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Published on: February 17, 2023
Hypoxia-Responsive Tetrameric Supramolecular Polypeptide Nanoprodrugs for Combination Therapy
Yue Ding1, Wei Yu1, Rongkai Shen2
1School of Chemistry and Chemical Engineering, Nantong University, Nantong, 226019, P. R. China.
Abstract:
Despite the intense progress of photodynamic and chemotherapy, however, they cannot prevent solid tumor invasion, metastasis, and relapse, along with inferior efficacy and severe side effects. The hypoxia-responsive nanoprodrugs integrating photodynamic functions are highly sought to address the above-mentioned problems and overcome the tumor hypoxia-reduced efficacy. Herein, a hypoxia-responsive tetrameric supramolecular polypeptide nanoprodrug (SPN-TAPP-PCB4) is constructed from the self-assembly of tetrameric porphyrin-central poly(l-lysine-azobenzene-chlorambucil) (TAPP-(PLL-Azo-CB)4) and an anionic water-soluble [2]biphenyl-extended-pillar[6]arene (AWBpP6) via the synergy of hydrophobic, π-π stacking, and host-guest interactions. Upon laser irradiation, the central TAPP can convert oxygen to generate single oxygen (1 O2 ) to kill tumor cells. Furthermore, under the acidic and PDT-aggravated hypoxia tumor cell microenvironment, SPN-TAPP-PCB4 is rapidly disassembled, and then efficiently releases activated CB through the hypoxic-responsive cleavage of azobenzene linkages. Both in vitro and in vivo biological studies showcase synergistic cancer-killing actions between photodynamic therapy (PDT) and chemotherapy (CT) with negligible toxicity. Consequently, this supramolecular polypeptide nanoprodrug offers an effective strategy to design a hypoxia-responsive nanoprodrug for a potential combo PDT-CT transition.
Insights
This study introduces a novel hypoxia-responsive nanoprodrug that combines photodynamic therapy and chemotherapy. This dual-action approach effectively targets solid tumors, overcoming limitations of current treatments with minimal toxicity.
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.
