Nanoscaled Poly(l‑glutamic acid)/Doxorubicin-Amphiphile
Complex as pH-responsive Drug Delivery System for Effective Treatment
of Nonsmall Cell Lung Cancer
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Abstract
Nonsmall cell lung cancer (NSCLC)
is the leading cause of cancer-related death worldwide. Herein, we
develop a polypeptide-based block ionomer complex formed by anionic
methoxy poly(ethylene glycol)-<i>b</i>-poly(l-glutamic
acid) (mPEG-<i>b</i>-PLG) and cationic anticancer drug doxorubicin
hydrochloride (DOX·HCl) for NSCLC treatment. This complex spontaneously
self-assembled into spherical nanoparticles (NPs) in aqueous solutions
via electrostatic interaction and hydrophobic stack, with a high loading
efficiency (almost 100%) and negative surface charge. DOX·HCl
release from the drug-loaded micellar nanoparticles (mPEG-<i>b</i>-PLG-DOX·HCl) was slow at physiological pH, but obviously
increased at the acidic pH mimicking the endosomal/lysosomal environment.
In vitro cytotoxicity and hemolysis assays demonstrated that the block
copolypeptide was cytocompatible and hemocompatible, and the presence
of copolypeptide carrier could reduce the hemolysis ratio of DOX·HCl
significantly. Cellular uptake and cytotoxicity studies suggested
that mPEG-<i>b</i>-PLG-DOX·HCl was taken up by A549
cells via endocytosis, with a slightly slower cellular internalization
and lower cytotoxicity compared with free DOX·HCl. The pharmacokinetics
study in rats showed that DOX·HCl-loaded micellar NPs significantly
prolonged the blood circulation time. Moreover, mPEG-<i>b</i>-PLG-DOX·HCl exhibited enhanced therapeutic efficacy, increased
apoptosis in tumor tissues, and reduced systemic toxicity in nude
mice bearing A549 lung cancer xenograft compared with free DOX·HCl,
which were further confirmed by histological and immunohistochemical
analyses. The results demonstrated that mPEG-<i>b</i>-PLG
was a promising vector to deliver DOX·HCl into tumors and achieve
improved pharmacokinetics, biodistribution and efficacy of DOX·HCl
with reduced toxicity. These features strongly supported the interest
of developing mPEG-<i>b</i>-PLG-DOX·HCl as a valid
therapeutic modality in the therapy of human NSCLC and other solid
tumors