In vivopharmacokinetics, biodistribution and anti-tumor effect of paclitaxel-loaded targeted chitosan-based polymeric micelle

Abstract

A water-insoluble anti-tumor agent, paclitaxel (PTX) was successfully incorporated into noveltargeted polymeric micelles based on tocopherol succinate-chitosan-polyethylene glycol-folic acid (PTX/TS-CS-PEG-FA). The aim of the present study was to evaluate the pharmacokinetics, tissue distribution and efficacy of PTX/TS-CS-PEG-FA in comparison to Anzatax Õ in tumor bearing mice. The micellar formulation showed higher in vitro cytotoxicity against mice breast cancer cell line, 4T1, due to the folate receptor-mediated endocytosis. The IC 50 value of PTX, a concentration at which 50% cells are killed, was 1.17 and 0.93 mM for Anzatax Õ and PTX/TS-CS-PEG-FA micelles, respectively. The in vivo anti-tumor efficacy of PTX/TS-CS-PEG-FA, as measured by reduction in tumor volume of 4T1 mouse breast cancer injected in Balb/c mice was significantly greater than that of Anzatax Õ . Pharmacokinetic study in tumor bearing mice revealed that the micellar formulation prolonged the systemic circulation time of PTX and the AUC of PTX/TS-CS-PEG-FA was obtained 0.83-fold lower than Anzatax Õ . Compared with Anzatax Õ , the V d , T 1/2ß and MRT of PTX/TS-CS-PEG-FA was increased by 2.76, 2.05 and 1.68-fold, respectively. As demonstrated by tissue distribution, the PTX/TS-CS-PEG-FA micelles increased accumulation of PTX in tumor, therefore, resulted in anti-tumor effects enhancement and drug concentration in the normal tissues reduction. Taken together, our evaluations show that PTX/TS-CS-PEG-FA micelle is a potential drug delivery system of PTX for the effective treatment of the tumor and systematic toxicity reduction, thus, the micellar formulation can provide a useful alternative dosage form for intravenous administration of PTX. KeywordsBiodistribution, in vivo anti-tumor effect, Paclitaxel, pharmacokinetics, targeted polymeric micelle History

A Rapid and Sensitive HPLC Method for Quantitation of Paclitaxel in Biological Samples using Liquid-Liquid Extraction and UV Detection: Application to Pharmacokinetics and Tissues Distribution Study of Paclitaxel Loaded Targeted Polymeric Micelles in.....

“…In this direction, numerous drug delivery carriers including emulsions (4,5), liposomes (6)(7)(8), nanoparticles (9)(10)(11), and polymeric micelles (12)(13)(14)(15) have been extensively studied for delivery of PTX into the cancer cells via parenteral administration. We have recently developed a novel targeted polymeric micelle formulation, through synthesizing tocopherol succinate-chitosan-polyethylene glycol-folate (TS-CS-PEG-FA), for delivering of PTX into cancer cells (16). PTX-loaded micelles (PTX/TS-CS-PEG-FA) exhibited decreased toxicity and increased efficacy compared to Anzatax ® (Cremophor ® EL-based formulation of PTX) in a breast tumor model in Balb/c mice (16).…”

Liver-targeting self-assembled hyaluronic acid-glycyrrhetinic acid micelles enhance hepato-protective effect of silybin after oral administration

“…Importantly, due to the small size of micelles, previous reports described that the drugloaded nanoparticles could be absorbed in intact form by enterocytes or M cells via endocytic pathway after oral administration (Mathot et al, 2007;Li et al, 2010;Al-Hilal et al, 2013). Thereafter, the micellar delivery system is possible to improve pharmacokinetic and biodistribution profiles, such as longer blood circulation and higher targeting activity by passive or active mechanisms (Lian et al, 2013;Rezazadeh et al, 2015).…”

Zonisamide-loaded triblock copolymer nanomicelles as a novel drug delivery system for the treatment of acute spinal cord injury

“…14,15 The hydrophobic segments of micelles become packed together in aggregates (core), which serve as a storage site for poorly water-soluble drugs and can act as a nanodepot for these agents. 16,17 The common advantage of these drug delivery systems is that micelles are resistant to glomerular filtration, which could extend their retention time in the blood. 18 Furthermore, micelles can facilitate the passage of drugs through the blood-brain barrier and blood-spinal cord barrier (BSCB), increasing therapeutic efficacy and safety compared to conventional pharmaceutical dosage forms.…”

“…However, complete release was not seen in this drug release studies, which may be due to the drug aggregating over time in the release medium or during the freezing of the release samples before measurement. 16,40,41 Inflammation plays a role in the progression of secondary SCI. The activated microglial cells can induce oxidative stress when cultured with neuronal cells.…”