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Inhalable iron redox cycling powered nanoreactor for amplified ferroptosis-apoptosis synergetic therapy of lung cancer

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Nano Research 2024年第6期17卷 5435-5451页

作者： Linjing wu Wenhao Wang Mengqin Guo Fangqin Fu Wenhua Wang Tszching Sung Meihong Zhang Ziqiao Zhong chuanbin wu Xin Pan Zhengwei Huang College of Pharmacy Jinan UniversityGuangzhou 511436China School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China

Fenton reaction centered ferroptosis-apoptosis synergetic therapy has emerged as a promising tumor elimination strategy.However,the low intracellular Fenton level and accumulation of therapeutics at the lesion site greatly limit the efficacy of ferroptosis therapy.To overcome these two bottlenecks,an inhalable metal polyphenol network(MPN)-hybrid liposome,encoded as LDG,was proposed for enhancing the intracellular Fenton reaction level by co-delivering the ferroptosis inducer dihydroartemisinin(DHA)and the ferrous ion(Fe2+)donor MPN.The synthesized LDG had excellent nebulization performance which significantly improved the accumulation in the lungs,about 8.2 times of intravenous injection.In terms of anticancer mechanisms,MPN raised the intracellular level of Fe2+by constructing iron cycling in the weakly acidic environment of tumors.Triggered by Fe2+,DHA with peroxide-bridge structure underwent a high level of Fenton-like reaction,promoted the production of intracellular reactive oxygen species(ROS)and induced strong ferroptosis while cooperating with apoptosis.LDG exhibited extraordinary antitumor ability in an orthotopic lung tumor model,whose tumor inhibition efficiency was 1.53(P=0.0014)and 1.32(P=0.0183)times of the LG group(liposomes coated with gallic acid(GA)-Fe MPN)and LD group(liposomes loaded with DHA),respectively,showing the strongest anticancer effect.In conclusion,the constructed MPN-hybrid liposomes could be a potent custom nanoplatform for pulmonary delivery and underscored the great potential of ferroptosis-apoptosis synergetic therapy.

关键词： lung cancer pulmonary delivery ferroptosis metallic polyphenol network

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Plasma protein corona forming upon fullerene nanocomplex:Impact on both counterparts

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Particuology 2023年第2期73卷 26-36页

作者： Linjing wu Fangqin Fu Wenhao Wang Wenhua Wang Zhengwei Huang Ying Huang Xin Pan chuanbin wu College of Pharmacy Jinan UniversityGuangzhou510632China School of Pharmaceutical Sciences Sun Yat-Sen UniversityGuangzhou510006China

Protein corona refers to the structure composed of biomolecules adsorbed on the surface of nanomaterials.The study on the effect of the interaction between protein and nanoparticles can provide an important guide for the application of nanodrug delivery.To provide a reference for the research on fullerene(C60)nanocomplex drug delivery systems,this work studied the interaction between C60 nanocomplex and a variety of plasma proteins.Research showed that the protein binding with C60 nanocomplex did not change the charge properties of protein.The proteins induced the aggregation of C60 nanocomplex.The circular dichroism spectra showed that the secondary structure of the proteins changed after binding to C60 nanocomplex.The ultraviolet-visible spectra showed that the effect of C60 nanocomplex on proteins was concentration-dependent.The fluorescence spectra showed that C60 nanocomplex could intrinsic fluorescence alteration of proteins.The adsorption capacity of C60 nanocomplex to proteins was changed at 0 h and 4 h.The interaction between nanocomplex and proteins might affect the morphological characteristics of nanocomplex and the conformation of proteins.This work could provide a reference for the research and development of C60 nanocomplex and other carbon-based nanocomplex as nanoparticulate drug delivery systems.

