Photodynamic Therapy Of Melanoma Skin Cancer Using Lysosome-targeting AuTCs@La-MCS

Malignant melanoma is the most lethal form of skin cancer and its incidence has risen faster than almost any other cancer over the course of the last 50 years.Currently,surgery is the main treatment option for most melanoma;however,since the malignant tissues cannot be resected entirely,residues will usually cause a high cancer recurrence rate.Although chemotherapy has been applied to combine with surgical resection to reduce the postoperative recurrence rate,the effectiveness is unsatisfactory yet.As a minimally invasive treatment,Photodynamic therapy（PDT）has merged as a promising treatment for malignant melanoma.Various nanomaterials have been widely used as photosensitizers to produce a large amount of reactive oxygen species（ROS）to kill tumor cells under exciting light,but most of them lacked targeting effect.In the present study,Au（I）-Thiolate Complexes@La-doped mesoporous calcium silicate（AuTCs@La-MCS）were designed for lysosome-targeting melanoma PDT.Mesoporous calcium silicate（MCS）has a characteristically porous structure with many pores and a large pore volume,which has been used as a potential drug delivery carrier for cancer treatment.Metal ions(Mg²⁺,Ba²⁺,Sr²⁺,La³⁺)doping in calcium silica is demonstrated to enlarge the surface area and regulate the morphology and size of MCS particles,which lead to high drug loading capability.Furthermore,MCS could not only improve the stability and biocompatibility of drug/nanomaterials loaded into its compartment,but also realize their p H-responsive payload release.Mesoporous lanthanum-doped calcium silicate（La-MCS）was synthesized by lanthanum-doped MCS.Then,glutathione（GSH）-protected Au（I）-sulfhydryl compound（AuTCs）was obtained by in-situ reduction of Au（III）deposition in the pores of La-MCS,and AuTCs@La-MCS structure was obtained.After being located in melanoma lysosome,cationic La³⁺in mesoporous calcium silicate structure could be released in the acidic compartments and induced AuTCs aggregate into Au NCs gradually to generate aggregation-induced emission（AIE）fluorescence,which can be applied for imaging guide therapy in vitro and in vivo.La³⁺-dependent swelling of Au NCs inhibits HSP 70 expression and induces lysosomal membrane permeation（LMP）to sensitized melanoma for PDT under simulated sunlight radiation（SSR）.The lysosomal targeting AuTCs@La-MCS nanodiagnostic system enables imaging while enhancing PDT.The nano-diagnosis and treatment system has demonstrated excellent performance in the diagnosis and treatment of malignant melanoma at molecular,cellular and animal levels,providing a new idea for personalized diagnosis and treatment of malignant melanoma in the future.