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Doxorubicin-conjugated siRNA lipid nanoparticles for combination cancer therapy

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1429-1437页

作者： Kamila Butowska Xuexiang Han Ningqiang Gong Rakan El-Mayta Rebecca MHaley Lulu Xue Wenqun Zhong Wei Guo Karin Wang Michael J.Mitchell Department of Bioengineering University of PennsylvaniaPhiladelphiaPA 19104USA Intercollegiate Faculty of Biotechnology University of Gdańsk&Medical University of GdańskGdańsk 80-307Poland Department of Biology University of PennsylvaniaPhiladelphiaPA 19104USA Department of Bioengineering Temple UniversityPhiladelphiaPA 19122USA Abramson Cancer Center Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104USA Institute for Immunology Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104USA Cardiovascular Institute Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104USA Institute for Regenerative Medicine Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104USA

Evasion of apoptosis is a hallmark of cancer,attributed in part to overexpression of the antiapoptotic protein B-cell lymphoma 2(Bcl-2).In a variety of cancer types,including lymphoma,Bcl-2 is overexpressed.Therapeutic targeting of Bcl-2 has demonstrated efficacy in the clinic and is the subject of extensive clinical testing in combination with chemotherapy.Therefore,the development of co-delivery systems for Bcl-2 targeting agents,such as small interfering RNA(siRNA),and chemotherapeutics,such as Doxorubicin(DOX),holds promise for enabling combination cancer therapies.Lipid nanoparticles(LNPs)are a clinically advanced nucleic acid delivery system with a compact structure suitable for siRNA encapsulation and delivery.Inspired by ongoing clinical trials of albumin-hitchhiking Doxorubicin prodrugs,here we developed a DOX-siRNA co-delivery strategy via conjugation of Doxorubicin to the surface of siRNAloaded LNPs.Our optimized LNPs enabled potent knockdown of Bcl-2 and efficient delivery of DOX into the nucleus of Burkitts'lymphoma(Raji)cells,leading to effective inhibition of tumor growth in a mouse model of lymphoma.Based on these results,our LNPs may provide a platform for the co-delivery of various nucleic acids and DOX for the development of new combination cancer therapies.

关键词： Lipid nanoparticles Doxorubicin Bcl-2 siRNA delivery Chemotherapy Lymphoma

LRP1B suppresses HCC progression through the NCSTN/PI3K/AKT signaling axis and affects Doxorubicin resistance

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Genes & Diseases 2023年第5期10卷 2082-2096页

作者： Xiangyu Zhai Zhijia Xia Gang Du Xinlu Zhang Tong Xia Delin Ma Xiaosong Li Bin Jin Hao Zhang Department of Hepatobiliary Surgery The Second Hospital of Shandong UniversityJinanShandong 250033China Department of General Visceraland Transplant SurgeryLudwig-Maximilians-University MunichMunich 81377Germany Department of Reproductive Medicine Central Hospital Affiliated to Shandong First Medical UniversityJinanShandong 250013China Organ Transplant Department Qilu Hospital of Shandong UniversityJinanShandong 250012China Clinical Molecular Medicine Testing Center The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China

Accumulating evidence supports the association of somatic mutations with tumor occurrence and development.We aimed to identify somatic mutations with important implications in hepatocellular carcinoma(HCC)and explore their possible mechanisms.The gene mutation profiles of HCC patients were assessed,and the tumor mutation burden was calculated.Gene mutations closely associated with tumor mutation burden and patient overall survival were identified.In vivo and in vitro experiments were performed to verify the effects of putative genes on proliferation,invasion,drug resistance,and other malignant biological behaviors of tumor cells.Fourteen genes with a high mutation frequency were identified.The mutation status of 12 of these genes was closely related to the mutation burden.Among these 12 genes,LRP1B mutation was closely associated with patient prognosis.Nine genes were associated with immune cell infiltration.The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal Doxorubicin.LRP1B could directly bind to NCSTN and affect its protein expression level,thereby regulating the PI3K/AKT pathway.Our mutational analysis revealed complex and orchestrated liposomal alterations linked to Doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.

