Engineering of redox-triggered polymeric lipid hybrid nanocarriers for selective drug delivery to cancer cells

Tunable redox-sensitive polymeric-lipid hybrid nanocarriers (RS-PLHNCs) were fabricated using homogenization and nanoprecipitation methods. These nanocarriers were composed of novel redox-cholesterol with disulfide linkages and synthesized by conjugating cholesterol with dithiodipropionic acid <i>via</i> esterification. Berberine (BBR) was loaded into the fabricated nanocarriers to investigate the selective uptake of BBR by cancer cells as well as its release and enhanced cytotoxicity. The optimized BBR nanocarriers BBR NP-17 and -18 exhibited a spherical shape and uniform distribution, with a particle size of 124.7 ± 1.2 nm and 185.2 ± 1.6 nm and a zeta potential of -5.9 ± 2.5 mV and -20.3 ± 1.1 mV, respectively. These NCs released >80% BBR in a simulated intracellular tumor microenvironment (TME), while only 30%-45% was released under normal physiological conditions. The accelerated drug release in the TME was due to disulfide bond cleavage and ester bond hydrolysis in the presence of GSH and acidic pH, whereas under normal conditions, the NCs remained stable/undissociated. Cellular uptake studies confirmed enhanced BBR uptake in GSH-rich cancer cells (H1975) compared with normal cells (BEAS-2B and HEK293A). Following uptake, compared with the free form of the drug, the optimized nanocarriers displayed significant selective cytotoxicity and apoptosis in cancer cells by notably downregulating anti-oxidant (NFE2L2, HO-1, NQO1, and TXRND1) and anti-apoptotic (MCL-1) genes while upregulating pro-apoptotic genes (PUMA and NOXA). This resulted in increased oxidative stress, thereby inducing selective apoptosis in the GSH-rich lung cancer cells. These results suggest that the synthesized novel NCs hold great potential for specifically delivering drugs to cancer cells (with a reduced environment) while sparing normal cells, thus ensuring safe and efficient cancer therapy.