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Nanoplateletsomes restrain metastatic tumor formation through decoy and active targeting in a preclinical mouse model

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3427-3447页

作者： Longlong Zhang Yuefei Zhu Xunbin Wei Xing Chen Yang Li Ying Zhu Jiaxuan Xia Yiheng huang yongzhuo huang Jianxin Wang Zhiqing Pang Department of Pharmaceutics School of PharmacyFudan UniversityShanghai 201203China Key Laboratory of Smart Drug Delivery Ministry of EducationShanghai 201203China State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer InstituteMed-X Research Institute and School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai 200030China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Institute of Materia Medica Academy of Chinese and Western Integrative MedicineFudan UniversityShanghai 201203China

Platelets buoy up cancer metastasis via arresting cancer cells, enhancing their adhesion, and facilitating their extravasation through the vasculature. When deprived of intracellular and granular contents, platelet decoys could prevent metastatic tumor formation. Inspired by these, we developed nanoplatesomes by fusing platelet membranes with lipid membranes(P-Lipo) to restrain metastatic tumor formation more efficiently. It was shown nanoplateletsomes bound with circulating tumor cells(CTC)efficiently, interfered with CTC arrest by vessel endothelial cells, CTC extravasation through endothelial layers, and epithelial-mesenchymal transition of tumor cells as nanodecoys. More importantly, in the mouse breast tumor metastasis model, nanoplateletsomes could decrease CTC survival in the blood and counteract metastatic tumor growth efficiently by inhibiting the inflammation and suppressing CTC escape. Therefore, nanoplatelesomes might usher in a new avenue to suppress lung metastasis.

关键词： Nanoplateletsome Breast cancer Tumor metastasis Circulating tumor cells Nanodecoy Immunosuppressive micrometastatic environment Lung pre-metastasis

Neutralization of SARS-CoV-2 pseudovirus using ACE2-engineered extracellular vesicles

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1523-1533,F0004页

作者： Canhao Wu Qin Xu Huiyuan Wang Bin Tu Jiaxin Zeng Pengfei Zhao Mingjie Shi Hong Qiu yongzhuo huang Artemisinin Research Center First Clinical SchoolGuangzhou University of Chinese MedicineGuangzhou 510450China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Zhongshan Institute for Drug Discovery SIMMCASZhongshan 528437China Center of Clinical Pharmacology The Second Affiliated Hospital of Zhejiang UniversitySchool of MedicineHangzhou 310009China NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients Shanghai 201203China Taizhou University School of Advanced StudyInstitute of Natural Medicine and Health ProductTaizhou 318000China

The spread of coronavirus disease 2019(COVID-19)throughout the world has resulted in stressful healthcare burdens and global health crises.Developing an effective measure to protect people from infection is an urgent need.The blockage of interaction between angiotensin-converting enzyme 2(ACE2)and S protein is considered an essential target for anti-severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)drugs.A full-length ACE2 protein could be a potential drug to block early entry of SARS-Co V-2 into host cells.In this study,a therapeutic strategy was developed by using extracellular vesicles(EVs)with decoy receptor ACE2 for neutralization of SARS-Co V-2.The EVs embedded with engineered ACE2(EVs-ACE2)were prepared;the EVs-ACE2 were derived from an engineered cell line with stable ACE2 expression.The potential effect of the EVs-ACE2 on anti-SARS-Co V-2 was demonstrated by both in vitro and in vivo neutralization experiments using the pseudovirus with the S protein(S-pseudovirus).EVs-ACE2 can inhibit the infection of S-pseudovirus in various cells,and importantly,the mice treated with intranasal administration of EVs-ACE2 can suppress the entry of S-pseudovirus into the mucosal epithelium.Therefore,the intranasal EVs-ACE2 could be a preventive medicine to protect from SARS-Co V-2 infection.This EVs-based strategy offers a potential route to COVID-19 drug development.

