Combination of chemotherapy and gene therapy has become an emerging strategy for cancer treatment. Here, a well-defined polymer-drug conjugate (PDC) of pH-sensitive poly(ethylene glycol)-b-poly(dimethylaminoethylmethacrylate)-b-poly(2-hydroxyethylmethacrylate-formylbenzoic acid) (PEG-b-PDMAEMA-b-P(HEMA-FBA)) with doxorubicin (DOX) was developed for effective co-delivery of DOX and antisense oligonucleotide GTI2040 (a ribonucleotide reductase inhibitor) to MCF-7 breast cancer cells. A precursor triblock copolymer, PEG-b-PDMAEMA-b-PHEMA, was obtained by two consecutive atom transfer radical polymerization (ATRP) steps using a PEG-based macroinitiator. Subsequently, the PDC was developed by modifying the copolymer with 4-formybenzoic acid (FBA), followed by the conjugation of DOX via pH-responsive imine linkage. The PDC formed DOX-containing self-assembled nanoparticles (DOX-SAN) in aqueous solutions, which readily condensed with negatively charged GTI2040 gene to form stable GTI2040/DOX-SAN at N/P ratio of 30. Gel retardation assay confirmed the binding ability of GTI2040 with DOX-SAN, and dynamic light scattering (DLS) analysis showed that the GTI2040/DOX-SAN nanocomplex (N/P = 30) had a zeta potential of 21.0 mv and a hydrodynamic size of 136.4 nm. The DOX-SAN exhibited favorable pH-triggered release of DOX at pH 5.5. In vitro cytotoxicity study demonstrated the enhanced therapeutic efficacy of GTI2040/DOX-SAN nanocomplex compared with DOX-SAN treatment alone, due to downregulation of the R2 small subunit protein of ribonucleotide reductase involved in DNA synthesis. These results suggested that the pH-responsive self-assembled triblock copolymer is promising for combinatorial delivery of DOX and GTI2040 to inhibit cancer metastasis.

Well-defined pH-responsive self-assembled block copolymer for effective co-delivery of doxorubicin and antisense oligonucleotide to breast cancer cells

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.