Enzyme/pH-sensitive polyHPMA–DOX conjugate as a biocompatible and efficient anticancer agent

Abstract

In this study, to enhance the therapeutic function and reduce the side-effects of doxorubicin (DOX), a biodegradable N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-DOX conjugate has been prepared through reversible addition fragmentation chain transfer (RAFT) polymerization and conjugation chemistry, and the anticancer agent DOX was covalently linked to the polymeric vehicle through a pH-responsive hydrazone bond. The cellular mechanisms of the conjugate were explored, and the therapeutic indexes were studied as well. The high molecular weight (MW) polymeric conjugate (94 kDa) was degraded into products with low MW (45 kDa) in the presence of lysosomal cathepsin B and also showed pH-responsive drug release behavior. In vitro cellular mechanism studies revealed that the polymeric conjugate was uptaken by the 4T1 cells, leading to cell apoptosis and cytotoxicity to cancer cells, while the polymeric conjugate demonstrated excellent in vivo biosafety even at a high dose. Compared to free DOX, the conjugate has a much longer half-life in pharmacokinetics and accumulates in tumors with a much higher amount. The conjugate therefore has a much greater in vivo anticancer efficacy against 4T1 xenograft tumors and shows subtle side-effects, which were confirmed via tumor size and weight, immunohistochemistry and histological studies. Overall, this polymeric conjugate may be used as an enzyme/pH-sensitive anticancer agent.

Biodegradable Nanoparticles Mediated Co-delivery of Erlotinib (ELTN) and Fedratinib (FDTN) Toward the Treatment of ELTN-Resistant Non-small Cell Lung Cancer (NSCLC) via Suppression of the JAK2/STAT3 Signaling Pathway

“…Although the cytotoxicity of free drugs (ELTN+FDTN) was slightly greater than the co-delivery NPs, it could be attributed to the incomplete in vitro release of ELTN and FDTN from NPs in the absence of intratumoral acidic microenvironment. In comparison, drug-free NPs exhibited unremarkable cytotoxicity at high concentration up to 20 μM ELTN equivalent, which was reflective of the desired safety profiles of the NPs due to the use of biocompatible and biodegradable polymeric materials ( Jiao et al, 2018 ; Lv et al, 2018 ; Ou et al, 2018 ).…”

Review of the Mechanism of Nanocarriers and Technological Developments in the Field of Nanoparticles for Applications in Cancer Theragnostics

“…Some examples for the same are poly­(N-[2-hydroxypropyl]-methacrylamide) (polyHPMA) and HPMA. The HPMA-mediated drug conjugates, which are to be used for chemotherapy, have shown the potential to overcome MDR. , The pathway for the action is endocytosis, on the other hand, in the lysosome of the cell the hydrolysis of the conjugate of the polymer-drug took place with the help of an enzymatic reaction. Owing to this the drug is released from the conjugate.…”

Cancer Nanomedicine: A New Era of Successful Targeted Therapy

“…Drug-loaded sodium bis(2-ethylhexyl) sulfosuccinate (AOT)-alginate NPs significantly increased the chemotherapy cytotoxicity in resistant cells and overcome P-gp-mediated drug resistance [69]. [70,71]. The endocytosis pathway is the mechanism of action whereas the conjugation of polymer-drug was hydrolyzed by enzymatic reaction in the lysosome of the cells, resulting in the release of the drug from the conjugate.…”