Gambogic acid

Melanoma is characterized by its aggressiveness, high metastatic potential, and numerous mutations, which limit the effectiveness of current treatments. To address this issue, we developed a dissolvable microneedle (MN) system composed of poly(2-ethyl-2-oxazoline) (PEtOz) and chondroitin sulfate (CS). This MN system was loaded with liposomes containing both a NIR-II photothermal small molecule (IRLy) and the natural anticancer agent Gambogic acid (GA), forming Lip(IRLy + GA) MNs. The integration of the dissolvable microneedle with drug-loaded liposomes aligns with the mechanical properties and skin penetration efficiency required for effective drug delivery. It enables minimally invasive, painless, and precise administration of IRLy and GA. Under NIR-II 1064 nm laser irradiation, Lip(IRLy + GA) effectively inhibited melanoma by disrupting blood vessels, inducing apoptosis, and altering mitochondrial membrane potential. In a subcutaneous melanoma (A375) model in nude mice, the combination of Lip(IRLy + GA) and laser treatment demonstrated a synergistic effect, enhancing both photothermal and chemotherapeutic outcomes. This research presents a promising strategy that combines NIR-II photothermal agents with natural chemotherapeutic drugs and highlights the potential of microneedles in combination therapies for superficial skin cancers like melanoma.

Gambogic acid(GA)is a natural compound that exhibits strong antitumor activity against a variety of tumors. However, its poor water solubility, low specificity, and high toxicity lead to inevitable systemic adverse effects. To minimize side effects, combining gambogic acid (GA) with delivery systems such as nanohydrogels to develop an in situ vaccine system (ISV) shows great promise. In this study, we loaded GA into a novel in situ nanocomposite hydrogel vaccine system (Gel-NPs@GA) along with a near-infrared (NIR) fluorescent dye, IR-1061. The Gel-NPs@GA system allowed for temperature-triggered gelation, simplifying injection and the in vivo formation of a drug-releasing gel, with near-infrared monitoring for drug metabolism. Slow, continuous release of gelatinase-targeted GA nanoparticles from the hydrogel occurs, followed by cleavage of mPEG-peptide-PCL conjugates by gelatinase, causing particle aggregation for endocytosis by tumor cells. This approach tackled solubility issues and curbs excessive GA release, boosting therapeutic drug levels. The sustained GA release induces tumor cell apoptosis, releasing tumor antigens and reprogramming the immune-suppressive tumor microenvironment. In the CT26 colorectal cancer mice model, this in situ vaccine system significantly inhibited tumor growth. By integrating information about immune cell clusters within the tumor microenvironment with RNA sequencing results, we hypothesized that Gel-NPs@GA could synergistically stimulate the immune response through various pathways, promote the maturation of dendritic cells (DCs), increase the infiltration of T cells, and thereby remodel the tumor's immune microenvironment.