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Pathological BBB Crossing Melanin-Like Nanoparticles as Metal-Ion Chelators and Neuroinflammation Regulators against Alzheimer’s Disease

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Research 2024年第1期6卷 687-706页

作者： Qianqian Huang Chaoqing Jiang Xue Xia Yufan Wang Chenxing Yan Xiaorong Wang Ting Lei Xiaotong Yang Wenqin Yang Guo Cheng huile gao Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry West China School of PharmacySichuan UniversityChengdu 610041P.R.China Laboratory of Molecular Translational Medicine Center for Translational MedicineKey Laboratory of Birth Defects and Related Diseases of Women and Children(Sichuan University)Ministry of EducationDepartment of PediatricsWest China Second University HospitalSichuan UniversityChengdu 610041P.R.China

Inflammatory responses,manifested in excessive oxidative stress and microglia overactivation,together with metal ion-triggered amyloid-beta(Aβ)deposition,are critical hallmarks of Alzheimer’s disease(AD).The intricate pathogenesis causes severe impairment of neurons,which,in turn,exacerbates Aβaggregation and facilitates AD ***,multifunctional melanin-like metal ion chelators and neuroinflammation regulators(named PDA@K)were constructed for targeted treatment of *** this platform,intrinsically bioactive material polydopamine nanoparticles(PDA)with potent metal ion chelating and ROS scavenging effects were decorated with the KLVFF peptide,endowing the system with the capacity of enhanced pathological blood–brain barrier(BBB)crossing and lesion site accumulation via Aβ*** vitro and in vivo experiment revealed that PDA@K had high affinity toward Aβand were able to hitch a ride on Aβto achieve increased pathological BBB *** engineered PDA@K effectively mitigated Aβaggregate and alleviated neuroinflammation.

关键词： oxidative aggregation chelating

Dual-responsive supramolecular photodynamic nanomedicine with activatable immunomodulation for enhanced antitumor therapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 765-780页

作者： Siqin He Lulu Wang Dongxu Wu Fan Tong Huan Zhao Hanmei Li Tao Gong huile gao Yang Zhou Key Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical SciencesHainan UniversityHaikou 570200China Key Laboratory of Drug-Targeting and Drug Delivery System West China School of PharmacySichuan UniversityChengdu 610041China Revvity Inc. WalthamMA 02451USA School of Food and Biological Engineering Chengdu UniversityChengdu 610106China

A major challenge facing photodynamic therapy(PDT) is that the activity of the immuneinduced infiltrating CD8^(+)T cells is subject to the regulatory T lymphocytes(Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment(TME), a supramolecular photodynamic nanoparticle(DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin(DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration(Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of *** guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

关键词： Photodynamic therapy Immunosuppressive microenvironment Immunomodulator Dual-responsive Supramolecularassembly Checkpointblockade

Combination losartan with hyaluronic acid modified diethyldithiocarbamate loaded hollow copper sulfide nanoparticles for the treatment of breast cancer and metastasis

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Chinese Chemical Letters 2024年第3期35卷 406-414页

作者： Haili Hu Weiwei Zhang Lei Lei Fan Tong Huilin Zhang Yiwei Zhang Wenqin Yang Yilu Tang Ruyi Lin Xue Xia Jiamei Li Shiyong Song huile gao Key Laboratory of Drug Targeting and Drug Delivery Systems West China School of PharmacySichuan UniversityChengdu 610041China School of Pharmacy Henan UniversityKaifeng 475004China Department of Public Health Chengdu Medical CollegeChengdu 610500China

