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Doxorubicin-conjugated siRNA Lipid nanoparticles for combination cancer therapy

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

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Monitoring the in vivo siRNA release from Lipid nanoparticles based on the fluorescence resonance energy transfer principle

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Asian Journal of Pharmaceutical Sciences 2023年第1期18卷 72-85页

作者： Lei Sun Jinfang Zhang Jing-e Zhou JingWang Zhehao Wang Shenggen Luo Yeying Wang Shulei Zhu Fan Yang Jie Tang Wei Lu Yiting Wang Lei Yu Zhiqiang Yan Institute of Biomedical Engineering and Technology Shanghai Engineering Research Center of Molecular Therapeutics and New Drug DevelopmentSchool of Chemistry and Molecular EngineeringEast China Normal UniversityShanghai 200062China Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development School of Chemistry and Molecular EngineeringEast China Normal UniversityShanghai 200062China

The siRNA-loaded Lipid nanoparticles have attracted much attention due to its significant gene silencing effect and successful marketization.However,the in vivo distribution and release of siRNA still cannot be effectively monitored.In this study,based on the fluorescence resonance energy transfer(FRET)principle,a fluorescence dye Cy5-modified survivin siRNA was conjugated to nanogolds(Au-DR-siRNA),which were then wrapped with Lipid nanoparticles(LNPs)for monitoring the release behaviour of siRNA in vivo.The results showed that once Au-DR-siRNA was released from the LNPs and cleaved by the Dicer enzyme to produce free siRNA in cells,the fluorescence of Cy5 would change from quenched state to activated state,showing the location and time of siRNA release.Besides,the LNPs showed a significant antitumor effect by silencing the survivin gene and a CT imaging function superior to iohexol by nanogolds.Therefore,this work provided not only an effective method for monitoring the pharmacokinetic behaviour of LNP-based siRNA,but also a siRNA delivery system for treating and diagnosing tumors.

关键词： Survivin siRNA Lipid nanoparticles In vivo release Nanogolds Fluorescence resonance energy transfer

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Functionalized Lipid nanoparticles modulate the blood-brain barrier and eliminate α-synuclein to repair dopamine neurons

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 120-135页

作者： Xiaomei Wu Renxiang Yuan Yichong Xu Kai Wang Hong Yuan Tingting Meng Fuqiang Hu Department of Pharmacy Ruijin HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai 200000China College of Pharmaceutical Science Zhejiang UniversityHangzhou 310058China Jinhua Institute of Zhejiang University Jinhua 321299China

The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression. Peptide drugs, such as exenatide (Exe), with potential disease-modifying efficacy, have difficulty in crossing the blood-brain barrier (BBB) due to their large molecular weight. Herein, we fabricate multi-functionalized Lipid nanoparticles (LNP) Lpc-BoSA/CSO with BBB targeting, permeability-increasing and responsive release functions. Borneol is chemically bonded with stearic acid and, as one of the components of Lpc-BoSA/CSO, is used to increase BBB permeability. Immunofluorescence results of brain tissue of 15-month-old C57BL/6 mice show that Lpc-BoSA/CSO disperses across the BBB into brain parenchyma, and the amount is 4.21 times greater than that of conventional LNP. Motor symptoms of mice in Lpc-BoSA/CSO-Exe group are significantly improved, and the content of dopamine is 1.85 times (substantia nigra compacta) and 1.49 times (striatum) that of PD mice. α-Synuclein expression and Lewy bodies deposition are reduced to 51.85% and 44.72% of PD mice, respectively. Immunohistochemical mechanism studies show AKT expression in Lpc-BoSA/CSO-Exe is 4.23 times that of PD mice and GSK-3β expression is reduced to 18.41%. Lpc-BoSA/CSO-Exe could reduce the production of α-synuclein and Lewy bodies through AKT/GSK-3β pathway, and effectively prevent the progressive deterioration of Parkinson's disease. In summary, Lpc-BoSA/CSO-Exe increases the entry of exenatide into brain and promotes its clinical application for Parkinson's disease therapy.

