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Paclitaxel-lipid prodrug liposomes for improved drug delivery and breast carcinoma therapy

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Chinese Chemical Letters 2024年第2期35卷 335-340页

作者： Xin Wu Xinmei Chen Xinyu Wang haisheng he Jianming Chen Wei Wu Key Laboratory of Smart Drug Delivery of MOE School of PharmacyFudan UniversityShanghai 201203China Department of Pharmacy Fujian University of Traditional Chinese MedicineFuzhou 350122China Shanghai Wei Er Lab Shanghai 201707China Shanghai Skin Disease Hospital Tongji University School of MedicineShanghai 200443China

Paclitaxel(PTX)is widely applied for the treatment of unresectable and metastasis breast carcinoma as well as other cancers,whereas its efficacy is always impeded by poor *** are one kind of the most successful drug carriers which are capable of solubilizing PTX and improving patients’tolerance owing to excellent biocompatibility and ***,poor compatibility between PTX and liposomes compromises the stability,drug loading and anti-tumor capacity of liposomal *** address this issue,three lipids with various chain lengths,namely,myristic acid(MA,14C),palmitic acid(PA,16C)and stearic acid(SA,18C),were conjugated to PTX via ester bonds and the synthesized prodrugs with high lipophilicity were further formulated into liposomes,*** liposomes show high stability and drug loadings,as well as sustained drug *** chain lengths of lipids are negatively correlated with drug release and enzymatic conversion rates,which further impact the pharmacokinetics,tumor accumulation,and anti-tumor efficacy of liposomal *** rapid nor slow drug release facilitates high tumor accumulation as well as anti-tumor efficacy of *** all liposomes,PTX-PA-loaded liposomes show the longest circulation and highest tumor accumulation of PTX and exert the most potent anti-tumor capacities in vivo,owing to its moderate drug release and enzymatic conversion *** its superior safety,PTX-PA liposomes hold potential for further clinical translation.

关键词： Paclitaxel Lipids Prodrugs Liposomes Drug release Chemotherapy

Adapting liposomes for oral drug delivery

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Acta Pharmaceutica Sinica B 2019年第1期9卷 36-48页

作者： haisheng he Yi Lu Jianping Qi Quangang Zhu Zhongjian Chen Wei Wu Key Laboratory of Smart Drug Delivery of MOE and PLA School of Pharmacy Fudan University Shanghai Dermatology Hospital

Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes,oral delivery of liposomes is impeded by various barriers such as instability in the gastrointestinal tract,difficulties in crossing biomembranes, and mass production problems. By modulating the compositions of the lipid bilayers and adding polymers or ligands, both the stability and permeability of liposomes can be greatly improved for oral drug delivery. This review provides an overview of the challenges and current approaches toward the oral delivery of liposomes.

关键词： Liposomes Oral Drug delivery Stability Absorption Bioavailability

Oral delivery of insulin by barbed microneedles actuated by intestinal peristalsis

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Chinese Chemical Letters 2024年第9期35卷 6-8页

作者： Qin Yu haisheng he Jianping Qi Yi Lu Wei Wu Shanghai Skin Disease Hospital Tongji University School of MedicineShanghai 200443China Key Laboratory of Smart Drug Delivery of MOE School of PharmacyFudan UniversityShanghai 201203China

Oral formulations are always preferred to injections due to the advantages of high patient compliance,no biohazardous needle waste,and low requirements for administration ***,the presence of multiple gastrointestinal(GI)barriers,including extreme gastric acidity and a broad pH gradient,digestive enzymes,thick and variable mucus layers,and tight junctions in the enteric epithelia,restricts the rate and extent of oral *** active ingredients with favorable physicochemical properties.

关键词： needle extreme formulation

Biomimetic thiamine- and niacin-decorated liposomes for enhanced oral delivery of insulin

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Acta Pharmaceutica Sinica B 2018年第1期8卷 97-105页

作者： haisheng he Yi Lu Jianping Qi Weili Zhao Xiaochun Dong Wei Wu Key Laboratory of Smart Drug Delivery of MOE and PLA School of Pharmacy Fudan University