关键词： Doxorubicin Hepatocellular carcinoma LRP1B PI3K/AKT pathway Tumor mutation burden

Overexpressed SIRT6 ameliorates Doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling

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药学学报:英文版 2023年第6期13卷 2680-2700页

作者： Kezheng Peng Chenye Zeng Yuqi Gao Binliang Liu Liyuan Li Kang Xu Yuemiao Yin Ying Qiu Mingkui Zhang Fei Ma Zhao Wang The Ministry of Education Key Laboratory of Protein Science School of Pharmaceutical SciencesTsinghua UniversityBeijing 100084China Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China School of Medicine Tsinghua UniversityBeijing 100084China Department of Cardiac Surgery First Hospital of Tsinghua UniversityBeijing 100016China

Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore,overexpression of SIRT6 alleviated Doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of Doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated Doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of Doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during Doxorubicin treatment.Mechanistically, Doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during Doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against Doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated Doxorubicininduced cardiotoxicity and enhanced Doxorubicin-mediated tumor regression in tumor-bearing mice.These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.

关键词： SIRT6 Doxorubicin Cardiotoxicity Antitumor efficacy Ellagic acid Mitochondrial homeostasis Glycolysis SGK1

Tumor-Penetrating and Mitochondria-Targeted Drug Delivery Overcomes Doxorubicin Resistance in Lung Cancer

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Chinese Journal of Polymer Science 2023年第4期41卷 525-537,I0006页

作者： Meng-Xue Zhou Jia-Yu Zhang Xiao-Meng Cai Rui Dou Li-Fo Ruan Wen-Jiang Yang Wen-Chu Lin Jun Chen Yi Hu CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety Institute of High Energy Physics and University of Chinese Academy of Sciences(UCAS)Chinese Academy of Sciences(CAS)Beijing100049China Key Laboratory of Tea Biology and Resource Utilization of Ministry of Agriculture Tea Research InstituteChinese Academy of Agricultural SciencesHangzhou310008China Division of Nuclear Technology and Applications Institute of High Energy PhysicsChinese Academy of Sciences(CAS)Beijing100049China High Magnetic Field Laboratory Hefei Institutes of Physical ScienceChinese Academy of SciencesHefei230031China University of Science and Technology of China Hefei230026China

As one of the major challenges in tumor chemotherapy,multidrug resistance typically correlates with the poor drug penetration within tumor tissues and drug efflux by the ATP-driven efflux pumps in tumor cells.Herein,we design a kind of near-infrared(NIR)light-and acidity-activated micellar i PUTDN nanoparticle for mitochondria-targeting Doxorubicin(DOX)delivery to combat DOX resistance in small-cell lung cancer.While the PEGylated i PUTDN nanoparticles can keep stealth in blood circulation,NIR irradiation at the tumor region can peel off the PEG shell from the nanoparticles,and the exposed i RGD can facilitate deep tumor penetration of the nanoparticles.After being internalized by DOX-resistant H69AR cells,the poly(β-aminoester)s(PAE)-based nanoparticles can release the triphenylphosphonium(TPP)-conjugated DOX(TDOX)into the cytosol,which can further accumulate in mitochondria with the aid of TPP.Consequently,the mitochondrial membrane potential and ATP content are both reduced in DOX-resistant H69AR cells.The in vivo therapeutic results show that TDOX-loaded nanoparticles with the aid of NIR light irradiation can effectively suppress the DOX-resistant small-cell lung cancer without noticeable adverse effects.

关键词： Doxorubicin NIR/p H-dual sensitive nanoparticles Tumor penetration Mitochondria Drug resistance

Doxorubicin hydrochloride and L-arginine co-loaded nanovesicle for drug resistance reversal stimulated by near-infrared light

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Asian Journal of Pharmaceutical Sciences 2022年第6期17卷 924-937页

作者： Linping Jiang Kesi Wang Liyan Qiu Ministry of Educational(MOE)Key Laboratory of Macromolecular Synthesis and Functionalization Department of Polymer Science and EngineeringZhejiang UniversityHangzhou 310027China

Drug resistance is accountable for the inadequate outcome of chemotherapy in clinics.The newly emerging role of nitric oxide(NO)to conquer drug resistance has been recognized as a potential strategy.However,it remains a great challenge to realize targeted delivery as well as accurate release of NO at desired sites.Herein,we developed a PEGylated indocyanine green(m PEG-ICG)integrated nanovesicle system(PIDA)to simultaneously load Doxorubicin hydrochloride(DOX·HCl)and the NO donor L-arginine(L-Arg),which can produce NO triggered by NIR light irradiation and exert multimodal therapy to sensitize drug-resistant cancers.Upon 808 nm irradiation,the NO released from PIDA led to a decrease in mitochondrial membrane potential,an increase in ROS and significant ATP depletion in K562/ADR cells,thus inhibiting cell growth and resolving the problem of drug resistance.Consequently,the in vivo experiment on K562/ADR-bearing nude mice indicated that PIDA nanovesicles achieved significant anticancer efficacy with a tumor inhibition rate of 80.8%.Above all,PIDA nanovesicles offer guidance for designing nanoplatforms for drug-resistant cancer treatment.