关键词： Blood-brain barrier Lipid nanoparticles Brain delivery facilitation α-Symuclein Parkinson's disease

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β-Lactoglobulin stabilized Lipid nanoparticles enhance oral absorption of insulin by slowing down lipolysis

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Chinese Chemical Letters 2024年第4期35卷 287-291页

作者： Lu Li Suticha Chunta Xianzi Zheng Haisheng He Wei Wu Yi Lu School of Pharmacy&Key Laboratory of Smart Drug Delivery of MOE Fudan UniversityShanghai 201203China Department of Clinical Chemistry Faculty of Medical TechnologyPrince of Songkla UniversitySongkhla 90110Thailand Shanghai Skin Disease Hospital Tongji University School of MedicineShanghai 200433China Fudan Zhangjiang Institute Shanghai 201203China

lipid-based nanocarriers have staged a remarkable comeback in the oral delivery of proteins and peptides, but delivery efficiency is compromised by lipolysis. β-Lactoglobulin(β-lg) stabilized Lipid nanoparticles, including nanoemulsions(NE@β-lg) and nanocapsules(NC@β-lg), were developed to enhance the oral absorption of insulin by slowing down lipolysis due to the protection from β-lg. Cremophor EL stabilized nanoemulsions(NE@Cre-EL) were prepared and set as a control. The Lipid nanoparticles produced mild and sustained hypoglycemic effects, amounting to oral bioavailability of 3.0% ± 0.3%, 7.0% ± 1.1%, and7.7% ± 0.8% for NE@Cre-EL, NE@β-lg, and NC@β-lg, respectively. Aggregation-caused quenching(ACQ)probes enabled the identification of intact nanoparticles, which were used to investigate the in vivo and intracellular fates of the Lipid nanoparticles. In vitro digestion/lipolysis and ex vivo imaging confirmed delayed lipolysis from β-lg stabilized Lipid nanoparticles. NC@β-lg was more resistant to intestinal lipolysis than NE@β-lg due to the Ca^(2+)-induced crosslinking. Live imaging revealed the transepithelial transport of intact nanoparticles and their accumulation in the liver. Cellular studies confirmed the uptake of intact nanoparticles. Slowing down lipolysis via food proteins represents a good strategy to enhance the oral absorption of Lipid nanoparticles and thus co-formulated biomacromolecules.

关键词： β-Lactoglobulin Lipid nanoparticles Oral absorption Insulin Lipolysis Aggregation-caused quenching

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Development of a concentration-controlled sequential nanoprecipitation for making Lipid nanoparticles with high drug loading

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Aggregate 2023年第6期4卷 71-84页

作者： Letao Xu Xing Wang Guangze Yang Zihan Zhao Yilun Weng Yang Li Yun Liu Chun-Xia Zhao Australian Institute for Bioengineering and Nanotechnology The University of QueenslandSt.LuciaQueenslandAustralia School of Chemical Engineering Faculty of SciencesEngincering and TechnologyThe University of AdelaideAdelaideSouth AustraliaAustralia

lipid-based nanostructures have garnered considerable interests over the last two decades,and have achieved tremendous clinical success including theﬁrst clinical approval of a liposome(Doxil)for cancer therapy in 1995 and the recent COVID-19 mRNA lipid nanoparticle vaccines.Compared to liposomes which have a lipid bilayer surrounding an aqueous core,Lipid nanoparticles with a particle structure have several attractive advantages for encapsulating poorly water-soluble drugs such as better stability due to the particle structure,high drug encapsulation efﬁciency because of a pre-or co-drug-loading strategy.While many studies have reported the synthesis of Lipid nanoparticles for hydrophobic drug encapsulation,the pre-cise control of drug loading and encapsulation efﬁciency remains a signiﬁcant challenge.This work reports a new concentration-controlled nanoprecipitation plat-form technology for fabricating Lipid nanoparticles with tunable drug loading up to 70 wt%.This method is applicable for encapsulating a wide range of drugs from very hydrophobic to slightly hydrophilic.Using this facile method,nanoparticles with tunable drug loading exhibited excellent properties such as small particle size,narrow size distribution,good particle stability,showing great promise for future drug delivery applications.