关键词： Fullerene Nanocomplex Interaction Protein corona

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“Pincer movement”:Reversing cisplatin resistance based on simultaneous glutathione depletion and glutathione S-transferases inhibition by redox-responsive degradable organosilica hybrid nanoparticles

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Acta Pharmaceutica Sinica B 2022年第4期12卷 2074-2088页

作者： Boyi Niu Yixian Zhou Kaixin Liao Ting Wen Sixian Lao Guilan Quan Xin Pan chuanbin wu School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China College of Pharmacy Jinan UniversityGuangzhou 510632China

The therapeutic efficacy of cisplatin has been restricted by drug resistance of cancers.Intracellular glutathione(GSH)detoxification of cisplatin under the catalysis of glutathione S-transferases(GST)plays important roles in the development of cisplatin resistance.Herein,a strategy of“pincer movement”based on simultaneous GSH depletion and GST inhibition is proposed to enhance cisplatin-based chemotherapy.Specifically,a redox-responsive nanomedicine based on disulfide-bridged degradable organosilica hybrid nanoparticles is developed and loaded with cisplatin and ethacrynic acid(EA),a GST inhibitor.Responding to high level of intracellular GSH,the hybrid nanoparticles can be gradually degraded due to the break of disulfide bonds,which further promotes drug release.Meanwhile,the disulfide-mediated GSH depletion and EA-induced GST inhibition cooperatively prevent cellular detoxification of cisplatin and reverse drug resistance.Moreover,the nanomedicine is integrated into microneedles for intralesional drug delivery against cisplatin-resistant melanoma.The in vivo results show that the nanomedicine-loaded microneedles can achieve significant GSH depletion,GST inhibition,and consequent tumor growth suppression.Overall,this research provides a promising strategy for the construction of new-type nanomedicines to overcome cisplatin resistance,which extends the biomedical application of organosilica hybrid nanomaterials and enables more efficient chemotherapy against drug-resistant cancers.

关键词： Cancer therapy Cisplatin Drug resistance Glutathione depletion Glutathione Stransferases Disulfide bonds Organosilica hybrid nanoparticles Ethacrynic acid

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Self-assembly nanomicelle-microneedle patches with enhanced tumor penetration for superior chemo-photothermal therapy

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Nano Research 2022年第3期15卷 2335-2346页

作者： Ying Sun Minglong Chen Dan Yang Wanbing Qin Guilan Quan chuanbin wu Xin Pan School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China College of Pharmacy Jinan UniversityGuangzhou 510632China Jieyang Affiliated Hospital Sun Yat-Sen UniversityGuangzhou 522091China Physical Sciences at the Microscale Department of Polymer Science and EngineeringUniversity of Science and Technology of ChinaHefei 230026China

Nanomedicine with high specificity has been a promising tool for cancer diagnosis and therapy.However,the successful application of nanoparticle-based superficial cancer therapy is severely hindered by restricted deep tumor tissue accumulation and penetration.Herein,a self-assembly nanomicelle dissolving microneedle(DMN)patch according to the“nano in micro”strategy was conducted to co-deliver a first-line chemotherapeutic agent paclitaxel(PTX),and a photosensitizer IR780(PTX/IR780-NMs@DMNs)for chemo-photothermal synergetic melanoma therapy.Upon direct insertion into the tumor site,DMNs created a regular and multipoint three-dimensional drug depot to maximize the tumor accumulation.Accompanied by the DMN dissolution,the composition of the needle matrixes self-assembled into nanomicelles,which could efficiently penetrate deep tumor tissue.Upon laser irradiation,the nanomicelles could not only ablate tumor cells directly by photothermal conversion but also trigger PTX release to induce tumor cell apoptosis.In vivo results showed that compared with intravenous injection,IR780 delivered by PTX/IR780-NMs@DMNs was almost completely accumulated at the tumor site.The antitumor results revealed that the PTX/IR780-NMs@DMNs could effectively eliminate tumors with an 88%curable rate without any damage to normal tissues.This work provides a versatile and generalizable framework for designing self-assembly DMN-mediated combination therapy to fight against superficial cancer.

