Nanoscaled Poly(l-glutamic acid)/Doxorubicin-Amphiphile Complex as pH-responsive Drug Delivery System for Effective Treatment of Nonsmall Cell Lung Cancer

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)-b-poly(L-glutamic acid) (mPEG-b-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-b-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-b-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-b-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-b-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-b-PLG-DOX·HCl as a valid therapeutic modality in the therapy of human NSCLC and other solid tumors.

HPV Oncogene Manipulation Using Nonvirally Delivered CRISPR/Cas9 or Natronobacterium gregoryi Argonaute

“…However, reduced transfection efficiency was observed (Figure 1E), likely attributed to the undesired blocking effect of the PEG corona on endocytosis 19. When the F127 blending ratio was kept at 1 while the DNA condensation ratio was increased to over 30, the micelle was able to transfect HeLa cells with an efficiency of 101.7 to 238.3%, and 60.9 to 121.7%, compared with the optimized formulation of PEI and Lipofectamine 2000, respectively (Figure 1E; Figure S2A, Supporting Information).…”

Self‐Stabilized Hyaluronate Nanogel for Intracellular Codelivery of Doxorubicin and Cisplatin to Osteosarcoma

“…On the contrary, CDDP3.3 HANG/DOX 5.4 was taken up by the cells via endocytosis pathway, which had a temperate efficiency at the outset and then revealed the enhanced fluorescence signal after effective drug release 17. In addition, DOX encapsulated in the nanogel could display weaker fluorescence intensity compared with free DOX at the same concentration, as a result of self‐quenching effect of fluorescent molecule 18.…”

Epirubicin-Complexed Polypeptide Micelle Effectively and Safely Treats Hepatocellular Carcinoma

“…In physiological pH environment (i.e., pH 7.4), only 41.3% of loaded EPI released after 24 h incubation, while the cumulative release reached 58.6 and 78.5%, respectively, for the same duration at pH 6.8 and 5.5, which mimicked the intratumoral and intracellular acidic microenvironments. These results might attribute to the disruption of electrostatic interaction between EPI and mPEG-b-PGA because of the deionization of PGA moiety (pKa = 4.5) and ionization of EPI (pKa = 7.7) as the decrease of pH [16,27]. In addition, the increased hydrophilicity of EPI in acid condition, which was much lower than the pKa of EPI, also resulted in the acidity-accelerated drug release [16].…”

“…These results might attribute to the disruption of electrostatic interaction between EPI and mPEG-b-PGA because of the deionization of PGA moiety (pKa = 4.5) and ionization of EPI (pKa = 7.7) as the decrease of pH [16,27]. In addition, the increased hydrophilicity of EPI in acid condition, which was much lower than the pKa of EPI, also resulted in the acidity-accelerated drug release [16]. Thus, mPEG-b-PGA/EPI with pH-sensitive property could realize the controlled drug release and might perform better pharmacokinetic characteristics in vivo compared with free EPI.…”