Hypoxia-Responsive Tetrameric Supramolecular Polypeptide Nanoprodrugs for Combination Therapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Photodynamic therapy (PDT) and chemotherapy (CT) show limitations in preventing solid tumor invasion, metastasis, and relapse.
• Tumor hypoxia reduces the efficacy of conventional cancer therapies.
• There is a need for advanced therapeutic strategies that overcome tumor hypoxia and enhance treatment outcomes.

Purpose of the Study:

• To construct a hypoxia-responsive tetrameric supramolecular polypeptide nanoprodrug (SPN-TAPP-PCB4) integrating both photodynamic and chemotherapy functions.
• To investigate the synergistic effects of PDT and CT delivered by the nanoprodrug in a tumor microenvironment.
• To evaluate the efficacy and safety of the developed nanoprodrug for cancer treatment.

Main Methods:

• Self-assembly of tetrameric porphyrin-central poly(l-lysine-azobenzene-chlorambucil) (TAPP-(PLL-Azo-CB)4) with anionic water-soluble [2]biphenyl-extended-pillar[6]arene (AWBpP6).
• Utilized hydrophobic, π-π stacking, and host-guest interactions for nanoprodrug construction.
• Investigated laser-triggered singlet oxygen generation for PDT and hypoxia-responsive drug release for CT.

Main Results:

• The SPN-TAPP-PCB4 demonstrated efficient self-assembly and stability.
• Laser irradiation triggered singlet oxygen production, leading to cancer cell death.
• The acidic and hypoxic tumor microenvironment induced nanoprodrug disassembly and release of activated chlorambucil (CB).
• In vitro and in vivo studies confirmed synergistic anti-tumor effects between PDT and CT with negligible toxicity.

Conclusions:

• The developed hypoxia-responsive supramolecular polypeptide nanoprodrug (SPN-TAPP-PCB4) effectively combines PDT and CT.
• This strategy overcomes tumor hypoxia-associated limitations and offers enhanced anti-cancer efficacy.
• SPN-TAPP-PCB4 presents a promising platform for developing advanced combination cancer therapies.