关键词： Nitric oxide L-arginine Doxorubicin Indocyanine green Drug resistance Nanovesicle

MiR-24-3p Attenuates Doxorubicin-induced Cardiotoxicity via the Nrf2 Pathway in Mice

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Current Medical Science 2022年第1期42卷 48-55页

作者： Di FAN Hong-bin CHEN Yan LENG Shi-jun YANG Department of Cardiology Renmin Hospital of Wuhan UniversityWuhan 430060China Department of Cardiology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430060China Department of Pulmonary and Critical Care Medicine Renmin Hospital of Wuhan UniversityWuhan 430060China Department of Anesthesiology Renmin Hospital of Wuhan UniversityWuhan 430060China.

Objective:The nuclear factor erythroid 2(NFE2)-related factor 2(Nrf2)is associated with Doxorubicin(DOX)-induced cardiac injury.It has been reported that microRNA-24-3p(miR-24-3p)may regulate the Keapl by mRNA degradation,whereas Keapl can suppress the activation of Nrf2.However,the role of miR-24-3p in DOX-related cardiotoxicity remains unclear.

关键词： miR-24-3p Ros Doxorubicin nuclear factor erythroid 2-related factor 2 apoptosis

Balancing efficacy and safety of Doxorubicin-loaded albumin nanoparticles utilizing pH-sensitive Doxorubicin-fatty acid prodrugs

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Nano Research 2024年第6期17卷 5491-5500页

作者： Yuanhao Yu Shiyi Zuo Jiaxuan Song Lingxiao Li Tian Liu Jiayu Guo Yaqiao Li Danping Wang Qi Lu Helin Wang Dun Zhou Zhonggui He Xiaohong Liu Bingjun Sun Jin Sun School of Pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmacy The First Affiliated Hospital of Jinzhou Medical UniversityJinzhou 121001China Joint International Research Laboratory of Intelligent Drug Delivery Systems Ministry of EducationShenyang 110016China

Albumin nanoparticles(ANPs)offer unique advantages for antitumor drug delivery system,including non-immunogenicity and inherent tumor-targeting capacity.At present,only a few products,such as ABRAXANE®and FYARRO™,have been approved for clinical applications.The poor affinity of Doxorubicin(DOX)for albumin,coupled with its numerous severe adverse reactions,poses challenges in the fabrication of desirable albumin nanoparticles loaded with DOX.In this study,we developed prodrugs by conjugating fatty acids of varying lengths with DOX.Our aim was to investigate the balance between efficacy and safety through the selection of appropriate modules.We synthesized five pH-sensitive Doxorubicin-fatty acid prodrugs.Compared to free DOX,all DOX prodrug ANPs exhibited a uniform size distribution with desirable sizes of 150 nm.Additionally,DOX prodrugs with hydrazone bonds remained intact in blood circulation while releasing DOX within tumor cells.Significantly,the characteristics of prodrug ANPs were considerably influenced by the length of fatty acids,impacting their in vivo pharmacokinetics,antitumor effectiveness and tumor accumulation.This research offers a detailed understanding of the length of fatty acid influence on DOX-fatty acid prodrug-based ANPs,and it builds a good platform for creating ANPs which prioritize high drug loading,high efficiency,and minimal side effects.

关键词： fatty acid prodrug albumin Doxorubicin pH-sensitive bond nanomedicines

Safety evaluation of nanodiamond-Doxorubicin complexes in a Naïve Beagle canine model using hematologic,histological,and urine analysis

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Nano Research 2022年第4期15卷 3356-3366页

作者： Liping Wang Wenqiong Su Khan Zara Ahmad Xin Wang Ting Zhang Youyi Yu Edward Kai-Hua Chow Dean Ho Xianting Ding State Key Laboratory of Oncogenes and Related Genes Institute for Personalized MedicineSchool of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai 200030China Cancer Science Institute of Singapore Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117599Singapore The N.1 Institute for Health(N.1) National University of SingaporeSingapore 117456Singapore The Institute for Digital Medicine(WisDM) National University of SingaporeSingapore 117456Singapore Department of Pharmacology National University of SingaporeSingapore 117597Singapore Department of Biomedical Engineering National University of SingaporeSingapore 117583Singapore

