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Mimicking natural cholesterol assimilation to elevate the Oral delivery of liraglutide for type Ⅱ diabetes therapy

Asian Journal of Pharmaceutical Sciences 2022年第5期17卷 653-665页

作者： Ruinan Wu Zhanghan Wu Liyun Xing Xi Liu Lei Wu Zhou Zhou Lian Li Yuan Huang Key Laboratory of Drug-Targeting and Drug delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.However,administration of GLP-RA is mainly through repetitive subcutaneous injection,which may seriously decrease the compliance and safety.Herein,a bio-inspired Oral delivery system was designed to enhance the oral absorption of liraglutide(Lira),a kind of GLP-1 RA,by mimicking the natural cholesterol assimilation.25-hydroxycholesterol(25HC),a cholesterol derivative,was modified on the surfaced of Lira-loaded PLGA nanoparticles(Lira 25HC NPs)and functioned as a“top-down”actuator to facilitate unidirectional transcytosis across the intestinal epithelium.After Oral delivery,Lira 25HC NPs displayed improved therapeutic effect as compared with oral free Lira on typeⅡdiabetes db/db mice,as evidenced by multiple relieved diabetic symptoms including the enhanced glucose tolerance,repressed weight growth,improved liver glucose metabolism,decreased fasting blood glucose,HbA 1c,serum lipid,and increasedβcells activity.Surprisingly,the fasting blood glucose,liver glucose metabolism,and HbA1c of oral Lira-loaded 25HC NPs were comparable to subcutaneous injection of free Lira.Further mechanisms revealed that 25HC ligand could mediate the nanoparticles to mimic natural cholesterol absorption by exerting high affinity towards apical Niemann-Pick C1 Like 1(NPC1L1)and then basolateral ATP binding cassette transporter A1(ABCA1)overexpressed on the opposite side of intestinal epithelium.This cholesterol assimilation-mimicking strategy achieve the unidirectional transport across the intestinal epithelium,thus improving the oral absorption of liraglutide.In general,this study established a cholesterol simulated platform and provide promising insight for the Oral delivery of GLP-1 RA.

关键词： Glucagon-like peptide-1 Oral delivery Cholesterol assimilation Liraglutide TypeⅡdiabetes HbA 1c

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Intestine Enzyme-responsive Polysaccharide-based Hydrogel to Open Epithelial Tight Junctions for Oral delivery of Imatinib against Colon Cancer

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Chinese Journal of Polymer Science 2022年第10期40卷 1154-1164,I0007页

作者： Cong-Yu Wang Min Sun Zhen Fan Jian-Zhong Du Department of Polymeric Materials School of Materials Science and EngineeringTongji UniversityShanghai 201804China Department of Gynaecology and Obstetrics Shanghai Fourth People's HospitalSchool of MedicineTongji UniversityShanghai 200434China

Imatinib has been widely used as a selective kinase inhibitor for treating a variety of cancers,and this molecule is very hydrophobic so it is usually modified with mesylate salt in clinic to increase bioavailability.However,pH-dependent aqueous solubility and relatively high dosage of imatinib mesylate greatly reduce the clinical outcomes.To solve this problem,we developed an intestine enzyme-responsive hydrogel to efficiently encapsulate hydrophobic imatinib with long-term controlled release and enhanced intestinal permeability through oral administration.Methacrylic anhydride-modified carboxymethyl chitosan(MA-CMCS)was synthesized via amidation reaction and then MA-CMCS was crosslinked with photoinitator under UV-irradation to form a three-dimensional hydrophilic polymer network.The intestine enzyme responsiveness was endowed with imatinib-loaded hydrogel through hydrolyzation of glucosidic bond,which could achieve enzyme-triggered long-term drug release of up to 2 days.Furthermore,sodium deoxycholate was embedded into the hydrogel to synchronously open epithelial tight junctions with improved intestinal permeability.In vitro studies revealed similar lethality against colon cancer cell for both imatinib mesylate and imatinib-loaded hydrogels.Moreover,significantly enhanced in vivo tumor inhibition(6-fold higher compared to imatinib mesylate)was achieved after oral administration with imatinib-loaded hydrogels.Overall,this enzyme-responsive hydrogel could achieve long-term synchronous release of kinase inhibitor(imatinib)and tight junction permeation enhancer(sodium deoxycholate)at intestine with enhanced therapeutic efficiency,which could provide an effective approach to improve the bioavailability of hydrophobic anticancer chemodrugs with oral administration.

