Smart Nanoparticles as Advanced Anti-Akt Kinase Delivery Systems for Pancreatic Cancer Therapy

• Published in: ACS applied materials & interfaces Vol. 13; no. 47; pp. 55790 - 55805
• Main Authors: Gonzalez-Valdivieso, Juan, Garcia-Sampedro, Andres, Hall, Andrew R, Girotti, Alessandra, Arias, Francisco Javier, Pereira, Stephen P, Acedo, Pilar
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.12.2021
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and Medical Applications of Materials and Interfaces; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Delivery Systems; Drug Screening Assays, Antitumor; Humans; Lysosomes - chemistry; Nanoparticles - chemistry; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Particle Size; Peptides - chemistry; Peptides - pharmacology; Polymers - chemical synthesis; Polymers - chemistry; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Surface Properties; nanoparticle; pancreatic cancer; drug delivery; Akt; elastin-like recombinamer
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.1c14592

Pancreatic cancer is one of the deadliest cancers partly due to late diagnosis, poor drug delivery to the target site, and acquired resistance to therapy. Therefore, more effective therapies are urgently needed to improve the outcome of patients. In this work, we have tested self-assembling genetically engineered polymeric nanoparticles formed by elastin-like recombinamers (ELRs), carrying a small peptide inhibitor of the protein kinase Akt, in both PANC-1 and patient-derived pancreatic cancer cells (PDX models). Nanoparticle cell uptake was measured by flow cytometry, and subcellular localization was determined by confocal microscopy, which showed a lysosomal localization of these nanoparticles. Furthermore, metabolic activity and cell viability were significantly reduced after incubation with nanoparticles carrying the Akt inhibitor in a time- and dose-dependent fashion. Self-assembling 73 ± 3.2 nm size nanoparticles inhibited phosphorylation and consequent activation of Akt protein, blocked the NF-κB signaling pathway, and triggered caspase 3-mediated apoptosis. Furthermore, in vivo assays showed that ELR-based nanoparticles were suitable devices for drug delivery purposes with long circulating time and minimum toxicity. Hence, the use of these smart nanoparticles could lead to the development of more effective treatment options for pancreatic cancer based on the inhibition of Akt.