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Recombinant Trichosanthin-Loaded Nanoparticles with Tumor-Targeting and Cell-Penetrating Capabilities for Activatable
Lian-Hua Fu1, Minghuan Zhang2, Zeyao Zhu3
1Marshall Laboratory of Biomedical Engineering, International Cancer Center, Laboratory of Evolutionary Theranostics (LET), School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
Abstract:
Trichosanthin (TCS), a type I ribosome-inactivating protein, exerts its cytotoxic effects by inhibiting protein synthesis through depurination of 28S rRNA, resulting in apoptosis and cancer cell death. However, insufficient tumor specificity and limited cell-penetrating capabilities have restricted its applications. Herein, we engineered a recombinant TCS by inserting low-molecular-weight protamine (LMWP) and matrix metalloproteinase-selective peptide (MSP), thereby constructing a recombinant fusion protein (rTCS-LMWP-MSP, namely, rTLM) with enhanced tumor-targeting and cell-penetrating capabilities. Subsequently, manganese-doped calcium phosphate (MnCaP) nanoparticles were fabricated by bovine serum albumin (BSA)-templated mineralization to serve as a pH-responsive delivery system, which not only improves the biocompatibility of rTLM but also enables payload release activated by the acidic tumor microenvironment. Upon accumulation of BSA-MnCaP-rTLM in tumor tissues, the extracellular matrix metalloproteinase 2 (MMP2) could recognize and cleave MSP. This process not only enables tumor-targeting capability but also exposes the inserted LMWP to enhance cell-penetrating capability. When internalized by tumor cells, BSA-MnCaP could be degraded, leading to the release of rTCS-LMWP, which induces cell apoptosis. Simultaneously, the released Mn2+ ions catalyze the conversion of endogenous H2O2 into harmful hydroxyl radicals via a Fenton-like reaction, thus promoting the oxidative stress in tumor cells. Both in vitro and in vivo experiments confirmed the synergistic antitumor effects of BSA-MnCaP-rTLM. Our findings indicate that BSA-MnCaP-rTLM holds significant potential for effective cancer treatment.
Insights
Engineered trichosanthin (TCS) with targeting peptides and loaded into pH-responsive nanoparticles enhances cancer cell apoptosis. This novel delivery system improves tumor specificity and cell penetration for effective cancer treatment.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- Trichosanthin (TCS) is a ribosome-inactivating protein that induces cancer cell death but lacks tumor specificity and cell penetration.
- Developing targeted drug delivery systems is crucial for enhancing the efficacy of cytotoxic agents like TCS.
Purpose of the Study:
- To engineer a novel recombinant fusion protein (rTLM) of TCS with targeting and cell-penetrating moieties.
- To develop a pH-responsive nanoparticle delivery system (BSA-MnCaP) for rTLM, enhancing tumor targeting and controlled release.
- To evaluate the synergistic antitumor effects of the BSA-MnCaP-rTLM system in vitro and in vivo.
Main Methods:
- Constructed a recombinant fusion protein (rTCS-LMWP-MSP, rTLM) by inserting low-molecular-weight protamine (LMWP) and matrix metalloproteinase-selective peptide (MSP) into TCS.
- Fabricated manganese-doped calcium phosphate (MnCaP) nanoparticles templated by bovine serum albumin (BSA) for pH-responsive drug delivery.
- Investigated the tumor-targeting, cell-penetrating, and synergistic antitumor effects of BSA-MnCaP-rTLM through in vitro and in vivo experiments.
Main Results:
- The engineered rTLM exhibited enhanced tumor-targeting and cell-penetrating capabilities.
- The BSA-MnCaP nanoparticles demonstrated pH-responsive release of rTLM in the acidic tumor microenvironment.
- The combined system (BSA-MnCaP-rTLM) showed synergistic antitumor effects, inducing apoptosis and oxidative stress in cancer cells.
- Manganese ions released from nanoparticles catalyzed Fenton-like reactions, generating hydroxyl radicals and enhancing oxidative stress.
Conclusions:
- The BSA-MnCaP-rTLM system effectively overcomes the limitations of TCS, offering improved tumor specificity and cellular uptake.
- The pH-responsive nanoparticle delivery system enhances biocompatibility and enables targeted payload release.
- This novel nanomedicine holds significant potential for effective cancer treatment through combined apoptosis induction and oxidative stress promotion.
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