关键词： Carboxymethyl chitosan Imatinib Hydrogels Oral delivery Tight junctions

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Immune-awakening Saccharomyces-inspired nanocarrier for oral target delivery to lymph and tumors

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Acta Pharmaceutica Sinica B 2022年第12期12卷 4501-4518页

作者： Yuling Mao Xiudan Wang Caishun Chen Qinfu Zhao Yanfeng Liu Jinghai Zhang Siling Wang Department of Pharmaceutics School of PharmacyShenyang Pharmaceutical UniversityShenyang 110016China Department of Biomedical Engineering School of Medical DevicesShenyang Pharmaceutical UniversityShenyang 110016China School of Life Science and Bio-pharmaceutics Shenyang Pharmaceutical UniversityShenyang 110016China

Utilization of the intestinal lymphatic pathway will allow extraordinary gains in lymph and tumors cascade-targeted delivery of oral drugs and awakening the innate/adaptive immunity of the body and the lesion microenvironment,in addition to improving oral bioavailability relative to other means of delivery of oral drugs.Here,inspired by the specific invasion route of intestinal microorganisms,we pioneered an immune-awakening Saccharomyces-inspired mesoporous silicon nanoparticle(yMSN)for the ingenious cascade-targeted delivery of therapeutic cancer vaccines and antitumor drugs to lymph and tumors via the intestinal lymphatic pathway.Encouragingly,yMSN high-loaded tumor-specific antigens(OVA,11.9%)and anti-tumor drugs(Len,28.6%)with high stability,namely Len/OVA/yMSN,efficiently co-delivered OVA and Len to their desired target sites.Moreover,yMSN concomitantly awakened the innate antitumor immunity of dendritic cells and macrophages,strengthening vaccine-induced adaptive immune responses and reversing macrophage-associated immunosuppression in the tumor microenvironment.Surprisingly,Len/OVA/yMSN treatment resulted in excellent synergistic antitumor efficacy and long-term antitumor memory in OVA-Hepa1-6-bearing mice.This high-performance nanocarrier provides a novel approach for lesion-targeting delivery of oral drugs accompanied with awakening of the innate/adaptive immunity of the lesion environment,and also represents a novel path for the Oral delivery of diverse therapeutic agents targeting other lymph-mediated diseases.

关键词： Oral delivery Saccharomyces-inspired Immune-awakening nanoparticles Intestinal lymphatic pathway Vaccine delivery Cascade-targeted delivery Awakening the innate/adaptive immunity Co-delivery

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Bioinspired urease-powered micromotor as an active oral drug delivery carrier in stomach

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Bioactive Materials 2022年第3期7卷 54-62页

作者： Hyunsik Choi Sang Hoon Jeong Tae Yeon Kim Jeeyoon Yi Sei Kwang Hahn Department of Materials Science and Engineering Pohang University of Science and Technology(POSTECH)77 Cheongam-roNam-guPohangGyeongbuk37673South Korea

