Self-Assembling ELR-Based Nanoparticles as Smart Drug-Delivery Systems Modulating Cellular Growth via Akt

Abstract

This work investigates the physicochemical properties and in vitro accuracy of a genetically engineered drug delivery system based on elastin-like block recombinamers. The DNA recombinant technics allowed us to create this smart complex polymer containing bioactive sequences for internalization, lysosome activation under acidic pH and blockage of cellular growth by a small peptide inhibitor. The recombinant polymer reversibly self-assembled, when temperature was increased above 15°C, into nanoparticles with a diameter of 72 nm and negative surface charge. Furthermore, smart nanoparticles were showed to enter in the cells via clathrin-dependent endocytosis, and properly blocked phosphorylation and consequent activation of Akt kinase. This system provoked apoptosis-mediated cell death in breast and colorectal cancer cells, which possess higher expression levels of Akt, whereas non-cancerous cells, such as endothelial cells, fibroblasts and mesenchymal stem cells, were not affected. Hence, we conclude that the conformational complexity of this smart elastinlike recombinamer leads to achieve successful drug delivery in targeted cells and could be a promising approach as nanocarriers with bioactive peptides in order to modulate multiple cellular processes involved in different diseases.

Utilizing a Kidney-Targeting Peptide to Improve Renal Deposition of a Pro-Angiogenic Protein Biopolymer

“…It is also possible to design di-block ELPs containing a hydrophobic, low-transition temperature block and a hydrophilic, high-transition temperature block, which form nanoparticles at physiologic temperatures [15]. These constructs were used for chemotherapy and anti-cancer peptide delivery [16,17], ocular drug delivery [18], and immunotherapy [19], among others. If the transition temperature is tuned just above body temperature, ELPs can be used as carriers for thermally targeted drug delivery.…”

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

“…Our therapeutic construct included an Akt-in peptide, which inhibits the phosphorylation of the protein kinase Akt at serine 473. 28,35 This step is key for Akt cytoplasmic activation and its kinase activity regulating multiple signaling pathways. 25 Moreover, other bioactive sequences were added in order to allow the controlled release of the therapeutic inhibitor in the target cells.…”

“…32−34 In the present work, we have studied the effect of a novel therapeutic treatment based on smart self-assembling ELR NPs for controlled and precise drug delivery of an Akt inhibitor to patient-derived pancreatic cancer cells. Although these ELR NPs were previously characterized and studied in breast and colorectal in vitro cancer cell cultures, 35 this is the first time these NPs have been evaluated as a novel strategy for PDAC therapy, in patient-derived models, as a first step toward the development of a novel therapy. Therefore, we developed an advanced nanocarrier for controlled drug delivery, which could be a promising treatment for pancreatic cancer in combination with chemotherapy.…”

A double safety lock tumor-specific device for suicide gene therapy in breast cancer

“…In addition, tumor-specific promoters provide a safe and effective strategy for designing gene-therapy systems that can be adapted for use with various tumors or delivery systems. To date, ELRs and other polymers widely used as non-viral vectors, such as poly-lysine (PLL), polyethylenimine (PEI), polyethyleneglycol (PEG), chitosan, poly(lactic-co-glycolic acid) (PLGA), or poly(2-dimethylaminoethyl methacrylate) (pDMAEMA) [20], have found increasing applications in biomedicine due their inherent biocompatibility and smart properties [21][22][23][24][25][26][27][28][29]. A previous study showed the ability of ELRs joined to functional peptides to be used as delivery vectors with no cellular effects in vitro [30].…”