关键词： dissolving microneedle tumor penetration nanomicelle superficial tumor chemo-photothermal therapy

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Microneedles for Enhanced Topical Treatment of Skin Disorders:Applications,Challenges,and Prospects

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Engineering 2023年第11期30卷 170-189页

作者： Tingting Peng Yangyan Chen Wanshan Hu Yao Huang Minmin Zhang Chao Lu Xin Pan chuanbin wu International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development Ministry of Education of the People’s Republic of ChinaCollege of PharmacyJinan UniversityGuangzhou 511436China School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China Faculty of Pharmacy University of HelsinkiHelsinki 00014Finland

Microneedles(MNs)can be used for the topical treatment of skin disorders as they directly deliver therapeutics to the site of skin lesions,resulting in increased therapeutic efficacy while having minimum side effects.MNs are used to deliver different kinds of therapeutics(e.g.,small molecules,macromolecules,nanomedicines,living cells,bacteria,and exosomes)for treating various skin disorders,including superficial tumors,wounds,skin infections,inflammatory skin diseases,and abnormal skin appearance.The therapeutic efficacy of MNs can be improved by integrating the advantages of multiple therapeutics to perform combination therapy.Through careful designing,MNs can be further modified with biomimetic structures for the responsive drug release from internal and external stimuli and to enhance the transdermal delivery efficiency for robust therapeutic outcomes.Some studies have proposed the use of drug-free MNs as a promising mechanotherapeutic strategy to promote wound healing,scar removal,and hair regeneration via a mechanical communication pathway.Although MNs have several advantages,the practical application of MNs suffers from problems related to industrial manufacture and clinical evaluation,making it difficult for clinical translation.In this study,we summarized the various applications,emerging challenges,and developmental prospects of MNs in skin disorders to provide information on ways to advance clinical translation.

关键词： Microneedles Transdermal drug delivery system Skin disorders Treatments Challenges Prospects

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The effect of organic ligand modification on protein corona formation of nanoscale metal organic frameworks

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Chinese Chemical Letters 2022年第9期33卷 4185-4190页

作者： Wenhao Wang Huihui Liu Zhengwei Huang Fangqin Fu Wenhua Wang Linjing wu Ying Huang chuanbin wu Xin Pan School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China College of Pharmacy Jinan UniversityGuangzhou 511443China

Nanoscale metal organic frameworks(NMOFs)have been widely reported in biomedical field for their unique porous structure and tunable multifunctionality.However,when administrated in vivo,the protein corona will be formed on the surface of NMOFs,significantly affecting their biodistribution,pharmacokinetics and drug release.Few studies paid attention to the protein corona formation process and its influencing factors of NMOFs.As a well-established strategy for altering structure features of NMOFs,the organic ligand modification may have effect on the protein corona formation process,which is to be investigated.In this study,the zirconium(Zr)-based UIO66 was chosen as model NMOFs,the organic ligand of which was modified with amino group(-NH_(2))or carboxyl group(-COOH)to synthesize UIO66-NH_(2)and UIO66-2COOH,respectively.Bovine serum albumin(BSA)was chosen as model protein to investigate the protein corona formation process of NMOFs.The current results showed that the-COOH modification remarkably enhanced the BSA adsorption on NMOFs while-NH_(2)slightly decreased the protein binding affinity.These differences may be ascribed to the two different dominate protein corona formation modes,i.e.,surface coating mode and porous embedded mode.The protein corona formation did not affect the crystal phase of NMOFs but increased the content ofα-helix of BSA.Ultimately,upon protein corona formation,the cellular uptake of NMOFs was significantly affected.We believe our study will provide a new research paradigm to the design and applications of NMOFs.