关键词： SARS-CoV-2 COVID-19 Spike protein Pseudovirus Extracellular vesicles ACE2 Intranasal administration Neutralization

Inhaled heparin polysaccharide nanodecoy against SARS-CoV-2 and variants

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3187-3194页

作者： Bin Tu Huiyuan Wang Xinran An Jingkun Qu Qianqian Li Yanrong Gao Mingjie Shi Hong Qiu yongzhuo huang State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China University of Michigan College of Pharmacy Ann ArborMI 48109USA School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China Nanchang University College of Pharmacy Nanchang 330006China Zhongshan Institute for Drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshan 528437China NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients Shanghai 201203China Taizhou University School of Advanced StudyInstitute of Natural Medicine and Health ProductTaizhou 318000China

To the Editor:As of January 27,2022,there were 363,062,293 cases and 5,645,884deaths from the COVID-19 pandemic1.The prevalent mutated strains have aggravated the global pandemic2.SARS-Co V-2 is highly mutable,and the mutations on the spike(S)protein resulted in a high transmission of COVID-19 and vaccine breakthrough infection3.For example,there is a notable decrease in neutralizing ability of BNT162b2 vaccination-elicited antibodies against the Delta and other variants4,5,and attenuation of peak viral burden and vaccine effectiveness are reduced with Delta variant6.

关键词： SARS-CoV-2 Delta variant Heparan sulfate Spike protein Heparin nanoparticle Pulmonary delivery

Remodeling “cold” tumor immune microenvironment via epigenetic-based therapy using targeted liposomes with in situ formed albumin corona

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Acta Pharmaceutica Sinica B 2022年第4期12卷 2057-2073页

作者： Yang He Yuefei Fang Meng Zhang Yuge Zhao Bin Tu Mingjie Shi Bahtiyor Muhitdinov Akmal Asrorov Qin Xu yongzhuo huang State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Zhongshan Institute for Drug Discovery Chinese Academy of SciencesZhongshan 528437China Department of Pharmacy the First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Artemisinin Research Center Guangzhou University of Chinese MedicineGuangzhou 510450China Women’s Hospital School of MedicineZhejiang UniversityHangzhou 310006China Institute of Bioorganic Chemistry Uzbekistan Academy of SciencesTashkent 100125Uzbekistan National Medical Products Administration Key Laboratory for Quality Research and Evaluation of Pharmaceutical ExcipientsShanghai 201203China

There is a close connection between epigenetic regulation,cancer metabolism,and immunology.The combination of epigenetic therapy and immunotherapy provides a promising avenue for cancer management.As an epigenetic regulator of histone acetylation,panobinostat can induce histone acetylation and inhibit tumor cell proliferation,as well as regulate aerobic glycolysis and reprogram intratumoral immune cells.JQ1 is a BRD4 inhibitor that can suppress PD-L1 expression.Herein,we proposed a chemo-free,epigenetic-based combination therapy of panobinostat/JQ1 for metastatic colorectal cancer.A novel targeted binary-drug liposome was developed based on lactoferrin-mediated binding with the LRP-1 receptor.It was found that the tumor-targeted delivery was further enhanced by in situ formation of albumin corona.The lactoferrin modification and endogenous albumin adsorption contribute a dual-targeting effect on the receptors of both LRP-1 and SPARC that were overexpressed in tumor cells and immune cells(e.g.,tumor-associated macrophages).The targeted liposomal therapy was effective to suppress the crosstalk between tumor metabolism and immune evasion via glycolysis inhibition and immune normalization.Consequently,lactic acid production was reduced and angiogenesis inhibited;TAM switched to an anti-tumor phenotype,and the anti-tumor function of the effector CD8+T cells was reinforced.The strategy provides a potential method for remodeling the tumor immune microenvironment(TIME).