Biomimetic nanocarriers are emerging as efficient vehicles to facilitate dietary absorption of biomacromolecules. In this study, two vitamins, thiamine and niacin, are employed to decorate liposomes loaded with insulin, thus facilitating oral absorption via vitamin ligand–receptor interactions. Both vitamins are conjugated with stearamine, which works to anchor the ligands to the surface of *** prepared under optimum conditions have a mean particle size of 125–150 nm and an insulin entrapment efficiency of approximately 30%–36%. Encapsulation into liposomes helps to stabilize insulin due to improved resistance against enzymatic disruption, with 60% and 80% of the insulin left after 4 h when incubated in simulated gastric and intestinal fluids, respectively, whereas non-encapsulated insulin is broken down completely at 0.5 h. Preservation of insulin bioactivity against preparative stresses is validated by intra-peritoneal injection of insulin after release from various liposomes using the surfactant Triton X-100. In a diabetic rat model chemically induced by streptozotocin, both thiamine-and niacindecorated liposomes showed a comparable and sustained mild hypoglycemic effect. The superiority of decorated liposomes over conventional liposomes highlights the contribution of vitamin ligands. It is concluded that decoration of liposomes with thiamine or niacin facilitates interactions with gastrointestinal vitamin receptors and thereby facilitates oral absorption of insulin-loaded liposomes.

关键词： Liposomes Vitamin Thiamine Niacin Insulin Biomimetic Oral Drug delivery

The intragastrointestinal fate of paclitaxel-loaded micelles:Implications on oral drug delivery

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Chinese Chemical Letters 2021年第4期32卷 1545-1549页

作者： Iqbal Zoya haisheng he Luting Wang Jianping Qi Yi Lu Wei Wu Key Laboratory of Smart Drug Delivery of MOE School of PharmacyFudan University.Shanghai 201203China Center for Medical Research and Innovation Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghai 201399China

The goal of the present study is to elucidate the intragastrointestinal fate of micellar delivery systems by monitoring fluorescently labeled different micelles and the model drug paclitaxel(PTX).Both in vitro and ex vivo leakage studies showed fast PTX release in fluids while micelles remained intact,except in fedstate simulated intestinal fluid and fasted-state pig intestinal fluid,thus referring to the intact absorption of micelles and PTX leakage in the gastrointestinal tract with D-a-tocopherol polyethylene glycol 1000 succinate(TPGS)micelles showing higher stability than other *** groups of micelles were absorbed intact in Caco-2 and Caco-2/HT29-MTX cell models and the absorption of TPGS micelles was found to be higher than other *** transport of the micelles across Caco-2/Raji(1.6%-3.5%),Caco-2(0.8%-1%),and Caco-2/HT29-MTX(0.58%-1%)cell monolayers further verified the absorption of micelles and their subsequent transport;however,more TPGS micelles transported across cell monolayers than other ***,the histological examination also confirmed that micelles ente red the enterocytes and were transported to basolateral tissues and TPGS showed the stronger ability of penetration than other ***,these results are succinctly presenting the absorption of intact micelles in GIT confirmed by imaging evidence with prior leakage of the drug,upta ke by enterocytes and the transport of micelles that survive the digestion by enterocytes and mainly by microfold cells in material nature dependent way with TPGS showing better results than other *** conclusion,these results identify the mechanism by which the gastrointestinal tract processes micelles and point to the likely use of this approach in the design of micelles-based therapies.

关键词： Drug delivery Oral Micelles Paclitaxel In vivo fate

Rod-like mesoporous silica nanoparticles facilitate oral drug delivery via enhanced permeation and retention effect in mucus

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Nano Research 2022年第10期15卷 9243-9252页

作者： Wenjuan Liu Luyu Zhang Zirong Dong Kaiheng Liu haisheng he Yi Lu Wei Wu Jianping Qi School of Pharmacy Key Laboratory of Smart Drug Delivery of MOEFudan UniversityShanghai 201203China

The physiochemical characteristics of nanoparticles affect their in vitro and in vivo performance significantly,such as diameter,surface chemistry,and *** paper disclosed the effect of enhanced permeation and retention(EPR)in mucus caused by nanoparticle shape on improving oral *** spherical and rod-like mesoporous silica nanoparticles(MSNs)were used to evaluate shape effect of EPR in *** was loaded in MSNs as model *** in vitro release of fenofibrate from MSNs was dependent on nanoparticle shapes,but faster than that of raw *** drug release slowed down with the increase of aspect ratio due to longer channels in rod-like MSNs with higher aspect ***,in vivo study showed that the oral bioavailability of fenofibrate was the highest after loading in rod-like MSNs with aspect ratio of *** in vitro study of mechanisms revealed that superior mucus diffusion ability of rod-like MSNs with aspect ratio of 5 was conductive to higher ***,more rod-like MSNs with higher aspect ratio were able to diffuse into mucus and reside there compared to spherical and short counterparts,which demonstrated higher aspect ratio was beneficial to EPR effect of nanoparticles in *** study provides significant implication in rational oral drug carrier design.