关键词： controlled release drug delivery drug loading Lipid nanoparticles nanoprecipitation

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Scalable synthesis of Lipid nanoparticles for nucleic acid drug delivery using an isometric channel-size enlarging strategy

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Nano Research 2024年第4期17卷 2899-2907页

作者： Zesen Ma Haiyang Tong Sijin Lin Li Zhou Demeng Sun Baoqing Li Changlin Tian Jiaru Chu Department of Precision Machinery and Precision Instrumentation University of Science and Technology of ChinaHefei 230027China Key Laboratory of Precision Scientific Instrumentation of Anhui Higher Education Institutes University of Science and Technology of ChinaHefei 230027China Science Island Branch Graduate SchoolUniversity of Science and Technology of ChinaHefei 230026China Anhui Provincial Key Laboratory of High Field Magnetic Resonance Imaging High Magnetic Field LaboratoryHefei Institute of Physical ScienceChinese Academy of SciencesHefei 230031China Anhui Provincial Engineering Laboratory of Peptide Drugs University of Science and Technology of ChinaHefei 230027China School of Biomedical Engineering Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaSuzhou 215127China

Lipid nanoparticles(LNPs)have emerged as highly effective delivery systems for nucleic acid-based therapeutics.However,the broad clinical translation of LNP-based drugs is hampered by the lack of robust and scalable synthesis techniques that can consistently produce formulations from early development to clinical application.In this work,we proposed a method to achieve scalable synthesis of LNPs by scaling inertial microfluidic mixers isometrically in three dimensions.Moreover,a theoretical predictive method,which controls the mixing time to be equal across different chips,is developed to ensure consistent particle size and size distribution of the synthesized LNPs.LNPs loaded with small interfering RNA(siRNA)were synthesized at different flow rates,exhibiting consistent physical properties,including particle size,size distribution and encapsulation efficiency.This work provides a practical approach for scalable synthesis of LNPs consistently,offering the potential to accelerate the transition of nucleic acid drug development into clinical application.

关键词： Lipid nanoparticles nucleic acid delivery microfluidics scalable synthesis consistent particle size

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Surface engineering of Lipid nanoparticles: targeted nucleic acid delivery and beyond

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Biophysics Reports 2023年第5期9卷 255-278页

作者： Yi Lin Qiang Cheng Tuo Wei State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Department of Biomedical Engineering College of Future Technology Peking University Beijing Institute for Stem Cell and Regenerative Medicine University of Chinese Academy of Sciences

Harnessing surface engineering strategies to functionalize nucleic acid-Lipid nanoparticles(LNPs) for improved performance has been a hot research topic since the approval of the first si RNA drug, patisiran, and two m RNA-based COVID-19 vaccines, BNT162b2 and m RNA-1273. Currently, efforts have been mainly made to construct targeted LNPs for organ-or cell-type-specific delivery of nucleic acid drugs by conjugation with various types of ligands. In this review, we describe the surface engineering strategies for nucleic acid-LNPs, considering ligand types, conjugation chemistries, and incorporation methods. We then outline the general purification and characterization techniques that are frequently used following the engineering step and emphasize the specific techniques for certain types of ligands. Next,we comprehensively summarize the currently accessible organs and cell types, as well as the other applications of the engineered LNPs. Finally, we provide considerations for formulating targeted LNPs and discuss the challenges of successfully translating the “proof of concept” from the laboratory into the clinic. We believe that addressing these challenges could accelerate the development of surfaceengineered LNPs for targeted nucleic acid delivery and beyond.

关键词： Lipid nanoparticles Nucleic acid delivery Surface engineering Targeted delivery

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Storage Stability of Alpha-Lipoic Acid-loaded Lipid nanoparticles

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过程工程学报 2010年第2期10卷 332-338页

作者：唐金国夏强刘光煜 State Key Laboratory of Bioelectronics Southeast UniversityNanjingJiangsu 210096China Suzhou Key Laboratory of Biomedical Materials and Technology SuzhouJiangsu 215123China 3.Suzhou Nanohealth Biotech Co.Ltd. SuzhouJiangsu 215123China Suzhou Nanohealth Biotech Co.Ltd. SuzhouJiangsu 215123China

