Cellular Delivery of Doxorubicin via pH-Controlled Hydrazone Linkage Using Multifunctional Nano Vehicle Based on Poly(β-L-Malic Acid)

Abstract

Doxorubicin (DOX) is currently used in cancer chemotherapy to treat many tumors and shows improved delivery, reduced toxicity and higher treatment efficacy when being part of nanoscale delivery systems. However, a major drawback remains its toxicity to healthy tissue and the development of multi-drug resistance during prolonged treatment. This is why in our work we aimed to improve DOX delivery and reduce the toxicity by chemical conjugation with a new nanoplatform based on polymalic acid. For delivery into recipient cancer cells, DOX was conjugated via pH-sensitive hydrazone linkage along with polyethylene glycol (PEG) to a biodegradable, non-toxic and non-immunogenic nanoconjugate platform: poly(β-l-malic acid) (PMLA). DOX-nanoconjugates were found stable under physiological conditions and shown to successfully inhibit in vitro cancer cell growth of several invasive breast carcinoma cell lines such as MDA-MB-231 and MDA-MB- 468 and of primary glioma cell lines such as U87MG and U251.

Nanomedicine therapeutic approaches to overcome cancer drug resistance

“…In addition to T98G, the human glioblastoma cell line U251 is known to have MDR due to the high expression of P-glycoprotein and other ABC transporters. Another version of PMLA containing PEG, with Doxorubicin conjugated via pH-sensitive hydrazone linkage, was able to effectively inhibit growth of U251 more than Doxorubicin alone due to the modified drug uptake mechanism that evaded drug efflux pumps [112]. …”

Preparation and Characterization of Lipophilic Doxorubicin Pro-drug Micelles

“…This linker is stable at neutral pH and cleavable at acidic pH. 20,21 Thus, DOX is stably loaded in DSPE-PEG micelles as a pro-drug at neutral pH and has minimal drug leakage during storage and during circulation in the blood. Once DOX-PA micelles enter tumor cells through endocytosis, DOX-PA pro-drug will be cleaved and converted into free DOX in response to the acidic endosome environment (pH 5–6).…”

Covalent nano delivery systems for selective imaging and treatment of brain tumors

“…In a wider sense, the “assembly” module includes linkers that could be cleaved for e.g., drug release. Linkers connect the platform with functional modules including drugs, targeting antibodies or peptides, membrane destabilizing molecules or protecting molecules [11-23, 28, 39, 40]. Linkers such as peptides or polyethylene glycol (PEG) can vary in size and flexibility to allow a functional module approach, and interact optimally with its biological target such as a receptor or an enzyme active site, or anneal specifically with a nucleic acid of a given sequence.…”