Gemcitabine-Doxorubicin Combination Polymer-Drug Conjugate Prepared by SPAAC Click Chemistry: In Vitro...

Area of Science:

• Biomedical Engineering
• Polymer Chemistry
• Oncology

Background:

• Ovarian cancer (OC) treatment often relies on combination chemotherapy, but systemic toxicity limits efficacy.
• Polymer-drug conjugates (PDCs) offer a strategy to enhance therapeutic efficacy by combining synergistic drugs.
• Previous work established a strain-promoted [3 + 2] azide-alkyne cycloaddition (SPAAC) method for single-drug PDCs.

Purpose of the Study:

• To prepare and evaluate a novel gemcitabine-doxorubicin combination polymer-drug conjugate (PDC) for ovarian cancer (OC) therapy.
• To assess the drug release characteristics, cytotoxicity, and therapeutic potential of the combination PDC.
• To investigate the synergistic effects of combined gemcitabine and doxorubicin delivered via a PDC system.

Main Methods:

• Utilized a SPAAC-mediated polymerization method to synthesize a gemcitabine-doxorubicin combination PDC.
• Characterized the PDC for molecular weight and drug loading (gemcitabine: 36.6%, doxorubicin: 7.0%).
• Assessed drug release at pH 5.0 (cathepsin B-catalyzed) and hydrolytic stability at pH 7.4.
• Evaluated cytotoxicity against OVCAR-3 OC cells using combination index analysis and IC50 determination.

Main Results:

• The combination PDC exhibited a high molecular weight (1360 kDa) and substantial drug loading.
• The PDC demonstrated controlled drug release, triggered by cathepsin B at acidic pH, with stability at physiological pH.
• The combination PDC showed significantly greater cytotoxicity against OVCAR-3 cells (IC50 = 0.99 µg/mL) compared to individual drug PDCs.
• Synergistic effects were observed for free gemcitabine and doxorubicin in OVCAR-3 cells, with the combination PDC displaying potent anti-cancer activity.

Conclusions:

• The developed gemcitabine-doxorubicin combination PDC is a promising platform for targeted combination chemotherapy in ovarian cancer.
• The SPAAC polymerization method effectively produced a high-performance PDC with synergistic drug delivery capabilities.
• This approach holds potential for improving the therapeutic index and efficacy of ovarian cancer treatment by mitigating systemic toxicity.