Smart Nanoparticles as Advanced Anti-Akt Kinase Delivery Systems for Pancreatic Cancer Therapy
Juan Gonzalez-Valdivieso1, Andres Garcia-Sampedro2, Andrew R Hall2,3
1Smart Biodevices for NanoMed Group, University of Valladolid, Paseo Belén, Valladolid 47011, Spain.
Abstract:
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.
Insights
New elastin-like recombinamer nanoparticles effectively deliver Akt inhibitors to pancreatic cancer cells, reducing viability and triggering apoptosis. These smart nanoparticles show promise for improved pancreatic cancer treatment with minimal toxicity.
Area of Science:
- Biotechnology
- Nanomedicine
- Oncology
Background:
- Pancreatic cancer presents significant treatment challenges due to late diagnosis, poor drug delivery, and therapy resistance.
- Effective therapeutic strategies are crucial for improving patient outcomes in pancreatic cancer.
- Targeting key signaling pathways like Akt offers a potential therapeutic avenue.
Purpose of the Study:
- To evaluate the efficacy of self-assembling elastin-like recombinamer (ELR) nanoparticles carrying an Akt inhibitor for pancreatic cancer treatment.
- To assess nanoparticle uptake, localization, and impact on cancer cell viability and signaling pathways.
- To investigate the in vivo drug delivery potential and toxicity of ELR-based nanoparticles.
Main Methods:
- Genetically engineered ELRs were used to create self-assembling nanoparticles.
- Nanoparticle uptake and subcellular localization were analyzed using flow cytometry and confocal microscopy.
- Cell metabolic activity, viability, Akt phosphorylation, NF-κB pathway, and apoptosis were assessed.
- In vivo studies evaluated nanoparticle circulation time and toxicity.
Main Results:
- ELR nanoparticles demonstrated lysosomal localization within pancreatic cancer cells.
- Incubation with Akt inhibitor-loaded nanoparticles significantly reduced metabolic activity and cell viability in a time- and dose-dependent manner.
- Nanoparticles inhibited Akt phosphorylation, blocked the NF-κB pathway, and induced caspase 3-mediated apoptosis.
- In vivo assays confirmed long circulation times and minimal toxicity for ELR-based nanoparticles.
Conclusions:
- Self-assembling ELR nanoparticles are effective carriers for Akt inhibitors in pancreatic cancer.
- These nanoparticles show significant anti-cancer effects by inhibiting Akt signaling and inducing apoptosis.
- ELR-based nanoparticles represent a promising platform for developing advanced pancreatic cancer therapies with improved drug delivery and reduced toxicity.
