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Fine-tuning the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies via branched aliphatic functionalization

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Nano Research 2024年第4期17卷 2908-2918页

作者： Guanting Li Fengli Xia Hongying Xiao Shunzhe Zheng Shuwen Fu Han Qiao Qianhui Jin Xuanbo Zhang Dun Zhou Chutong Tian Jin Sun Zhonggui He Bingjun Sun department of pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China department of pharmaceutics College of PharmacyShenyang Pharmaceutical UniversityShenyang 110016China Emergency department The First Affiliated Hospital of Jinzhou Medical UniversityJinzhou 121001China

Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems.However,in the case of camptothecins-based prodrug nanoassemblies,linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies,which are highly unfavorable for sterilization through filtration,and may cause capillary blockage upon intravenous injection.The rational design of camptothecins-based prodrug nanoassemblies remains a challenge.Herein,we propose that branched aliphatic alcohol(BAA)functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies.Correspondingly,four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin(SN38)with BAAs of varying lengths via a tumor redox-responsive disulfide bond,which self-assemble into uniform spherical nanoparticles.The length of BAA was found to significant impact the multiple drug delivery process,including colloidal stability,drug release profiles and pharmacokinetics.Overall,SN38-C21 NPs(SN38-11-heneicosanol nanoparticles),featuring the longest BAA,showcased multiple therapeutic advantages,ultimately culminating the optimal antitumor efficacy and tolerance.The findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies,and provide valuable insights for developing translational camptothecins-based nanomedicines.

关键词： prodrug nanoassembly self-assembly antitumor efficacy tolerance 7-ethyl-10-hydroxycamptothecin(SN_(3)8)

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Advancements in nanotechnology for the delivery of phytochemicals

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Journal of Integrative Medicine 2024年第4期22卷 385-398页

作者： Divya Chauhan Pavan K.Yadav Nazneen Sultana Arun Agarwal Saurabh Verma Manish K.Chourasia Jiaur R.Gayen Division of pharmaceutics and Pharmacokinetics Central Drug Research Institute Council of Scientific and Industrial Research Academy of Scientific and Innovative Research

Phytosomes(phytophospholipid complex) are dosage forms that have recently been introduced to increase the stability and therapeutic effect of herbal medicine. Currently, bioactive herbs and the phytochemicals they contain are considered to be the best remedies for chronic diseases. One promising approach to increase the efficacy of plant-based therapies is to improve the stability and bioavailability of their bio-active ingredients. Phytosomes employ phospholipids as their active ingredients, and use their amphiphilic properties to solubilize and protect herbal extracts. The unique properties of phospholipids in drug delivery and their use in herbal medicines to improve bioavailability results in significantly enhanced health benefits. The introduction of phytosome nanotechnology can alter and revolutionize the current state of drug delivery. The goal of this review is to explain the application of phytosomes, their future prospects in drug delivery, and their advantages over conventional formulations.

关键词： Bioavailability Drug delivery system Phytochemical Phytosome Plant extracts

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Insulin therapy in type 2 diabetes: Insights into clinical efficacy, patient-reported outcomes, and adherence challenges

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World Journal of Diabetes 2024年第5期15卷 828-852页

作者： Mahmoud Emad-Eldin Gehan F Balata Eman A Elshorbagy Mona S Hamed Mohamed S Attia department of pharmacy Practice Faculty of PharmacyZagazig UniversityZagazig HFQM+872Al-Sharqia GovernorateEgypt department of pharmacy Practice Faculty of PharmacyHeliopolis UniversityCairo 44519Egypt department of pharmaceutics Faculty of PharmacyZagazig UniversityZagazig 44519Al-Sharqia GovernorateEgypt department of Internal Medicine Faculty of MedicineZagazig UniversityZagazig 44519Al-Sharqia GovernorateEgypt department of Community at Faculty of Medicine Zagazig UniversityZagazig 44519Al-Sharqia GovernorateEgypt