关键词： Tumor immune microenvironment Tumor-associated macrophage Epigenetic therapy Immune checkpoint Angiogenesis Panobinostat JQ1 Liposome

Author correction to"Neutralization of SARSCoV-2 pseudovirus using ACE2-engineered extracellular vesicles"[Acta Pharmaceutica Sinica B 12(2022)1523-1533]

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4664-4666页

作者： Canhao Wu Qin Xua Huiyuan Wang Bin Tu Jiaxin Zeng Pengtei Zhao Mingjie Shi Hong Qiu yongzhuo huang Artemisinin Research Center First Clinical SchoolGuangzhou University of Chinese MedicineGuangzhou 510450China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Zhongshan Institute for Drug Discovery SIMMCASZhongshan 528437China Center of Clinical Pharmacology the Second Affliated Hospital of Zhejiang UniversitySchool of MedicineHangzhou 310009China NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients Shanghai 201203China Taizhou University School of Advanced StudyInstitute of Natural Medicine and Health ProductTaizhou 3180China

The authors regret in the initially published version of this article,there is a misapplied image in Fig.3C.The corrected Fig.3 is provided below.

关键词： correction initially ACE2

Nanotechnology-based combination therapy for overcoming multidrug-resistant cancer

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Cancer Biology & Medicine 2017年第3期14卷 212-227页

作者： Meng Zhang Ergang Liu Yanna Cui yongzhuo huang Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Chemical Engineering School of Chemical Engineering and TechnologyTianjin UniversityTianjin 300072China Key Laboratory of Primate Neurobiology Institute of NeuroscienceChinese Academy of SciencesShanghai 200031China

Multidrug resistance(MDR) is a major obstacle to successful cancer treatment and is crucial to cancer metastasis and relapse.Combination therapy is an effective strategy for overcoming MDR. However, the different pharmacokinetic(PK) profiles of combined drugs often undermine the combination effect in vivo, especially when greatly different physicochemical properties(e.g.,those of macromolecules and small drugs) combine. To address this issue, nanotechnology-based codelivery techniques have been actively explored. They possess great advantages for tumor targeting, controlled drug release, and identical drug PK profiles. Thus,a powerful tool for combination therapy is provided, and the translation from in vitro to in vivo is facilitated. In this review, we present a summary of various combination strategies for overcoming MDR and the nanotechnology-based combination therapy.

关键词： Drug delivery nanotechnology multidrug resistance combination therapy cancer therapy

Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides

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Acta Pharmaceutica Sinica B 2016年第4期6卷 352-358页

作者： Tingting Lin Ergang Liu Huining He Meong Cheol Shin Cheol Moon Victor C.Yang yongzhuo huang Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis School of Pharmacy Tianjin Medical University Shanghai Institute of Materia Medica Chinese Academy of Sciences College of Pharmacy The University of Michigan College of Pharmacy and Research Institute of Pharmaceutical Sciences Gyeongsang National University College of Pharmacy Sunchon National University

Brain delivery of macromolecular therapeutics(e.g., proteins) remains an unsolved problem because of the formidable blood–brain barrier(BBB). Although a direct pathway of nose-to-brain transfer provides an answer to circumventing the BBB and has already been intensively investigated for brain delivery of small drugs,new challenges arise for intranasal delivery of proteins because of their larger size and hydrophilicity. In order to overcome the barriers and take advantage of available pathways(e.g., epithelial tight junctions, uptake by olfactory neurons, transport into brain tissues, and intra-brain diffusion), a low molecular weight protamine(LMWP) cell-penetrating peptide was utilized to facilitate nose-to-brain transport. Cell-penetrating peptides(CPP)have been widely used to mediate macromolecular delivery through many kinds of biobarriers. Our results show that conjugates of LMWP–proteins are able to effectively penetrate into the brain after intranasal administration.The CPP-based intranasal method highlights a promising solution for protein therapy of brain diseases.

