Cancer cell targeting, controlled drug release and intracellular fate of biomimetic membrane-encapsulated drug-loaded nano-graphene oxide nanohybrids

摘要

Nano-graphene oxide (NGO) has been proposed as a novel drug carrier. However, its poor biocompatibility and physiological stability as well as the lack of cancer targeting ability have limited its further application in cancer therapy. To solve this problem, we developed a novel nanohybrid, NGO/DOX@SPC-FA, by first allowing a soy phosphatidylcholine (SPC) membrane to encapsulate DOX-loaded NGO (NGO/DOX) and then modifying the SPC membrane with a PEGylated lipid-FA conjugate to achieve the presentation of cancer targeting folic acid (FA) on the nanohybrid surface. The SPC membrane (mimicking cell membrane) endowed the resultant nanohybrids (NGO/DOX@SPC-FA) with good stability and biocompatibility, high drug loading capability, efficient cellular uptake, and controlled drug release. Moreover, compared with NGO/DOX and SPC-modified NGO/DOX (NGO/DOX@SPC), the FA-modified NGO/DOX@SPC nanohybrids (NGO/DOX@SPC-FA) could deliver NGO/DOX to cancer cells with improved delivery and killing efficacy due to the presence of FA targeting motifs on their surface. The NGO/DOX@SPC-FA nanohybrids were found to be internalized specifically by FA-positive cancer cells (HeLa cells) through both macropinocytosis-directed engulfment and clathrin-dependent endocytosis, and then become localized into lysosomes. The in vivo biodistribution study showed that NGO/DOX@SPC-FA had high tumor targeting ability because of the active targeting mechanism with FA modification. The in vivo antitumor therapy study demonstrated that NGO/DOX@SPC-FA could significantly inhibit tumour growth and prolong the survival time of mice. Our results suggested that NGO/DOX@SPC-FA, as a novel drug delivery system with high drug loading and targeted delivery efficiency, holds promise for future cancer therapy.