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Few-Shot Identification of Active Therapeutic Peptide Networking with Gradient Dynamics against Cancer
Runzhi Xia1,2, Wei Sun1, Jiaming Liang2,3
1China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100029, P. R. China.
Abstract:
The treatment of osteosarcoma remains challenging due to limitations of chemotherapy. Anticancer peptides present a promising avenue as alternative therapeutic agents; however, they encounter significant drawbacks, including susceptibility to proteolytic degradation and constrained selectivity toward tumor. Herein, a few-shot peptide screening strategy is developed, yielding identification of RT2 (tumor-lytic peptide) and E16 (ionic-responsive self-assembling peptide). Their fusion E16-RT2 (ER) is engineered, exhibiting 175% enhanced tumor-selective cytotoxicity and cancer membrane targeting. By leveraging the dual functionality of ER, an injectable hydrogel encapsulating doxorubicin is developed, enabling gradient dynamics for tumor-specific drug release and sustained therapeutic efficacy (>9 d). Moreover, there is no systemic/organ toxicity in murine models dosed with the therapeutic network. The potential mechanism is proposed: charge-guided ER localization disrupts cancer membrane integrity, enabling therapeutics influx while sparing healthy cells, coupled with network degradation kinetics ensuring prolonged drug retention. This rational design paradigm establishes a clinically translatable platform combining tumor-perturbing peptides with smart biomaterials, effectively overcoming limitations of conventional agents. The demonstrated "safety-efficacy" profile positions this approach as a viable strategy for cancer treatment.
Insights
A novel peptide fusion (ER) enhances tumor-selective cancer cell killing and drug delivery. This injectable hydrogel platform shows high efficacy and no toxicity in preclinical models, offering a promising osteosarcoma treatment.
Area of Science:
- Biomaterials Science
- Oncology
- Drug Delivery
Background:
- Osteosarcoma treatment faces challenges with current chemotherapy limitations.
- Anticancer peptides offer potential but suffer from degradation and poor tumor selectivity.
- Developing targeted and effective cancer therapies is a critical unmet need.
Purpose of the Study:
- To engineer a novel peptide-drug conjugate for enhanced osteosarcoma treatment.
- To develop an injectable hydrogel system for controlled drug release and improved therapeutic outcomes.
- To evaluate the safety and efficacy of the novel therapeutic platform in preclinical models.
Main Methods:
- A few-shot peptide screening strategy identified RT2 and E16 peptides.
- Engineered a fusion peptide E16-RT2 (ER) with enhanced tumor-selective cytotoxicity.
- Developed an injectable hydrogel encapsulating doxorubicin with gradient release dynamics.
Main Results:
- The engineered ER peptide demonstrated 175% enhanced tumor-selective cytotoxicity and cancer membrane targeting.
- The hydrogel system provided sustained therapeutic efficacy for over 9 days.
- No systemic or organ toxicity was observed in murine models.
Conclusions:
- The ER peptide-hydrogel platform effectively overcomes limitations of conventional chemotherapy for osteosarcoma.
- The dual functionality of ER peptides and smart biomaterials offers a clinically translatable approach.
- The demonstrated safety-efficacy profile positions this platform as a viable strategy for cancer treatment.
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