Toward Personalized Peptide-Based Cancer Nanovaccines: A Facile and Versatile Synthetic Approach

• Published in: Bioconjugate chemistry Vol. 28; no. 11; pp. 2756 - 2771
• Main Authors: Kakwere, Hamilton, Ingham, Elizabeth S, Allen, Riley, Mahakian, Lisa M, Tam, Sarah M, Zhang, Hua, Silvestrini, Matthew T, Lewis, Jamal S, Ferrara, Katherine W
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15.11.2017
• Subjects: Alkynes; Alkynes - chemistry; Amino acids; Animals; Antigen-presenting cells; Antigens; Azides - chemistry; Biocompatibility; Cancer; Cancer immunotherapy; Cancer vaccines; Cancer Vaccines - chemistry; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; Cell Line, Tumor; Chemical synthesis; Click Chemistry; Conjugation; CpG islands; Cytometry; Dendritic cells; Electron microscopy; Epitopes; Female; Flow cytometry; Hydrophobicity; Immune clearance; Immune system; Immunogenicity; Immunotherapy; In vivo methods and tests; Light scattering; Melanoma; Melanoma, Experimental - drug therapy; Melanoma, Experimental - immunology; Membrane Proteins - chemistry; Membrane Proteins - immunology; Membrane Proteins - therapeutic use; Mice; Mice, Inbred C57BL; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - therapeutic use; Peptide Fragments - chemistry; Peptide Fragments - immunology; Peptide Fragments - therapeutic use; Peptides; Peptides - chemistry; Peptides - immunology; Peptides - therapeutic use; Photon correlation spectroscopy; Precision Medicine; Self-assembly; Toxicity; Transmission electron microscopy; Tumors; Vaccines
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.7b00502

Personalized cancer vaccines (PCVs) are receiving attention as an avenue for cancer immunotherapy. PCVs employ immunogenic peptide epitopes capable of stimulating the immune system to destroy cancer cells with great specificity. Challenges associated with effective delivery of these peptides include poor solubility of hydrophobic sequences, rapid clearance, and poor immunogenicity, among others. The incorporation of peptides into nanoparticles has the potential to overcome these challenges, but the broad range of functionalities found in amino acids presents a challenge to conjugation due to possible interferences and lack of reaction specificity. Herein, a facile and versatile approach to generating nanosized PCVs under mild nonstringent conditions is reported. Following a simple two-step semibatch synthetic approach, amphiphilic hyperbranched polymer–peptide conjugates were prepared by the conjugation of melanoma antigen peptides, either TRP2 (hydrophobic) or MUT30 (hydrophilic), to an alkyne functionalized core via strain-promoted azide–alkyne click chemistry. Self-assembly of the amphiphiles gave spherical nanovaccines (by transmission electron microscopy) with sizes in the range of 10–30 nm (by dynamic light scattering). Fluorescently labeled nanovaccines were prepared to investigate the cellular uptake by antigen presenting cells (dendritic cells), and uptake was confirmed by flow cytometry and microscopy. The TRP2 nanovaccine was taken up the most followed by MUT30 nanoparticles and, finally, nanoparticles without peptide. The nanovaccines showed good biocompatibility against B16–F10 cells, yet the TRP2 peptide showed signs of toxicity, possibly due to its hydrophobicity. A test for immunogenicity revealed that the nanovaccines were poorly immunogenic, implying the need for an adjuvant when administered in vivo. Treatment of mice with melanoma tumors showed that in combination with adjuvant, CpG, groups with the peptide nanovaccines slowed tumor growth and improved survival (up to 24 days, TRP2) compared to the untreated group (14 days).