Insulin therapy plays a crucial role in the management of type 2 diabetes as the disease progresses.Over the past century,insulin formulations have undergone significant modifications and bioengineering,resulting in a diverse range of available insulin products.These products show distinct pharmacokinetic and pharmacodynamic profiles.Consequently,various insulin regimens have em-erged for the management of type 2 diabetes,including premixed formulations and combinations of basal and bolus insulins.The utilization of different insulin regimens yields disparate clinical outcomes,adverse events,and,notably,patient-reported outcomes(PROs).PROs provide valuable insights from the patient’s perspective,serving as a valuable mine of information for enhancing healthcare and informing clinical decisions.Adherence to insulin therapy,a critical patient-reported outcome,significantly affects clinical outcomes and is influenced by multiple factors.This review provides insights into the clinical effectiveness of various insulin preparations,PROs,and factors impacting insulin therapy adherence,with the aim of enhancing healthcare practices and informing clinical decisions for individuals with type 2 diabetes.

关键词： Adherence Diabetes Insulin Patient-reported outcomes Pharmacokinetic Pharmacodynamic

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Advanced nano-based strategies for mRNA tumor vaccine

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Acta Pharmaceutica Sinica B 2024年第1期14卷 170-189页

作者： Yangqi Qu Jingjing Xu Tong Zhang Qinjun Chen Tao Sun Chen Jiang Key Laboratory of Smart Drug Delivery(Ministry of Education) Minhang HospitalState Key Laboratory of Medical NeurobiologyDepartment of PharmaceuticsSchool of PharmacyFudan UniversityShanghai 201203China

Tumor vaccine is a promising strategy for cancer immunotherapy by introducing tumor antigens into the body to activate specific anti-tumor immune responses.Along with the technological breakthroughs in genetic engineering and delivery systems,messenger ribonucleic acid(mRNA)technology has achieved unprecedented development and application over the last few years,especially the emergency use authorizations of two mRNA vaccines during the COVID-19 pandemic,which has saved countless lives and makes the world witness the powerful efficacy of mRNA technology in vaccines.However,unlike infectious disease vaccines,which mainly induce humoral immunity,tumor vaccines also need to activate potent cellular immunity to control tumor growth,which creates a higher demand for mRNA delivery to the lymphatic organs and antigen-presenting cells(APCs).Here we review the existing bottlenecks of mRNA tumor vaccines and advanced nano-based strategies to overcome those challenges,as well as future considerations of mRNA tumor vaccines and their delivery systems.

关键词： mRNA vaccine Nanoparticle Tumor vaccine Delivery system Stability Targeting Transfection Immunogenicity

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m^(6)A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation

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Frontiers of Medicine 2024年第3期18卷 499-515页

作者： Han Wu Weitao Jiang Ping Pang Wei Si Xue Kong Xinyue Zhang Yuting Xiong Chunlei Wang Feng Zhang Jinglun Song Yang Yang Linghua Zeng Kuiwu Liu Yingqiong Jia Zhuo Wang Jiaming Ju Hongtao Diao Yu Bian Baofeng Yang department of Pharmacology(National Key Laboratory of Frigid Zone Cardiovascular Diseases the State-Province Key Laboratories of Biomedicine-Pharmaceutics of ChinaKey Laboratory of Cardiovascular ResearchMinistry of Education)College of PharmacyHarbin Medical UniversityHarbin150081China

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction(MI)can lead to heart failure.RNA N6-methyladenosine(m^(6)A)methylation has been shown to play a pivotal role in the occurrence and development of many illnesses.In investigating the biological function of the m^(6)A reader YTHDF1 in cardiac fibrosis,adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts,and MI surgery in vivo and transforming growth factor-β(TGF-β)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models.Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis,whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development.Mechanistically,zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter.YTHDF1 augmented AXL translation and activated the TGF-β-Smad2/3 signaling pathway,thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis.Consistently,our data indicated that YTHDF1 was involved in activation,proliferation,and migration to participate in cardiac fibrosis in vitro.Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.