关键词： Protein corona NMOFs UIO66 Organic ligand modification BSA

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Mapping the intersection of nanotechnology and SARS-CoV-2/COVID-19:A bibliometric analysis

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Infectious Medicine 2022年第2期1卷 103-112页

作者： Xuejuan Zhang Mengqin Guo Zhengwei Huang Ying Huang chuanbin wu Xin Pan College of Pharmacy Jinan UniversityGuangzhou 510632China School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China

Background:Coronavirus disease 2019(COVID-19),caused by infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has imposed great medical and economic burdens on human society,and nanotech-nology is a promising technique for managing the ongoing COVID-19 pandemic.To drive further studies on anti-COVID-19 nanotechnology,this paper provides an analysis,from a bibliometric perspective,of the intersec-tion of nanotechnology and SARS-CoV-2/COVID-19.Methods:We analyzed the 2585 publications on nanotechnology and SARS-CoV-2/COVID-19 included in the Web of Science Core Collection from January 2019 to March 2022 to determine the bibliometric landscape.The basic bibliometric characteristics are summarized in this article.Results:Our bibliometric analysis revealed that the intersection between nanotechnology and SARS-CoV-2/COVID-19 is a cutting-edge field in the science community and that the related studies were multidisciplinary in nature.Studies on the structural basis of SARS-CoV-2,SARS-CoV-2 detection assays,and mRNA vaccines against COVID-19 provided the development foundation for this field.Conclusions:The current research focuses are the development of nanomaterial-based vaccines and SARS-CoV-2 detection methods,and the design of nanomedicines carrying SARS-CoV-2 inhibitors is a relatively burgeoning frontier.In summary,this bibliometric analysis of the intersection of nanotechnology and SARS-CoV-2/COVID-19 highlights the current research focuses of this field to inspire future studies on anti-COVID-19 nanotechnologies.

关键词： Bibiometric analysis Nano technology SARS-CoV-2 COVID-19 Web of Science

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A real-time and modular approach for quick detection and mechanism exploration of DPIs with different carrier particle sizes

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Acta Pharmaceutica Sinica B 2022年第1期12卷 437-450页

作者： Yingtong Cui Ying Huang Xuejuan Zhang Xiangyun Lu Jun Xue Guanlin Wang Ping Hu Xiao Yue Ziyu Zhao Xin Pan chuanbin wu School of Pharmaceutical Science Jinan UniversityGuangzhou 510006China School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China Micromeritics Instrument(Shanghai)Ltd”Shanghai 200135 China MEGGLE Group Shanghai Representative Office Shanghai 201315China Department of Pharmacology Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China

Dry powder inhalers(DPIs) had been widely used in lung diseases on account of direct pulmonary delivery, good drug stability and satisfactory patient compliance. However, an indistinct understanding of pulmonary delivery processes(PDPs) hindered the development of DPIs. Most current evaluation methods explored the PDPs with over-simplified models, leading to uncompleted investigations of the whole or partial PDPs. In the present research, an innovative modular process analysis platform(MPAP) was applied to investigate the detailed mechanisms of each PDP of DPIs with different carrier particle sizes(CPS). The MPAP was composed of a laser particle size analyzer, an inhaler device,an artificial throat and a pre-separator, to investigate the fluidization and dispersion, transportation,detachment and deposition process of DPIs. The release profiles of drug, drug aggregation and carrier were monitored in real-time. The influence of CPS on PDPs and corresponding mechanisms were explored. The powder properties of the carriers were investigated by the optical profiler and Freeman Technology four powder rheometer. The next generation impactor was employed to explore the aerosolization performance of DPIs. The novel MPAP was successfully applied in exploring the comprehensive mechanism of PDPs, which had enormous potential to be used to investigate and develop DPIs.

