Folate-Modified Poly(malic acid) Graft Polymeric Nanoparticles for Targeted Delivery of Doxorubicin: Synthesis, Characterization and Folate Receptor Expressed Cell Specificity.
A novel amphiphilic biodegradable cholesterol and poly(ethylene glycol)-folate grafted poly(α,β-malic acid) (PMA-g-Chol/PEG-FA) was synthesized and characterized as self-assembled nanoparticles for targeted delivery of doxorubicin (DOX). The nanoparticles showed extremely low critical aggregation concentrations (CAC), appropriate zeta potential, narrow size distribution, good stability in serum conditions and negligible toxicity. After encapsulation'of DOX, PMA-g-Chol/PEG-FA nanoparticles showed significantly reduced cell viability (up to 30% for Hela and 27% for 4T1 cells) compared with the non-targeted ones on carcinoma cells with different levels of folate receptor (FR) expression. While no difference was detected on HEK293 cells (FR receptor negative) between the two nanoparticles. Addition of extra free folate obviously decreased the cellular mortality and inhibited the cellular uptake of targeted nanoparticles. In the Hela/HEK293 co-culture model, folate conjugated nanoparticles showed specific affiliation with Hela cells other than HEK293 cells, indicating good targeting property of the delivery system. As detected from ex vivo fluorescent imaging, PMA-g-Chol/PEG-FA nanoparticles could accumulate at tumor site with higher selectivity compared to PMA-g-Chol/PEG nanoparticles and DOX x HCl. In vivo antitumor studies confirmed the significant tumor inhibition efficacy of drug-loaded PMA-g-Chol/PEG-FA nanoparticles with lower toxicity to normal tissues than DOX x HCI at the same dosage.
Yang
Y
Yang
Ning
N
Li
Yu
Y
Nie
Mingming
M
Sheng
Dong
D
Yue
Gang
G
Wang
James Z
JZ
Tang
Zhongwei
Z
Gu
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism*; D005492:Folic Acid / Q000737:chemistry / Q000493:pharmacokinetics*; D006367:HeLa Cells; D006801:Humans; D008293:Malates / Q000737:chemistry; D008297:Male; D008422:Materials Testing; D051379:Mice; D008807:Mice, Inbred BALB C; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D058726:Nanoconjugates / Q000008:administration & dosage / Q000737:chemistry / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D010316:Particle Size; D011108:Polymers / Q000737:chemistry; D013499:Surface Properties; D016896:Treatment Outcome
D000903:Antibiotics, Antineoplastic; D058973:Folate Receptors, GPI-Anchored; D008293:Malates; D053769:Nanocapsules; D058726:Nanoconjugates; D011108:Polymers; C121060:poly(malic acid); D004317:Doxorubicin; D005492:Folic Acid