l-Histidine-based pH-sensitive anticancer drug carrier micelle: Reconstitution and brief evaluation of its systemic toxicity

Abstract

Adoxorubicin (DOX)-carrier micellar system consisting of poly(histidine)(5K)-b-poly(ethylene glycol)(2K) and poly(L-lactic acid)(3K)-b-PEG(2K)-folate has been developed targeting the early endosomal pH and it have been convincingly proved that intracellular high dose strategy using such micelles is effective in overcoming multidrug resistance (MDR) of cancer cells. Due to the low DOX concentrations in the micelle solution obtained by dialysis and the lack of long-term stability of the micelles, stable and lyophilized micelle formulations were the subject of investigation reported here by using excipients of sucrose, PEG or Pluronic. The reconstituted micelle solutions were examined by particle size, pH sensitivity, and cytotoxicity for MDR cells and the results were compared with the non-lyophilized micelles. Among tested excipients, Pluronic F127 (33 wt%) added to the polymer/drug solution prior to dialysis resulted in a reconstituted product stable for a week and presented equivalent benefits as the fresh micelle formulation. The blank micelles did not present any apparent systemic toxicity in mice up to 2400 mg/kg i.v. injection (800 mg/(kg day) for 3 days). The brief toxicity of reconstituted DOX loaded micelles was examined by the maximum tolerated dose (MTD), which was approximately 7.5-fold higher than free DOX and guaranteeing further animal toxicity and efficacy study.

Docetaxel-loaded-lipid-based-nanosuspensions (DTX-LNS): Preparation, pharmacokinetics, tissue distribution and antitumor activity

“…Animals also were weighed every other day during the experiment period. The body weights of mice were monitored as an index of systemic toxicity (Oh et al, 2008). After 21 days, the animals were killed, and the tumor mass was harvested, weighed and photographed.…”

pH-sensitive and folic acid-targeted MPEG-PHIS/FA-PEG-VE mixed micelles for the delivery of PTX-VE and their antitumor activity

“…25 Therefore, pH-sensitive micelles have been chosen as the most attractive candidate to deliver antitumor agents to the cytoplasm or the nucleus where they are supposed to function. Among them, poly(histidine) (PHIS) is a promising "proton sponge" polymer, [26][27][28] because the imidazole ring endows PHIS with an amphoteric nature by protonation-deprotonation, 29,30 which makes micelles escape from endosomes/lysosomes and trigger the accelerated release of encapsulated drugs. However, PHIS is too sensitive to environmental pH that may influence the stability of micelles at normal pH.…”

A Review of Select Recent Patents on Novel Nanocarriers

“…An example formulation given by the authors was a micellar delivery system consisting of poly(His)-PEG and PLLA-PEG-poly(His)-ligand polymers. In an article published regarding this work [32], it was reported that this formulation successfully showed an increase in nanoparticle size with decreasing pH, as well as improved the cytotoxicity of encapsulated doxorubicin against multidrug resistant cancer cells.…”