关键词： cardiac fibrosis YTHDF1 AXL ZBED6 heart failure

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Combatting Antibiotic Resistance:Regulatory Exclusivities for New Antibiotic Development in the United States and Europe

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Infectious Diseases & Immunity 2024年第2期4卷 79-85页

作者： Vivek Reddy Murthannagari Vaishnavi Parimala Thumpati Ganesh GNK department of pharmaceutics JSS College of PharmacyJSS Academy of Higher Education&ResearchOotyNilgirisTamil Nadu 643001India.

Antimicrobial resistance is a global concern that has led to millions of deaths worldwide.Genetic changes occur naturally in pathogens such as viruses,bacteria,parasites,and fungi.To overcome these concerns,there is a need to develop a new generation of antimicrobials.In an effort to encourage innovation,both the United States(US)and the European Union have introduced exclusivity programs.The US offered 5 years of additional nonpatent exclusivity for Qualified Infectious Disease Products under the Generating Antibiotic Incentives Now Act.In parallel,the European Commission offers a patent extension of 12 months across Europe(EU)countries or the option to sell the vouchers to other pharmaceutical companies through transferable exclusivity extension vouchers.This review focuses on the most important innovative strategies of antibiotic development the drug approvals,their mode of action,spectra of activity,and targeting of microorganisms,in past 5 years were mentioned,and discusses how to overcome the challenges of drug approval under antibiotic exclusivity in the US and EU,which will benefit the companies to develop novel drugs in several nations.

关键词： Drug resistance,microbial Exclusivity FDA EMA New antibiotics WHO

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Understanding the Novel Approach of Nanoferroptosis for Cancer Therapy

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Nano-Micro Letters 2024年第9期16卷 501-556页

作者： Afsana Sheikh Prashant Kesharwani Waleed H.Almalki Salem Salman Almujri Linxin Dai Zhe‑Sheng Chen Amirhossein Sahebkar Fei Gao department of pharmaceutics School of Pharmaceutical Education and ResearchJamia HamdardNew Delhi 110062India department of Pharmacology and Toxicology Faculty of PharmacyUmm Al-Qura UniversityMakkahSaudi Arabia department of Pharmacology College of PharmacyKing Khalid University61421 Asir‑AbhaSaudi Arabia State Key Laboratory of Southwestern Chinese Medicine Resources Pharmacy SchoolChengdu University of Traditional Chinese MedicineChengdu 611130People’s Republic of China department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityNew York 11439USA Biotechnology Research Center Pharmaceutical Technology InstituteMashhad University of Medical SciencesMashhadIran Applied Biomedical Research Center Mashhad University of Medical SciencesMashhadIran

As a new form of regulated cell death,ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer cells.The molecular mechanism of ferroptosis depends on the induction of oxidative stress through excessive reactive oxygen species accumulation and glutathione depletion to damage the structural integrity of cells.Due to their high loading and structural tunability,nanocarriers can escort the delivery of ferro-therapeutics to the desired site through enhanced permeation or retention effect or by active targeting.This review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and metastasis.Additionally,we discussed the effect of ferroptosis-mediated therapy using nanoplatforms and their chemical basis in overcoming the barriers to cancer therapy.