While Doxorubicin(DOX)is one of the most common chemotherapeutic drugs for treating cancer,use of DOX must be managed carefully due to dose-related toxicity.Nanodiamond(ND)drug delivery system conjugated with DOX(NDX)has been reported to enhance treatment efficacy and attenuate toxicity in murine cancer models.In addition,extensive biocompatibility studies indicate that NDs seem to be well tolerated in non-human primates.Before the clinical translation of NDX,it is necessary to verify the safety of ND in large mammals.Studies of nanomedicine drug safety for large animal are not commonly reported,and this work represents a key milestone in bridging earlier advances towards clinical assessment.Herein,NDs’safety as a drug-delivery platform was evaluated in Naïve Beagle dogs.The study is performed with DOX,ND,and NDX in a dual-gender animal model using intravenous(IV)injection and hepatic portal vein(HPV)injection methods.The dogs are monitored for their health phenotype changes in continuous 5 days.Blood and urine obtained are for clinical pathology research.The results indicate that ND drug delivery platform significantly relieves DOX toxicity for Naïve Beagle dog model.This study provides guidance for the pre-clinical safety assessment of NDX therapy at large animal level.

关键词： nanomedicine Doxorubicin nanodiamonds safety biodistribution

TBC1D15 deficiency protects against Doxorubicin cardiotoxicity via inhibiting DNAPKcs cytosolic retention and DNA damage

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4823-4839页

作者： Wenjun Yu Haixia Xu Zhe Sun Yuxin Du Shiqun Sun Miyesaier Abudureyimu Mengjiao Zhang Jun Tao Junbo Ge Jun Ren Yingmei Zhang Department of Cardiology and Shanghai Institute of Cardiovascular Diseases Zhongshan HospitalFudan UniversityShanghai 200032China National Clinical Research Center for Interventional Medicine Shanghai 200032China Department of Cardiovascular Surgery Zhongnan Hospital of Wuhan UniversityWuhan 430071China Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery Wuhan 430071China Department of Cardiology Affiliated Hospital of Nantong UniversityNantong 226001China Cardiovascular Department Shanghai Xuhui Central HospitalZhongshan-Xuhui HospitalFudan UniversityShanghai 200030China Department of Cardiovascular Surgery Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510000China

Clinical application of Doxorubicin(DOX)is heavily hindered by DOX cardiotoxicity.Several theories were postulated for DOX cardiotoxicity including DNA damage and DNA damage response(DDR),although the mechanism(s)involved remains to be elucidated.This study evaluated the potential role of TBC domain family member 15(TBC1D15)in DOX cardiotoxicity.Tamoxifen-induced cardiac-specific Tbcldi5 knockout(Tbcldi5^(CKO))or Tbcldi5 knockin(Tbcldi5^(CKI))male mice were challenged with a single dose of DOx prior to cardiac assessment 1 week or 4 weeks following DOX challenge.Adenoviruses encoding TBC1D15 or containing shRNA targeting Tbcld15 were used for Tbcld15 overexpression or knockdown in isolated primary mouse cardiomyocytes.Our results re-vealed that DOX evoked upregulation of TBC1D15 with compromised myocardial function and overt mortality,the effects of which were ameliorated and accentuated by Tbcldi5 deletion and Tbcld15 overexpression,respectively.DOX overtly evoked apoptotic cell death,the effect of which was alleviated and exacerbated by Tbcld15 knockout and overexpression,respectively.Meanwhile,DOX provoked mitochondrial membrane potential collapse,oxidative stress and DNA damage,the effects of which were mitigated and exacerbated by Tbcld15 knockdown and overexpression,respectively.Further scrutiny revealed that TBC1D15 fostered cytosolic accumulation of the cardinal DDR element DNA-dependent protein kinase catalytic subunit(DNA-PKcs).Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation denoted an interaction between TBCID15 and DNA-PKcs at the segment 594-624 of TBC1D15.Moreover,overexpression of TBC1D15 mutant(A594-624,deletion of segment 594-624)failed to elicit accentuation of DOX-induced cytosolic retention of DNA-PKcs,DNA damage and cardiomyocyte apoptosis by TBC1D15 wild type.However,Tbcld15 deletion ameliorated DOXinduced cardiomyocyte contractile anomalies,apoptosis,mitochondrial anomalies,DNA damage and cytosolic DNA-PKcs accumulation,which were canceled off by DNA-PKcs inhibition

关键词： Doxorubicin Cardiotoxicity DNA damage DNA damage response Mitochondrial anomalies Cardiomyocyte apoptosis TBC1D15 DNA-PKcS