Multistimuli-responsive PEGylated polymeric bioconjugate-based nano-aggregate for cancer therapy

Abstract Biocompatible, stimuli-responsive, intelligent and efficient drug delivery systems are essential for effectively suppressing cancer and reducing toxic side effects of chemotherapeutic drugs. Herein, two strategies have been employed to develop a N-(1,3-dihydroxypropan-2-yl) methacrylamide (DHPMA)-derived polymer carrier for doxorubicin (DOX) with a long circulation time: increasing molecular weight (MW) of the DHPMA polymer through an enzyme-responsive oligopeptide linker; and further grafting poly(ethylene glycol) (PEG) onto the polymer chain via a disulfide bond (pDHPMA-DOX-SS-mPEG), resulting in nano-aggregate. The nano-aggregate enters into 4T1 cells through multiple endocytosis pathways and DOX released in the presence of a low pH and reductive enzymes contributes to significant apoptosis by decreasing mitochondria membrane potential and disrupting actin cytoskeletons. Significantly enhanced tumor accumulation of the nano-aggregate is evidenced from ex vivo fluorescence imaging in comparison with the bioconjugate (pDHPMA-DOX) with no PEGylation. This is supported with a much longer terminal half-life time up to 16.9 h for pDHPMA-DOX-SS-mPEG, significantly higher than 10.4 h for pDHPMA-DOX and 2.7 h for free drug DOX. Accordingly, the best tumor inhibitive effect has been achieved by pDHPMA-DOX-SS-mPEG confirmed by significant reduction in tumor volumes and undetectable active proliferative cells and positive endotheliocytes from immunohistochemical staining of CD31 and Ki-67 in the 4T1 tumor tissue. The results demonstrate that increased MW through biodegradable linkers and grafted PEG significantly contribute to an extended circulation time, reduced systemic toxicity and an enhanced therapeutic efficacy. Tumor microenvironment-responsive PEGylated DHPMA-derived polymeric bioconjugate-based nano-aggregate offer the promising anti-tumor effect.