Pteroyl-γ-l-glutamate/Pluronic® F68 modified polymeric micelles loaded with docetaxel for targeted delivery and reduced toxicity

Abstract

Targeting the cancerous cells is essential to improve the drug's efficacy and avoid toxicity to normal cells, which can be achieved by surface functionalizing the nanocarriers like polymeric micelles, using block copolymer with conjugation moiety. This could increase the drug-loaded nanocarriers targeting ability and avoid drug efflux by inhibiting P-gp. Cancer progression associated with a pro-tumorigenic tumor microenvironment with folate receptor (FR) can be treated by folic acid (FA) or pteroyl-γ-l-glutamate, a combination of pteroic acid and l-glutamic acid. The pteroyl-γ-l-glutamate modified carriers have FR targeting ability, whereas Pluronic® F68 has P-glycoprotein (P-gp) inhibition property. Therefore our study aimed to develop FA-linked Pluronic® F68 (FA-PF68) micelles for docetaxel trihydrate (DTX) delivery. The linkage of pteroyl-γ-l-glutamate and PF68 were preliminarily determined by UV- spectroscopy and was confirmed by DSC and FTIR. The encapsulation of DTX in micelles by thin-film hydration results in forming FA-PF68-DTX micelles. This surface functionalization demonstrated increased particle size upto 152.2 nm. Moreover, it shows better physical stability due to non-significant changes in ζ-potential. The spherical shape of FA-PF68-DTX micelles was observed in SEM with higher entrapment efficiency (94.75 ± 1.89 %). The sustained release of DTX of about 80.25 ± 1.53 % and 47.56 ± 0.89 % was observed during the first 24 h from FA-PF68-DTX and PF68-DTX micelles, respectively. The FA-PF68-DTX micelles show greater efficiency against MDA-MB-231 cells with lower viability. The histopathological study revealed the non-toxicity of FA-F68 conjugate on the liver, kidney and lung cells. It proved the potential of synthesized pteroyl-γ-l-glutamate/poly (ethylene glycol-propylene glycol-ethylene glycol) modified FA-PF68-DTX micelles for targeting the overexpressed FR on the tumor cells.