Self-propelling micro-and nano-motors(MNMs)have been extensively investigated as an emerging oral drug delivery carrier for gastrointestinal(GI)tract diseases.However,the propulsion of current MNMs reported so far is mostly based on the redox reaction of metals(such as Zn and Mg)with severe propulsion gas generation,remaining non-degradable residue in the GI tract.Here,we develop a bioinspired enzyme-powered biopolymer micromotor mimicking the mucin penetrating behavior of Helicobacter pylori in the stomach.It converts urea to ammonia and the subsequent increase of pH induces local gel-sol transition of the mucin layer facilitating the penetration into the stomach tissue layer.The successful fabrication of micromotors is confirmed by high-resolution transmission electron microscopy,electron energy loss spectroscopy,dynamic light scattering analysis,zeta-potential analysis.In acidic condition,the immobilized urease can efficiently converted urea to ammonia,comparable with that of neutral condition because of the increase of surrounding pH during propulsion.After administration into the stomach,the micromotors show enhanced penetration and prolonged retention in the stomach for 24 h.Furthermore,histological analysis shows that the micromotors are cleared within 3 days without causing any toxicity in the GI tract.The enhanced penetration and retention of the micromotors as an active Oral delivery carrier in the stomach would be successfully harnessed for the treatment of various GI tract diseases.

关键词： Micro-and nanomotors Polydopamine Urease Oral delivery Stomach diseases

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In vivo testing of mucus-permeating nanoparticles for oral insulin delivery using Caenorhabditis elegans as a model under hyperglycemic conditions

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Acta Pharmaceutica Sinica B 2021年第4期11卷 989-1002页

作者： Ana LMartínez-López Carlos JGonzález-Navarro Paula Aranaz JoséLVizmanos Juan MIrache NANO-VAC Research Group Department of Chemistry and Pharmaceutical TechnologySchool of Pharmacy and NutritionUniversity of NavarraPamplona 31080Spain Center for Nutrition Research School of Pharmacy and NutritionUniversity of NavarraPamplona 31080Spain Department of Biochemistry&Genetics School of ScienceUniversity of NavarraPamplona 31080Spain Navarra Institute for Health Research(IdiSNA) Pamplona 31080Spain

The aim was to evaluate the potential of mucus-permeating nanoparticles for the oral administration of insulin.These nanocarriers,based on the coating of zein nanoparticles with a polymer conjugate containing PEG,displayed a size of 260 nm with a negative surface charge and an insulin payload of 77 mg/mg.In intestinal pig mucus,the diffusivity of these nanoparticles(PPA-NPs)was found to be 20-fold higher than bare nanoparticles(NPs).These results were in line with the biodistribution study in rats,in which NPs remained trapped in the mucus,whereas PPA-NPs were able to cross this layer and reach the epithelium surface.The therapeutic effcacy was evaluated in Caenorhabditis elegans grown under high glucose conditions.In this model,worms treated with insulin-loaded in PPA-NPs displayed a longer lifespan than those treated with insulin free or nanoencapsulated in NPs.This finding was associated with a signifcant reduction in the formation of reactive oxygen species(ROS)as well as an important decrease in the glucose and fat content in worms.These effects would be related with the mucus-permeating ability of PPA-NPs that would facilitate the passage through the intestinal peritrophic-like dense layer of worms(similar to mucus)and,thus,the absorption of insulin.

关键词： Nanoparticles Oral delivery Mucus-permeating Biodistribution Insulin Caenorhabditis elegans ROS

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Oral delivery of proteins and peptides:Challenges, status quo and future perspectives

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Acta Pharmaceutica Sinica B 2021年第8期11卷 2416-2448页

作者： Quangang Zhu Zhongjian Chen Pijush Kumar Paul Yi Lu Wei Wu Jianping Qi Shanghai Skin Disease Hospital Tongji University School of MedicineShanghai 200443China Key Laboratory of Smart Drug delivery of MOE School of PharmacyFudan UniversityShanghai 201203China Department of Pharmacy Gono Bishwabidyalay(University)Mirzanagar SavarDhaka 1344Bangladesh

Proteins and peptides(PPs)have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy,but fewer side effects.Owing to the poor stability and limited permeability through gastrointestinal(GI)tract and epithelia,the therapeutic PPs are usually administered by parenteral route.Given the big demand for oral administration in clinical use,a variety of researches focused on developing new technologies to overcome GI barriers of PPs,such as enteric coating,enzyme inhibitors,permeation enhancers,nanoparticles,as well as intestinal microdevices.Some new technologies have been developed under clinical trials and even on the market.This review summarizes the history,the physiological barriers and the overcoming approaches,current clinical and preclinical technologies,and future prospects of Oral delivery of PPs.

