PLGA nanoparticle-mediated delivery of tumor antigenic peptides elicits effective immune responses

Wenxue Ma¹, Mingshui Chen¹, Sharmeela Kaushal^1,2, Michele McElroy^1,2, Yu Zhang³, Cengiz Ozkan³, Michael Bouvet^1,2, Carol Kruse⁴, Douglas Grotjahn⁵, Thomas Ichim⁶, Boris Minev<sup>1,7,8

1</sup>Moores Cancer Center, University of California San Diego, ²Department of Surgery, University of California San Diego, ³Laboratory of Biomaterials and Nanotechnology, University of California Riverside, ⁴UCLA Division of Neurosurgery, Los Angeles, ⁵Chemistry Department, San Diego State University, San Diego, ⁶MediStem Inc. San Diego, ⁷UCSD Division of Neurosurgery, San Diego, ⁸Genelux Corporation, San Diego, CA, USA

Abstract: The peptide vaccine clinical trials encountered limited success because of difficulties associated with stability and delivery, resulting in inefficient antigen presentation and low response rates in patients with cancer. The purpose of this study was to develop a novel delivery approach for tumor antigenic peptides in order to elicit enhanced immune responses using poly(DL-lactide-co-glycolide) nanoparticles (PLGA-NPs) encapsulating tumor antigenic peptides. PLGA-NPs were made using the double emulsion-solvent evaporation method. Artificial antigen-presenting cells were generated by human dendritic cells (DCs) loaded with PLGA-NPs encapsulating tumor antigenic peptide(s). The efficiency of the antigen presentation was measured by interferon-γ ELISpot assay (Vector Laboratories, Burlingame, CA). Antigen-specific cytotoxic T lymphocytes (CTLs) were generated and evaluated by CytoTox 96^® Non-Radioactive Cytotoxicity Assay (Promega, Fitchburg, WI). The efficiency of the peptide delivery was compared between the methods of emulsification in incomplete Freund’s adjuvant and encapsulation in PLGA-NPs. Our results showed that most of the PLGA-NPs were from 150 nm to 500 nm in diameter, and were negatively charged at pH 7.4 with a mean zeta potential of -15.53 ± 0.71 mV; the PLGA-NPs could be colocalized in human DCs in 30 minutes of incubation. Human DCs loaded with PLGA-NPs encapsulating peptide induced significantly stronger CTL cytotoxicity than those pulsed with free peptide, while human DCs loaded with PLGA-NPs encapsulating a three-peptide cocktail induced a significantly greater CTL response than those encapsulating a two-peptide cocktail. Most importantly, the peptide dose encapsulated in PLGA-NPs was 63 times less than that emulsified in incomplete Freund’s adjuvant, but it induced a more powerful CTL response in vivo. These results demonstrate that the delivery of peptides encapsulated in PLGA-NPs is a promising approach to induce effective antitumor CTL responses in vivo.

Keywords: peptide delivery, nanotechnology, dendritic cells, vaccination

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