropilin 1 antibody Fab' fragment conjugated liposomal docetaxel for active targeting of tumours.

Neuropilin-1, a transmembrane receptor entailed in wide range of human tumour cell lines and diverse neoplasms, mediates the effects of VEGF and Semaphorins during the processes of cellular proliferation, survival and migration. In view of this, we had developed and evaluated in vitro and in vivo efficacy of anti-neuropilin-1 immunoliposomes against neuropilin-1 receptor expressing tumours. The PEGylated liposomes loaded with docetaxel were prepared using thin film hydration method. Functionalised PEGylated liposomes were prepared using post-insertion technique. Anti-neuropilin-1 immunoliposomes were prepared by covalently conjugating Fab' fragments of neuropilin-1 antibody to functionalised PEGylated liposomes via thioether linkage. In vivo evaluation of Taxotere and liposomal formulations was performed using intradermal tumour model to demonstrate anti-angiogenic and tumour regression ability. The modified Fab' fragments and immunoliposomes were found to be immunoreactive against A549 cells. Further, docetaxel loaded PEGylated liposomes and PEGylated immunoliposomes demonstrated higher in vitro cytotoxicity than Taxotere formulation at the same drug concentration and exposure time. The live imaging showed distinctive cellular uptake of functional immunoliposomes. Further, significant decrease in micro-blood vessel density and tumour volumes was observed using bio-engineered liposomes. The results clearly highlight the need to seek neuropilin-1 as one of the prime targets in developing an anti-angiogenic therapy.

Bone metastasis targeting: a novel approach to reach bone using Zoledronate anchored PLGA nanoparticle as carrier system loaded with Docetaxel.

In spite of good research in drug delivery, bone targeting remains largely unexplored. Even some of the bone diseases are seldom cured just because of poor distribution of drug at the bone site. Zoledronate (ZOL) having strong affinity towards bone and its utility in bone metastasis management makes it perfect ligand for bone targeting. Recent studies revealed that ZOL in combination with docetaxel showed significant synergism in the management of bone metastasis. From the results, it is clear that ZOL-conjugated PLGA nanoparticles (NPs) showed more cellular uptake than pegylated PLGA NPs with change in cellular uptake route. In vitro studies on MCF-7 and BO2 cell line revealed that ZOL anchored PLGA-PEG NPs showed enhanced cell cytotoxicity, increase in cell cycle arrest and more apoptotic activity. PLGA-PEG-ZOL NPs found to block mevalonate pathway and increase accumulation of apoptotic metabolites such as ApppI. In vivo animal studies using technetium-99m radiolabeling showed prolong blood circulation half-life, reduced liver uptake and significantly higher retention of ZOL tagged NPs at the bone site with enhanced tumor retention. Here, we can conclude that the targeting ability of ZOL enhanced by strong affinity to bone, enhanced endocytosis of ZOL anchored PLGA-PEG NPs.