关键词： Intranasal protein delivery Brain targeting Cell-penetrating peptide Low molecular weight protamine Blood–brain barrier

Biomimetic albumin-modified gold nanorods for photothermo-chemotherapy and macrophage polarization modulation

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Acta Pharmaceutica Sinica B 2018年第1期8卷 74-84页

作者： Dongdong Li Meng Zhang Fan Xu Yingzhi Chen Binfan Chen Ya Chang Huihai Zhong Hongyue Jin yongzhuo huang Shanghai Institute of Materia Medica Chinese Academy of Sciences Nano Sci-Tech Institute University of Science and Technology of China Shanghai University College of Sciences

Nanotechnology-based photothermal therapy has attracted great attention in the past decade. Nevertheless, photothermal therapy has some inherent drawbacks, such as the uneven heat production and limited laser penetration, often leading to insufficient treatment outcomes. Here, we developed a combination strategy to improve cancer therapy. The biomimetic albumin-modified gold nanorods(AuNRs) were prepared with incorporation of paclitaxel(PTX). This therapeutic system was characterized by several features. First, the albumin modification enhanced the biocompatibility and colloidal stability. Second, the surface-coated albumin promoted cellular uptake via the albumin-binding protein pathway. Third, PTX was incorporated via hydrophobic interaction between PTX and the albumin lipophilic domain. Fourth, the system can be used for combined photothermo-chemotherapy for yielding synergistic effects. The antitumor activity of the system was evaluated both in vitro and in vivo using the HCT116 colon cancer cell and tumor model. The combination therapy was found with an enhanced treatment efficiency and no obvious side effect. Most importantly, the thermal effect was also discovered with the ability to modulate the tumor microenvironments and suppress the macrophages polarization towards the M2 pro-tumor phenotype. It could be a mechanism for photothermal immunotherapy. The combination strategy and the system provide a potential method for cancer therapy.

关键词： Photothermal therapy Paclitaxel Combination therapy Gold nanorods Albumin Tumor-associated macrophage

Improved method for synthesis of low molecular weight protamine–siRNA conjugate

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Acta Pharmaceutica Sinica B 2018年第1期8卷 116-126页

作者： Zhili Yu Junxiao Ye Xing Pei Lu Sun Ergang Liu Jianxin Wang yongzhuo huang Seung Jin Lee Huining He Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics School of PharmacyTianjin Medical University College of Pharmacy Tsinghua University Collaborative Innovation Center of Chemical Science and Chemical Engineering and Technology Tianjin University Key Laboratory of Smart Drug Delivery Ministry of Education & PLA Department of Pharmaceutics School of Pharmacy Fudan University Ministry of Education & PLA Shanghai Institute of Materia Medica Chinese Academy of Sciences Department of Pharmacy Ewha Womans University Seodaemun-gu

RNAi technology has aroused wide public interest due to its high efficiency and specificity to treat multiple types of diseases. However, the effective delivery of siRNA remains a challenge due to its large molecular weight and strong anionic charge. Considering their remarkable functions in vivo and features that are often desired in drug delivery carriers, biomimetic systems for siRNA delivery become an effective and promising strategy. Based on this, covalent attachment of synthetic cell penetrating peptides(CPP) to siRNA has become of great interest. We developed a monomeric covalent conjugate of low molecular weight protamine(LMWP, a well-established CPP) and siRNA via a cytosol-cleavable disulfide linkage using PEG as a crosslinker. Results showed that the conjugates didn't generate coagulation, and exhibited much better RNAi potency and intracellular delivery compared with the conventional charge-complexed CPP/siRNA aggregates. Three different synthetic and purification methods were compared in order to optimize synthesis efficiency and product yield. The methodology using hetero-bifunctional NHS–PEG–OPSS as a crosslinker to synthesize LMWP–siRNA simplified the synthesis and purification process and produced the highest yield. These results pave the way towards siRNA biomimetic delivery and future clinical translation.

关键词： Cell penetrating peptide siRNA Conjugate Conjugation yield Biomimetic delivery Crosslinker