关键词： mesoporous silica nanoparticles shape effect fenofibrate mucus layer enhanced permeation and retention effect

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

The long-circulating effect of pegylated nanoparticles revisited via simultaneous monitoring of both the drug payloads and nanocarriers

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2479-2493页

作者： Wufa Fan Haixia Peng Zhou Yu Luting Wang haisheng he Yuhua Ma Jianping Qi Yi Lu Wei Wu Key Laboratory of Smart Drug Delivery of MOE School of PharmacyFudan UniversityShanghai 201203China Center for Medical Research and Innovation Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghai 201399China Shanghai Skin Disease Hospital Tongji University School of MedicineShanghai 200443China Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province School of PharmacyQinghai Nationalities UniversityXining 810007China

The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin(DOX)-loaded methoxy polyethylene glycol-polycaprolactone(mPEG-PCL) nanoparticles. Comparison of the kinetic profiles of both DOX and nanocarriers verifies the long-circulating effect, though of limited degree, as a result of pegylation. The nanocarrier profiles display fast clearance from the blood despite dense PEG decoration;DOX is cleared faster than the nanocarriers. The nanocarriers circulate longer than DOX in the blood, suggesting possible leakage of DOX from the nanocarriers. hepatic accumulation is the highest among all organs and tissues investigated, which however is reversely proportionate to blood circulation time. Pegylation and reduction in particle size prove to extend circulation of drug nanocarriers in the blood with simultaneous decrease in uptake by various organs of the mononuclear phagocytic system. It is concluded that the long-circulating effect of mPEG-PCL nanoparticles is reconfirmed by monitoring of either DOX or the nanocarriers, but the faster clearance of DOX suggests possible leakage of a fraction of the payloads. The findings of this study are of potential translational significance in design of nanocarriers towards optimization of both therapeutic and toxic effects.

关键词： Long-circulating In vivo fate Aggregation-caused quenching Nanoparticles mPEG-PCL Doxorubicin Drug delivery Pharmacokinetics

Julolidinyl aza-BODIPYs as NIR-Ⅱ fluorophores for the bioimaging of nanocarriers

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3155-3168页

作者： Chang Liu Yifan Cai Zichen Zhang Yi Lu Quangang Zhu haisheng he Zhongjian Chen Weili Zhao Wei Wu 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 MediChinal Chemistry School of PharmacyFudan UniversityShanghai 201203China

The aggregation-caused quenching(ACQ)rationale has been employed to improve the fluorescence imaging accuracy of nanocarriers by precluding free probe-derived ***,its usefulness is undermined by limited penetration and low spatiotemporal resolution of NIR-Ⅰ(700-900 nm)bioimaging owing to absorption and diffraction by biological tissues and tissue-derived *** study aimed to develop ACQ-based NIR-Ⅱ(1000-1700 nm)probes to further improve the imaging resolution and *** strategy employed is to install highly planar and electron-rich julolidine into the 3,5-position of aza-BODIPY based on the larger substituent *** newly developed probes displayed remarkable photophysical properties,with intense absorption centered at approximately 850 nm and bright emission in the 950-1300 nm *** with the NIR-Ⅰ counterpart P2,the NIR-Ⅱ probes demonstrated superior water sensitivity and quenching ***1 and ACQ6 exhibited more promising ACQ effects with absolute fluorescence quenching at water fractions above 40% and higher quenching stability with less than 2.0% fluorescence reillumination in plasma after 24 h of *** calculations verified that molecular planarity is more important than hydrophobicity for ACQ ***,in vivo and ex vivo reillumination studies revealed less than 2.5% signal interference from prequenched ACQ1,in contrast to 15% for P2.

关键词： 3,5-Julolidinyl Aza-BODIPY Nanocarriers Near-infraredⅡ Fluorescence imaging Aggregation-caused quenching Polymeric micelles Polymeric nanoparticles