The application of photothermal therapy(PTT)is greatly limited by the low accumulation of photothermal agents,uneven photothermal distribution,and heat endurance of cancer *** still,despite PTT enhances immunogenicity,the anti-tumor immune efficacy is still unsatisfactory due to the inefficient immunogenic cell death(ICD)induction and poor infiltration of immune *** solve the above problems of PTT,we developed hyaluronic acid(HA)modified hollow copper sulfide nanoparticles encapsulating diethyldithiocarbamate(DDTC)to construct a breast tumor targeting and near infrared(NIR)photo-responsive drug delivery system(D-HCuS@HA),which further combined with losartan to improve the accumulation and penetration in the tumor *** irradiation,D-HCuS@HA realized enhanced PTT and released cytotoxic Cu(DDTC)_(2)to eliminate heat endurance tumor cells,thereby enhancing antitumor effect and inducing effective ***,the combination with losartan could remodel the tumor microenvironment,allowing more T cells to infiltrate into the tumor,and significantly inhibiting the occurrence and development of metastatic *** vitro/vivo results revealed the great potential of D-HCuS@HA combined with losartan,which provides a new paradigm for anti-tumor and anti-metastases.

关键词： Targeted drug delivery system Hollow copper sulfide nanoparticles Photothermal therapy Hyaluronic acid Breast cancer Anti-metastasis

Targeted nanomedicines remodeling immunosuppressive tumor microenvironment for enhanced cancer immunotherapy

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Acta Pharmaceutica Sinica B 2022年第12期12卷 4327-4347页

作者： Yanyan Xu Jingyuan Xiong Xiyang Sun huile gao Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China Healthy Food Evaluation Research Center West China School of Public Health and West China Fourth HospitalSichuan UniversityChengdu 610041China Hongqiao International Institute of Medicine Tongren HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200336China

Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ***,low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to ***,it has become evident that,although the immunosuppressive tumor microenvironment(TME)plays a pivotal role in facilitating tumor progression and metastasis,it also provides various potential targets for remodeling the immunosuppressive TME,which can consequently bolster the effectiveness of antitumor response and tumor ***,the particular characteristics of TME,in turn,can be exploited as avenues for designing diverse precise targeting *** general,it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME,thus improving the therapeutic outcomes and clinical translation prospects of ***,we will illustrate several formation mechanisms of immunosuppressive *** importantly,a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients'immune systems,will be ***,we will discuss the existing obstacles and future perspectives in the development of antitumor ***,the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.

关键词： Cancer immunotherapy Immunosuppressive tumor microenvironment Tumor microenvironment normalization Targeted nanomedicines Drug delivery Environment-responsive nanoparticles Combinational therapy Tumor treatment

Co-delivery of photosensitizer and diclofenac through sequentially responsive bilirubin nanocarriers for combating hypoxic tumors

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1416-1431页

作者： Yang Zhou Fan Tong Weilong Gu Siqin He Xiaotong Yang Jiamei Li Yue-Dong gao huile gao Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610064China Core Technology Facility of Kunming Institute of Zoology Chinese Academy of SciencesKunming 650223China Chinese Academy of Sciences Territorial Core Facility of Kunming Biological Diversity Regional Center Kunming 650223China

Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac(Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species(ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A(LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1a(HIF-1a) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.

关键词： Bilirubin nanoparticles ROS-responsive drug release Charge reversal Photodynamic therapy Hypoxia Diclofenac LDHA inhibition HIF-1a inhibition

Carrier-free nanodrugs with efficient drug delivery and release for cancer therapy:From intrinsic physicochemical properties to external modification

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Bioactive Materials 2022年第2期7卷 220-240页

作者： Heng Mei Shengsheng Cai Dennis Huang huile gao Jun Cao Bin He National Engineering Research Center for Biomaterials Sichuan UniversityChengdu 610064China West China School of Pharmacy Sichuan UniversityChengdu610064China Department of Biomedical Engineering The University of Texas at AustinAustinTX78731USA

The considerable development of carrier-free nanodrugs has been achieved due to their high drug-loading capability,simple preparation method,and offering“all-in-one”functional platform ***,the native defects of carrier-free nanodrugs limit their delivery and release behavior throughout the in vivo journey,which significantly compromise the therapeutic efficacy and hinder their further development in cancer *** this review,we summarized and discussed the recent strategies to enhance drug delivery and release of carrier-free nanodrugs for improved cancer therapy,including optimizing the intrinsic physicochemical properties and external ***,the corresponding challenges that carrier-free nanodrugs faced are discussed and the future perspectives for its application are *** hope this review will provide constructive information for the rational design of more effective carrier-free nanodrugs to advance therapeutic treatment.

