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Delivery of a Cancer-Testis Antigen-Derived Peptide Using Conformationally Restricted Dipeptide-Based Self-Assembled
Priyanka Verma1, Saikat Biswas1, Nitin Yadav1
1International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India.
Abstract:
Use of tumor-associated antigens for cancer immunotherapy is limited due to their poor in vivo stability and low cellular uptake. Delivery of antigenic peptides using synthetic polymer-based nanostructures has been actively pursued but with limited success. Peptide-based nanostructures hold much promise as delivery vehicles due to their easy design and synthesis and inherent biocompatibility. Here, we report self-assembly of a dipeptide containing a non-natural amino acid, α,β-dehydrophenylalanine (ΔF), into nanotubes, which efficiently entrapped a MAGE-3-derived peptide (M3). M3 entrapped in F-ΔF nanotubes was more stable to a nonspecific protease treatment and both F-ΔF and F-ΔF-M3 showed no cellular toxicity for four cancerous and noncancerous cell lines used. F-ΔF-M3 showed significantly higher cellular uptake in RAW 267.4 macrophage cells compared to M3 alone and also induced in vitro maturation of dendritic cells (DCs). Immunization of mice with F-ΔF-M3 selected a higher number of IFN-γ secreting CD8+ T cells and CD4+ T compared to M3 alone. On day 21, a tumor growth inhibition ratio (TGI, %) of 41% was observed in a murine melanoma model. These results indicate that F-ΔF nanotubes are highly biocompatible, efficiently delivered M3 to generate cytotoxic T lymphocytes responses, and able to protect M3 from degradation under in vivo conditions. The F-ΔF dipeptide-based nanotubes may be considered as a good platform for further development as delivery agents.
Insights
Novel peptide nanotubes efficiently deliver cancer antigens for immunotherapy, enhancing stability and immune response. This biocompatible platform shows promise for cancer treatment by improving antigen uptake and generating cytotoxic T lymphocytes.
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Immunotherapy
Background:
- Current cancer immunotherapy faces challenges with tumor-associated antigen stability and cellular uptake.
- Synthetic polymer nanostructures for peptide delivery have shown limited success.
- Peptide-based nanostructures offer advantages in design, synthesis, and biocompatibility.
Purpose of the Study:
- To develop a novel peptide-based nanostructure for improved delivery of cancer antigens.
- To evaluate the stability, cellular uptake, and immunogenicity of the developed nanostructure.
- To assess the therapeutic efficacy of the nanostructure in a preclinical cancer model.
Main Methods:
- Self-assembly of a dipeptide (F-ΔF) containing a non-natural amino acid (α,β-dehydrophenylalanine) into nanotubes.
- Entrapment of a MAGE-3 derived peptide (M3) within the F-ΔF nanotubes.
- Assessment of protease stability, cellular toxicity, cellular uptake, dendritic cell maturation, T cell responses, and tumor growth inhibition in a murine melanoma model.
Main Results:
- F-ΔF nanotubes efficiently entrapped M3, enhancing its stability against protease degradation.
- F-ΔF and F-ΔF-M3 exhibited no cellular toxicity and demonstrated significantly higher cellular uptake in macrophages compared to M3 alone.
- F-ΔF-M3 induced dendritic cell maturation, increased cytotoxic T lymphocyte responses, and achieved 41% tumor growth inhibition in mice.
Conclusions:
- F-ΔF dipeptide-based nanotubes are a highly biocompatible and effective platform for delivering cancer antigens.
- The nanostructure protects antigens from degradation and enhances their uptake, leading to potent anti-tumor immune responses.
- This peptide nanotube system holds significant potential for the development of advanced cancer immunotherapy delivery agents.
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