关键词： Proteins Peptides Oral delivery Permeation enhancer Enzyme inhibitor Stability Clinical

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oral nanoparticles containing naringenin suppress atherosclerotic progression by targeting delivery to plaque macrophages

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Nano Research 2023年第1期16卷 925-937页

作者： Mengran Guo Zhongshan He Zhaohui Jin Lingjing Huang Jingmei Yuan Shugang Qin Xinchun Wang Lili Cao Xiangrong Song Department of Critical Care Medicine Department of Anesthesiology and Translational Neuroscience CenterDepartment of Clinical PharmacyFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610000China First Affiliated Hospital of the Medical College Shihezi UniversityShihezi 832008China College of Medicine Chengdu UniversityChengdu 610000China

Atherosclerosis is the main cause of ischemic stroke and myocardial infarction diseases.Nanoparticles have shown unique benefits for atherosclerosis treatment by targeting the lesional macrophages of plaques.However,most of the nanocarriers are administered intravenously,which is inconvenient and may cause complications.Herein,we developed an oral lipid-polymer based nanoparticles(FA-LNPs)decorated with folic acid,which can not only effectively overcome intestinal mucosal-epithelial barrier by increasing the transmembrane transport through intestinal epithelial and the accumulation in Peyer’s patches but also actively target to the aortic plaque sites and accumulate in lesional macrophages.Subsequently,naringenin(Nrg),one of the antiinflammation drugs,was designed to be the oral nanomedicine(FA-LNPs/Nrg)for the first time via the encapsulation of FALNPs.FA-LNPs/Nrg presented highly anti-atherosclerotic efficacy.After the atherosclerotic ApoE−/−mice were treated by FALNPs/Nrg via oral administration for three months,the aortic lesion area,plaque area,and necrotic core area of the aortic root were significantly decreased.Meanwhile,the lipid-related blood parameters recovered to normal levels.Our study provides a promising approach to atherosclerosis treatment based on the novel oral targeting delivery system.

关键词： atherosclerosis macrophages Peyer’s patches Oral delivery folic acid naringenin

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Mesoporous silica nanoparticles with chiral pattern topological structure function as“antiskid tires”on the intestinal mucosa to facilitate oral drugs delivery

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Asian Journal of Pharmaceutical Sciences 2023年第2期18卷 106-123页

作者： Wei Xin Lin Wang Jiahui Lin Yanbu Wang Qi pan Yang Han Zhiye Bao Shun Zong Ying Cheng Xuchun Chen Lin Zhao Heran Li School of Pharmacy China Medical UniversityShenyang 110122China The First Hospital of China Medical University Shenyang 110001China

The weak adhesion between nanocarriers and the intestinal mucosa was one of the main reasons caused the failure in Oral delivery.Inspired by the“antiskid tires”with complex chiral patterns,mesoporous silica nanoparticles AT-R@CMSN exhibiting geometrical chiral structure were designed to improve the surface/interface roughness in nanoscale,and employed as the hosting system for insoluble drugs nimesulide(NMS)and ibuprofen(IBU).Once performing the delivery tasks,AT-R@CMSN with rigid skeleton protected the loaded drug and reduced the irritation of drug on gastrointestinal tract(GIT),while their porous structure deprived drug crystal and improved drug release.More importantly,AT-R@CMSN functioned as“antiskid tire”to produce higher friction on intestinal mucosa and substantively influencedmultiple biological processes,including“contact”,“adhesion”,“retention”,“permeation”and“uptake”,compared to the achiral S@MSN,thereby improving the oral adsorption effectiveness of such drug delivery systems.By engineering AT-R@CMSN to overcome the stability,solubility and permeability bottlenecks of drugs,orally administered NMS or IBU loaded AT-R@CMSN could achieve higher relative bioavailability(705.95%and 444.42%,respectively)and stronger anti-inflammation effect.In addition,AT-R@CMSN displayed favorable biocompatibility and biodegradability.Undoubtedly,the present finding helped to understand the oral adsorption process of nanocarriers,and provided novel insights into the rational design of nanocarriers.

