The mitochondria’s complexity and its novel roles in human health and disease are becoming increasingly evident, and the need to therapeutically target mitochondria is more urgent. Beyond its role in primary energy development, mitochondria are now recognized to play critical roles in cell regulatory processes, production of essential cell proliferation building blocks, reactive oxygen species for various redox reactions regulating cell metabolism, innate immunity, apoptosis regulation, and even oncogenic signaling. These functions provide an attractive anticancer target. However, specific therapeutic targeting of the mitochondria remains problematic. Colloidal nanoparticles (NP) can be fine-tuned for mitochondria targeting, and therein lies the opportunity to develop efficient anticancer therapy.<br/>Here we present the development of mitochondria-targeting peptide-coated polymeric nanoparticles. The coating is achieved by self-assembly of the peptides on the NP’s surface. Among the peptide library used, sequences with repeating arginine amino acids are taken into consideration for targeting, or motifs containing lysine-leucine-alanine-lysine (KLAK) sequence. As the internal membrane of the mitochondria is negatively charged, we also explored the positively charged targeting group triphenylphosphate (TPP) as a part of the NP’s coating. The NPs were synthesized via the nanoprecipitation method, producing NPs of sizes 100 and 300 nm, with low polydispersity of 0.2. The NPs were stable in buffer for 72 h. The zeta potential of the NPs was found to be –32 mV indicating a stable colloid. The core of the NP was composed of FDA-approved PLGA polymer, with anticancer drugs (e.g., taxol, doxorubicin) loaded via reversible covalent bonds. The PLGA modifications resulted in a degradable colloidal NP. In this endeavor, we also assessed the anticancer properties of the developed NP platform using various ovarian cancer cell lines to evaluate the biological activity of the NPs. These experiments show promising results in our endeavor to fine-tune the developed self-assembled mitochondria targeting colloidal particles.

Developing mitochondria-targeting polymeric nanoparticles using peptides as non-covalent stabilizers

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.