关键词： Carrier-free nanodrugs Drug delivery and release Intrinsic physicochemical properties External modification Therapeutic efficacy

Sequentially responsive size reduction and drug release of core-satellite nanoparticles to enhance tumor penetration and effective tumor suppression

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Chinese Chemical Letters 2023年第5期34卷 489-493页

作者： Jiayi Sun Jingyang Li Xi Li Lu Yang Yitong Liu huile gao Li Xiang State Key Laboratory of Southwestern Chinese Medicine Resources Innovative Institute of Chinese Medicine and PharmacyChengdu University of Traditional Chinese MedicineChengdu 611137China Public Health Clinical Center of Chengdu Chengdu 610061China The Third Affiliated Hospital of Chengdu University of TCM/Chengdu Pidu District Hospital of Traditional Chinese Medicine Chengdu 611730China West China School of Pharmacy Sichuan UniversityChengdu 610041China

Poor tumor accumulation remains a serious challenge for nanomedicines to achieve ideal antitumor *** different size preferences for systematic circulation,tumor retention and deep permeation have attracted great attention when designing antineoplastic nano-delivery ***,we developed a nano-system which can shrink its size in tumor microenvironment to achieve better tumor retention and *** this work,the cationic bovine serum albumin-protected,doxorubicin-loaded gold nanoclusters(CAuNC-DOX)and amino-functionalized mesoporous silica nanoparticles(MSN)are connected by Fe^(2+)and are further coated with hyaluronic acid(HA)to obtain a core-satellite MSN-Fe-CAuNCDOX@HA nano system(MFADH).When reaching the tumor site,the HA shell,which endows the system with both good biocompatibility and preferable tumor targeting ability,was disintegrated,followed by acid-stimulated release of small-sized pharmacological unit—CAuNC-DOX for further tumor *** demonstrated in both in vitro and in vivo results,MFADH showed excellent antitumor effect,providing a proof of concept for the feasibility of shrinkable nanoplatforms in tumor treatment.

关键词： Size reducible Tumor penetration Core-satellite structure Mesoporous silica nanoparticles Gold nanoclusters Experimental techniques

Dual-responsive nanoparticles with transformable shape and reversible charge for amplified chemo-photodynamic therapy of breast cancer

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3354-3366页

作者： Wenfeng Jia Rui Liu Yushan Wang Chuan Hu Wenqi Yu Yang Zhou Ling Wang Mengjiao Zhang huile gao Xiang gao Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610064China Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of BiotherapyWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China

Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention,which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6(Ce6), hydrophilic chemotherapeutic drug berberrubine(BBR) and matrix metalloproteinase-2(MMP-2) response peptide(PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6(BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine(PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively,we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.

关键词： Shape transformation Charge reversal Chemo-photodynamic therapy Self-delivery MMP-2 response p H response Carrier-free nanoparticles Breast cancer

Progress and perspectives on targeting nanoparticles for brain drug delivery

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Acta Pharmaceutica Sinica B 2016年第4期6卷 268-286页

作者： huile gao Key Laboratory of Drug Targeting and Drug Delivery Systems West China School of Pharmacy Sichuan University

Due to the ability of the blood–brain barrier(BBB) to prevent the entry of drugs into the brain, it is a challenge to treat central nervous system disorders pharmacologically. The development of nanotechnology provides potential to overcome this problem. In this review, the barriers to brain-targeted drug delivery are reviewed, including the BBB, blood–brain tumor barrier(BBTB), and nose-to-brain barrier. Delivery strategies are focused on overcoming the BBB, directly targeting diseased cells in the brain, and dual-targeted delivery. The major concerns and perspectives on constructing brain-targeted delivery systems are discussed.

关键词： Brain targeting Nanoparticles Dual targeting Intranasal delivery Blood–brain barrier