关键词： Ferroptosis Nanoparticles Ferrotherapy Cancer Genes Nanotechnology Toxicity Reactive oxygen species

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Author correction to“Immune-awakening Saccharomyces-inspired nanocarrier for oral target delivery to lymph and tumors”[Acta Pharmaceutica Sinica B 12(2022)4501-4518]

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1478-1482页

作者： Yuling Mao Xiudan Wang Caishun Chen Qinfu Zhao Yanfeng Liu Jinghai Zhang Siling Wang department of pharmaceutics School of PharmacyShenyang Pharmaceutical University103 Wenhua RoadShenyang110016China department of Biomedical Engineering School of Medical DevicesShenyang Pharmaceutical University103 Wenhua RoadShenyang110016China School of Life Science and Bio-pharmaceutics Shenyang Pharmaceutical University103 Wenhua RoadShenyang110016China

The authors regret that there is an error in the article Fig.9D1 due to the mistake of copying and pasting in the process of assembling figures and negligence in the proofreading,and also a mislabled error in the supp... 详细信息

关键词： correction supporting proof

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Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

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Oncology Research 2024年第4期32卷 769-784页

作者： HUAN GAO JIE ZHANG TONY GKLEIJN ZHAOYONG WU BING LIU YUJIN MA BAOYUE DING DONGFENG YIN Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics Department of PharmaceuticsCollege of MedicineJiaxing UniversityJiaxing314001China department of pharmacy The General Hospital of Xinjiang Military RegionUrumqi830000China department of Pathology and Medical Biology University Medical Center GroningenUniversity of GroningenGroningen9713 GZThe Netherlands department of Pathology Laboratory of Experimental OncologyErasmus MCRotterdam3015 GDThe Netherlands department of pharmacy Jiaxing Maternal and Child Health Care HospitalAffiliated Hospital of Jiaxing UniversityJiaxing314001China Qinghai Enlu Biotechnology Co. Ltd.Haidong810700China

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

关键词： Pluronic micelles Targeted nanotherapeutics Nanoparticulate drug delivery system Breast cancer with bone metastasis Therapeutic efficacy

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An emerging terpolymeric nanoparticle pore former as an internal recrystallization inhibitor of celecoxib in controlled release amorphous solid dispersion beads:Experimental studies and molecular dynamics analysis

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2669-2684页

作者： Jamie Anne Lugtu-Pe Xuning Zhang Sako Mirzaie Hao Han R.Chang Nour AL-Mousawi Kuan Chen Yongqiang Li Anil Kane Daniel Bar-Shalom Xiao Yu Wu Advanced pharmaceutics and Drug Delivery Laboratory Leslie Dan Faculty of PharmacyUniversity of TorontoToronto M5S 3M2Canada Candoo Pharmatech Company Inc. Mississauga L5N 5M1Canada department of pharmacy University of CopenhagenCopenhagen DK-2100Denmark Patheon by Thermo Fisher Scientific Toronto Region Operations(TRO)Mississauga L5N 3X4Canada

Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate.However,most new chemical entities exhibit poor water solubility,and hence are exempt from such benefits.Although combining drug amorphization with controlled release formulation is promising to elevate drug solubility,like other supersaturating systems,the problem of drug recrystallization has yet to be resolved,particularly within the dosage form.Here,we explored the potential of an emerging,non-leachable terpolymer nanoparticle(TPN)pore former as an internal recrystallization inhibitor within controlled release amorphous solid dispersion(CRASD)beads comprising a poorly soluble drug(celecoxib)reservoir and insoluble polymer(ethylcellulose)membrane.Compared to conventional pore former,polyvinylpyrrolidone(PVP),TPN-containing membranes exhibited superior structural integrity,less crystal formation at the CRASD bead surface,and greater extent of celecoxib release.All-atom molecular dynamics analyses revealed that in the presence of TPN,intra-molecular bonding,crystal formation tendency,diffusion coefficient,and molecular flexibility of celecoxib were reduced,while intermolecular H-bonding was increased as compared to PVP.This work suggests that selection of a pore former that promotes prolonged molecular separation within a nanoporous controlled release membrane structure may serve as an effective strategy to enhance amorphicity preservation inside CRASD.

关键词： Controlled release amorphous solid dispersion Poorly soluble drug Internal recrystallization Membrane-reservoir coated beads Molecular dynamics simulation Effect of pore formers Terpolymer nanogel Drug-polymer interactions

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