The starvation therapy mediated by the lonidamine (LND) was limited by the low drug delivery efficiency, off-target effect and compensative glutamine metabolism. Herein, a hyaluronic acid (HA)-modified reduction-responsive micellar nanosystem co-loaded with glycolysis and glutamine metabolism inhibitor (LND and bis-2-(5-phenylacetmido-1,2,4-thiadiazol-2-yl)ethyl sulfide, BPTES) was constructed for tumor-targeted dual-starvation therapy. The in vitro and in vivo results collectively suggested that the fabricated nanosystem could effectively endocytosed by tumor cells via HA receptor-ligand recognition, and rapidly release starvation-inducers LND and BPTES in response to the GSH-rich intratumoral cytoplasm. Furthermore, the released LND and BPTES were capable of inducing glycolysis and glutamine metabolism suppression, and accompanied by significant mitochondrial damage, cell cycle arrest and tumor cells apoptosis, eventually devoting to the blockade of the energy and substance supply and tumor killing with high efficiency. In summary, [email protected] @B nanosystem significantly inhibited the compensatory glycolysis and glutamine metabolism via the dual-starvation therapy strategy, blocked the indispensable energy and substance supply of tumors, consequently leading to the desired tumor starvation and effective tumor killing with reliable biosafety.
Hyaluronic acid (HA) has been widely used in cosmetics and topical preparations owing to its favorable moisturizing property and potential in enhancing drugs' skin permeability. Here, the influencing factors and underlying mechanism of HA on skin penetration were carefully investigated, and HA-modified Undecylenoyl-Phenylalanine (UP) liposomes (HA-UP-LPs) were designed as a proof of principle for efficacious transdermal drug delivery strategy to enhance the skin penetration and retention. An in vitro penetration test (IVPT) of HA with different molecular weights showed that low molecular weight HA (LMW-HA, 5 kDa and 8 kDa) could pass through the stratum corneum (SC) barrier and enter into the epidermis and dermis layers, whereas its high molecular counterparts (HMW-HA) were trapped on the SC surface. Mechanistic studies revealed that LMW-HA could interact with keratin and lipid in the SC meanwhile exerted a substantial skin hydration effect, which may partially contribute to the SC penetration benefit. In addition, the surface decoration of HA drove an energy-dependent caveolae/lipid raft-mediated endocytosis of the liposomes through direct binding to the CD44 receptors widely expressed on skin cell membranes . Notably, IVPT showed a 1.36-fold and 4.86-fold increase in skin retention of UP and a 1.62-fold and 5.41-fold increase in skin penetration of UP with HA-UP-LPs over UP-LPs and free UP at 24 h, respectively. As a result, the anionic HA-UP-LPs (−30.0 mV) showed enhanced drug skin penetration and retention compared with conventional cationic bared UP-LPs (+21.3 mV) on both in vitro mini-pig skin as well as in vivo mouse skin. Overall, the usage of LMW-HA might offer opportunities in developing novel topical preparations and skin care products with improved transdermal penetration and retention.
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