关键词： Chiral mesoporous silica Bio-adhesion Oral delivery Intestinal mucosa Nanocarrier design

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Milk-derived exosomes as a promising vehicle for Oral delivery of hydrophilic biomacromolecule drugs

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Asian Journal of Pharmaceutical Sciences 2023年第2期18卷 137-149页

作者： Yuting Li Liyun Xing Lingling Wang Xi Liu Licheng Wu Mingjie Ni Zhou Zhou Lian Li Xiuxiu Liu Yuan Huang Key Laboratory of Drug-Targeting and Drug delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we systematically investigated the effects of drug loading methods and physicochemical properties(lipophilicity and molecular weight)on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions.Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method,drug lipophilicity,drug molecular weight and exosome/drug proportions.Of note,we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes,which was attributed to the efficient loading capacity and sustained release behavior.Furthermore,milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs(octreotide,exendin-4 and salmon calcitonin).Collectively,our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.

关键词： Milk-derived exosomes Loading efficiency Drug lipophilicity Molecular weight Drug release Oral delivery

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Overcoming oral insulin delivery barriers： application of cell penetrating peptide and silica-based nanoporous composites

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Frontiers of Chemical Science and Engineering 2013年第1期7卷 9-19页

作者： Huining HE Junxiao YE Jianyong SHENG Jianxin WANG Yongzhuo HUANG Guanyi CHEN Jingkang WANG Victor C YANG School of Chemical Engineering and Technology Tianjin University Tianjin 300072 China Department of Pharmaceutics School of Pharmacy Fudan University Key Laboratory of Smart Drug delivery Ministry of Education & PLA Shanghai 201203 China Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China School of Environmental Science and Engineering State Key Laboratory of Engines Tianjin University Tianjin 300072 China Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics School of Pharmacy Tianjin Medical University Tianjin 300070 China Department of Pharmaceutical Sciences College of Pharmacy University of Michigan Michigan 48109-1065 USA

oral insulin delivery has received the most attention in insulin formulations due to its high patient compliance and, more importantly, to its potential to mimic the physiologic insulin secretion seen in non-diabetic individuals. However, oral insulin delivery has two major limitations： the enzymatic barrier that leads to rapid insulin degradation, and the mucosal barrier that limits insulin＇s bioavailability. Several approaches have been actively pursued to circumvent the enzyme barrier, with some of them receiving promising results. Yet, thus far there has been no major success in overcoming the mucosal barrier, which is the main cause in undercutting insulin＇s oral bioavailability. In this review of our group＇s research, an innovative silica-based, mucoadhesive oral insulin formulation with encapsulated-insulin/cell penetrating peptide （CPP） to overcome both enzyme and mucosal barriers is discussed, and the preliminary and convincing results to confirm the plausibility of this oral insulin delivery system are reviewed. In vitro studies demonstrated that the CPPinsulin conjugates could facilitate cellular uptake of insulin while keeping insulin＇s biologic functions intact. It was also confirmed that low molecular weight protamine （LMWP） behaves like a CPP peptide, with a cell translocation potency equivalent to that of the widely studied TAT. The mucoadhesive properties of the produced silica-chitosan composites could be controlled by varying both the pH and composition; the composite consisting of chitosan （25wt-%） and silica （75 wt-%） exhibited the greatest mucoadhesion at gastric pH. Furthermore, drugrelease from the composite network could also be regulated by altering the chitosan content. Overall, the universal applicability of those technologies could lead to development of a generic platform for Oral delivery of many other bioactive compounds, especially for peptide or protein drugs which inevitably encounter the poor bioavailability issues.

关键词： insulin cell penetrating peptide mucoadhesive composites Oral delivery

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