POS8-0919
Triphenylphosphonium-Modified Cationic Hydroxyethylcellulose Polyplexes for Mitochondria-Targeted Gene Delivery and Cancer Therapy
Topic
S8. Frontiers of Functional Polymers in Biology and Medicine
When and Where
Oct 1, 2026
08:30 - 09:30
Room 301 (Grand Ballroom)
Session Chairs
Jinkee HONG
Ki Su KIM
Presenter(s)
Seoyeon Park (Seoul National University)
Co-Author(s)
Abstract
Mitochondria serve as central metabolic hubs in cancer cells, making mitochondrial targeting an attractive therapeutic strategy by overcoming drug efflux, disrupting energy metabolism, and restoring apoptosis. However, this approach is limited by the highly negative membrane potential and hydrophobic inner membrane of mitochondria. Triphenylphosphonium (TPP) is a representative targeting moiety that enables efficient mitochondrial permeation and accumulation. Accordingly, a TPP-conjugated, biocompatible cellulose-based cationic polymer system was developed to enhance anticancer efficacy.
As a biocompatible gene carrier, hydroxyethyl cellulose was conjugated with PEI2k as previously reported. HECP2k was subsequently conjugated with different ratios of TPP and characterized by 1H NMR and GPC. Polyplex formation was evaluated using agarose gel electrophoresis and DLS. In vitro cytotoxicity was assessed by MTT assay, and cellular uptake of the polyplexes was quantified by flow cytometry. Mitochondrial and cytosolic fractions were isolated using a mitochondrial fractionation kit.
To improve biocompatibility, anionic pPBA was coated onto the HECP2k-TPP polyplexes. The pPBA-coated pDNA polyplexes maintained nanosized structures and nucleic acid complexation ability while reducing charge-associated cytotoxicity in MDA-MB-231 cells. pPBA coating ratios of 10–30 showed the most favorable balance between reduced cytotoxicity, preserved cellular uptake, and mitochondrial localization.
In the therapeutic efficacy assay, the pPBA10-coated siRNA polyplexes maintained suitable nanosized morphology, and siATP6 delivery induced pronounced anticancer responses, including increased apoptosis, elevated ROS generation, and decreased ATP6 mRNA expression. These findings suggest that siATP6 was successfully delivered and induced mitochondrial dysfunction and apoptosis-related responses through target gene silencing.
As a biocompatible gene carrier, hydroxyethyl cellulose was conjugated with PEI2k as previously reported. HECP2k was subsequently conjugated with different ratios of TPP and characterized by 1H NMR and GPC. Polyplex formation was evaluated using agarose gel electrophoresis and DLS. In vitro cytotoxicity was assessed by MTT assay, and cellular uptake of the polyplexes was quantified by flow cytometry. Mitochondrial and cytosolic fractions were isolated using a mitochondrial fractionation kit.
To improve biocompatibility, anionic pPBA was coated onto the HECP2k-TPP polyplexes. The pPBA-coated pDNA polyplexes maintained nanosized structures and nucleic acid complexation ability while reducing charge-associated cytotoxicity in MDA-MB-231 cells. pPBA coating ratios of 10–30 showed the most favorable balance between reduced cytotoxicity, preserved cellular uptake, and mitochondrial localization.
In the therapeutic efficacy assay, the pPBA10-coated siRNA polyplexes maintained suitable nanosized morphology, and siATP6 delivery induced pronounced anticancer responses, including increased apoptosis, elevated ROS generation, and decreased ATP6 mRNA expression. These findings suggest that siATP6 was successfully delivered and induced mitochondrial dysfunction and apoptosis-related responses through target gene silencing.