关键词： Dry powder inhaler Carrier particle size Pulmonary delivery process Real-time monitor Quick detection

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An oxygen reservoir-irrigated photoimmunotherapy of malignant melanoma

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Nano Research 2023年第2期16卷 2875-2884页

作者： Yao Huang Tingting Peng Yangyan Chen Fapeng Zhang Wanshan Hu XinYi Gao Hongyu Chen Ping Tang chuanbin wu Xin Pan School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education(MOE)of China Jinan UniversityGuangzhou 511436China College of Pharmacy Jinan UniversityGuangzhou 511436China Department of Biliary-Pancreatic Surgery Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhou 510120China School of Pharmacy Shanghai University of Traditional Chinese MedicineShanghai 201203China Shenzhen University General Hospital Shenzhen 518055China

Tumor hypoxia is the pivotal factor limiting the therapeutic efficacy of photodynamic therapy(PDT),and can be partly improved by either the oxygen economizing or the oxygen supplementation strategies.Nevertheless,the current studies scarcely integrated the merits of both strategies and neglected the bottleneck of poor oxygen infiltration in deep tumors,resulting in PDT resistance.Herein,we developed an oxygen reservoir-irrigated PDT which integrates oxygen supply,oxygen economizing,and oxygen infiltration altogether.Specifically,mitochondria-targeted mesoporous prussian blue nanoparticles(Ce6@TPB)were fabricated to bridge the gap between oxygen economizing and oxygen supplementation by reducing oxygen output while increasing oxygen input.Hyaluronidase-loaded microneedles were further developed to pave the way for deep PDT with increased infusion of oxygen and photosensitizer by degrading dense extracellular matrix.The modulation of tumor oxygenation and permeability during PDT leads to the complete eradication of primary melanoma and strong immunogenic cell death.Its further combination with checkpoint-blockade inhibitor greatly suppressed the proliferation of distal tumors by reprogramming immune microenvironments,as evidenced by the depletion of M2 macrophage,increased infiltration of anti-tumor immune cells,and elevated excretion of immune cytokines.Therefore,such an oxygen reservoir-irrigated PDT potentiates powerful photoimmunotherapy and provides a favorable prospect for tumor treatment.

关键词： oxygen reservoir prussian blue nanoparticle hyaluronidase microneedle photodynamic therapy tumor microenvironment

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A triple-enhanced chemodynamic approach based on glucosepowered hybrid nanoreactors for effective bacteria killing

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Nano Research 2023年第2期16卷 2682-2694页

作者： Jintao Fu Yixian Zhou Ting Liu Wenhao Wang Yiting Zhao Ying Sun Yiming Zhang Wenxuan Qin Zhongwei Chen Chao Lu Guilan Quan chuanbin wu Xin Pan School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China College of Pharmacy Jinan UniversityGuangzhou 511443China

Rapid evolution of multidrug resistance in bacterial pathogens is outpacing the development of new antibiotics,and chemodynamic therapy(CDT)provides an excellent alternative.However,achieving highly efficient CDT is still a great challenge,since the pH in the infection site is close to neutral and the supply of H_(2)O_(2)is inadequate.We herein constructed the antibacterial nanoreactors.Indocyanine green(ICG)and glucose oxidase(GOx)were incorporated into homologous zeolitic imidazolate framework-8(ZIF-8)nanoparticles coating with metal polyphenol network(MPN)composed by Fe^(3+)and tannic acid(TA).The well-designed nanoreactors could simultaneously break the pH and H_(2)O_(2)limitations,and generate hyperthermia under irradiation,thus realizing a triple-enhanced CDT for high-efficiency sterilization.Furthermore,the nanoreactors could combine CDT with photothermal therapy(PTT)and photodynamic therapy(PDT),which not only improved the bactericidal efficiency and broadened the antibacterial spectrum,but also alleviated the antibiotics resistance issues.Remarkably,the proposed nanoreactors achieved a robust in vitro bacterial killing against Gram-positive methicillin-resistant Staphylococcus aureus(MRSA)and Gram-negative Pseudomonas aeruginosa.The nanoreactors achieved an 99.7%MRSA reduction in an MRSA-induced murine abscess model accompanied with negligible toxicity.Overall,this study provides a promising strategy for multiple-enhanced CDT and multimodal combined therapy for pathogenic infections.

关键词： metal-organic frameworks glucose oxidase photothermal therapy photodynamic therapy localized bacterial infection

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