Preparation Of Polydopamine-Based Multifunctional Nanomaterials And Applications In Anti-Tumor Therapy

With the rise of cancer patients,the shortcomings of traditional treatment methods are becoming increasingly prominent.Therefore,there is an urgent need to develop new cancer treatment strategies tailored to specific cancer issues,in order to alleviate the side effects of traditional treatment methods and improve treatment effectiveness.Medical advances in nanotechnology have encouraged new cancer treatment strategies using multifunctional nanoparticles（NPs）.Polydopamine（PDA）is considered to have great clinical application value due to its advantages such as biocompatibility,biodegradability,photothermal effect,and easy synthesis.Therefore,this article has prepared three kinds of multifunctional NPs based on PDA with different application potential for specific cancer problems.And its application in antitumor therapies was explored through in vitro and in vivo experiments.The specific experimental content and results are as follows:（1）The upregulation of heat shock proteins（HSPs）associated with thermal activation limits the effectiveness of mild photothermal therapy（mill-PTT）.Therefore,we prepared PDA/Cu/ICG/R modified with integrin targeting cyclic peptide（c RGD）and loaded with Cu²⁺and indocyanine green（ICG）simultaneously.PDA/Cu/ICG/R can limit ATP synthesis through the dual mitochondrial disruption pathway,downregulate the expression of HSP90,and improve the mill-PTT effect of PDA.Through in vivo imaging system（IVIS）and photoacoustic（PA）imaging to monitor the enrichment of PDA/Cu/ICG/R in the tumor site for selecting,the optimal laser“ON”time.In addition,PDA/Cu/ICG/R can also respond to p H and release Cu²⁺and ICG on demand.The biodegradability of PDA greatly reduces the risk of toxicity caused by long-term retention of PDA/Cu/ICG/R in vivo.Finally,the mild-PTT effect of PDA was successfully improved by NIR“switch”controlled double mitochondrial destruction pathway.（2）Due to the depth of tissue penetration of NIR,the application of mild-PTT in deep tumors is limited.Therefore,we continued to develop a NIR-II triggered prostate membrane antigen（PSMA）targeting Au@PDA/PEG-PI targeted-PTT strategy.The synthesized urea-based PSMA inhibitor（PI-PEG）containing glutamic acid has a high affinity for PSMA targets(binding energy=-8.3 kcal mol^-1)and can be used as a favorable target for targeting PSMA.Au@PDA with broad NIR absorption（700-1100nm）was synthesized by a simple“one-pot”method and modified with PI-PEG to obtain Au@PDA/PEG-PI with PSMA targeting.This work showed that the prepared Au@PDA/PEG-PI not only has high selectivity for PSMA,but also can effectively ablate PSMA expression by targeting PTT under the maximum allowable exposure（MPE）of NIR-II laser.In addition,Au@PDA/PEG-PI also has the potential for photoacoustic（PA）imaging and computed tomography（CT）imaging.（3）Due to the innate resistance of cancer cells to apoptosis,the efficacy of PTT-triggered apoptosis is limited.Therefore,we continue to develop Fe/ppa@PDA/B that can consume glutathione（GSH）and self-sufficient oxygen（O₂）regulated by superoxide dismutase（SOD）enzyme for synergistic ferroptosis and cell apoptosis.We prepared Fe/ppa@PDA/B that can consume glutathione（GSH）and self-sufficient oxygen（O₂）by a simple method,which can be applied for the synergistic anti-tumor strategy of SDT-induced apoptosis and ferroptosis.Mesoporous Fe₃O₄ acts as a Fe source for ferroptosis,increases ferroptosis sensitivity by consuming GSH,and serves as a carrier for the transport of small molecule sonosensitizer pyropheophorbide-a（ppa）.The PDA coating can not only avoid the ineffective leakage of ppa during the circulation,but also endow Fe/ppa@PDA/B with active targeting ability to cancer cells..This synergistic anti-tumor strategy of apoptosis and ferroptosis induced by GSH depletion and self-sufficient O₂regulated by SOD.