pH-activatable oxidative stress amplifying dissolving microneedles for combined chemo-photodynamic therapy of melanoma  

作　　者：Yanjuan Huang Hualu Lai Jingwen Jiang Xiaoyu Xu Zishan Zeng Lingling Ren Qiuxing Liu Meixu Chen Tao Zhang Xin Ding Chunshun Zhao Shengmiao Cui 

机构地区：[1]School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [2]School of Traditional Chinese Medicine,Guangdong Pharmaceutical University,Guangzhou 510006,China [3]Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems,Guangdong Pharmaceutical University,Guangzhou 510006,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2022年第5期679-696,共18页亚洲药物制剂科学（英文）

基　　金：supported by the National Natural Science Foundation of China(Grant number:81973256/H3008);Guangdong Basic and Applied Basic Research Foundation(Grant number:2021A1515010475);the Fundamental Research Funds for the Central Universities(22qntd4505).

摘　　要：Photodynamic therapy(PDT)-mediated oxidation treatment is extremely attractive for skin melanoma ablation,but the strong hydrophobicity and poor tumor selectivity of photosensitizers,as well as the oxygen-consuming properties of PDT,leading to unsatisfactory therapeutic outcomes.Herein,a tumor acidic microenvironment activatable dissolving microneedle(DHA@HPFe-MN)was developed to realize controlled drug release and excellent chemo-photodynamic therapy of melanoma via oxidative stress amplification.The versatile DHA@HPFe-MN was fabricated by crosslinking a self-synthesized protoporphyrin(PpIX)-ADH-hyaluronic acid(HA)conjugate HA-ADH-PpIX with“iron reservoir”PA-Fe 3+complex in the needle tip via acylhydrazone bond formation,and dihydroartemisinin(DHA)was concurrently loaded in the hydrogel network.HA-ADH-PpIX with improved water solubility averted undesired aggregation of PpIX to ensure enhanced PDT effect.DHA@HPFe-MN with sharp needle tip,efficient drug loading and excellent mechanical strength could efficiently inserted into skin and reach the melanoma sites,where the acidic pH triggered the degradation of microneedles,enabling Fe-activated and DHA-mediated oxidation treatment,as evidenced by abundant reactive oxygen species(ROS)generation.Moreover,under light irradiation,a combined chemo-photodynamic therapeutic effect was achieved with amplified ROS generation.Importantly,the Fe-catalyzed ROS production of DHA was oxygen-independent,which work in synergy with the oxygen-dependent PDT to effectively destroy tumor cells.This versatile microneedles with excellent biosafety and biodegradability can be customized as a promising localized drug delivery system for combined chemo-photodynamic therapy of melanoma.

关 键 词：MELANOMA Dissolving microneedles Chemo-photodynamic therapy Oxidation treatment DIHYDROARTEMISININ Hyaluronic acid 

分 类 号：R73-36[医药卫生—肿瘤]