Alpha-lipoic acid-loaded Lipid nanoparticles(ALA-LNs) were prepared by high pressure homogenization method.The influences of storage conditions such as time and temperature on the physical and chemical storage stability of ALA-LNs were studied in details.The stability was evaluated by particle size and polydispersity index,morphology of ALA-LNs,and capacity of ALA loading.The dilution and pH stability of ALA-LNs suspensions were also studied.After three months storage,the mean size of ALA-LNs at 4 and 40 ℃ was increased by 2.68% and 3.62% compared with the original size,respectively.ALA-LNs stored at 40 ℃ had ellipsoid shape and the mean size was about 152 nm(SD=23.6).The loading capacity of ALA at 40 ℃ was much higher than those stored at other two temperatures.The good dilution and pH stability were also demonstrated.The sample had good fluidity even at 4 ℃.

关键词： alpha-lipoic acid Lipid nanoparticles storage stability particle size particle morphology

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Preparation of oligopeptides grafted Lipid nanoparticles and its application in bone targeting drug delivery system

Preparation of oligopeptides grafted lipid nanoparticles and...

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2018年第十二届中国药物制剂大会

作者：陶珊 Fuqiang Hu Hong Yuan College of Pharmaceutical Sciences Zhejiang University

Osteoporosis is a common degenerative disease which results in abnormal thin and fracture of bones due to the imbalance in bone absorption and bone reconstruction. Nowadays, most of the treatments for osteoporosis are to inhibit bone resorption but not to promote new bone formation. Statins, especially simvastatin（SIM）, have been shown to be potent compounds that increase BMP-2 m RNA expression in osteoblasts so as to promote new bone formation. lipid nanocarriers have been greatly developed in recent years, especially Lipid nanoparticles, which are beneficial for drug retention. Several bone targeting molecules, such as bisphosphonates and tetracycline, have been studied for the treatment of bone disease. However, bisphosphonates can induce nephrotoxicity, hypocalcemia, osteonecrosis of the jaw and ocular dysfunction. Tetracycline has high affinity to hydroxyapatite, while it can make the teeth yellow and inhibit the skeletal growing of children. Oligopeptides, as a biocompatible compound, can accumulate in bones after intravenous injection, which makes it promising in bone targeting. In this study, oligopeptides grafted lipid carriers were synthesized and SIM-loaded Lipid nanoparticles were prepared with solvent diffusion method. In vivo and in vitro pharmacodynamic evaluation of SIM-loaded Lipid nanoparticles were carried out. SIM-loaded Lipid nanoparticles can realized targeting delivery of anti-osteoporosis drug simvastatin.

关键词： bone targeting Lipid nanoparticles simvastatin ASP osteoporosis

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lipid nanomaterials-based RNA therapy and cancer treatment

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Acta Pharmaceutica Sinica B 2023年第3期13卷 903-915页

作者： Xingcai Zhang Luo Hai Yibo Gao Guocan Yu Yingli Sun School of Engineering and Applied Sciences Harvard UniversityCambridge 02138MAUSA Central Laboratory National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital&Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhen 518116China Department of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Laboratory of Translational Medicine National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical Biology Department of ChemistryTsinghua UniversityBeijing 100084China University of Chinese Academy of Sciences Beijing 100101China CAS Key Laboratory of Genome Sciences and Information Beijing Institute of GenomicsChinese Academy of Sciences/China National Center for BioinformationBeijing 100101China

We summarize the most important advances in RNA delivery and nanomedicine.We describe lipid nanoparticle-based RNA therapeutics and the impacts on the development of novel drugs.The fundamental properties of the key RNA members are described.We introduced recent advances in the nanoparticles to deliver RNA to defined targets,with a focus on Lipid nanoparticles(LNPs).We review recent advances in biomedical therapy based on RNA drug delivery and state-of-the-art RNA application platforms,including the treatment of different types of cancer.This review presents an overview of current LNPs based RNA therapies in cancer treatment and provides deep insight into the development of future nanomedicines sophisticatedly combining the unparalleled functions of RNA therapeutics and nanotechnology.

关键词： Antisense oligonucleotides siRNA miRNA mRNA Cancer treatment Nanomedicine RNA therapy Lipid nanoparticles

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