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Chylomicron-mimicked Bio-self-assembling MSNs to improve bioavailability of Oral Drugs via Promoting lymphatic transport

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Chylomicron-mimicked Bio-self-assembling MSNs to improve bio...

The feasibility of oral targeted drug delivery: Gut immune to particulates?

2018年第十二届中国药物制剂大会

作者：毛玉玲 Qinfu ZHAO Da WANG Siling WANG Department of Pharmaceutics School of Pharmacy Shenyang Pharmaceutical University

lymphatic transport of oral drugs allows extraordinary gains in bioavailability and efficacy through avoidance of first-pass hepatic metabolism and reservation drugs at lymphatic tissues against lymphmediated diseases. This drug absorption pathway plays a win-win role in both pharmacokinetics and pharmacodynamics for antiretroviral therapy to fully suppress HIV. Herein, with the inspiration of triglyceride digestion process in the daily diet, we engineered a triglyceride-mimicked mesoporous silica nanocarrier（namely TMCMS） to promote lymphatic transport of antiretroviral drugs. Taking lopinavir（LNV） as a model antiretroviral drug with hurdles of poor solubility, high first pass effect and off-target disposition, TMCMS vector exhibited several properties belonging to ideal nanocarriers of high drug load, amorphous dispersion and controlled release in gastrointestinal tract, and also a perfect hydrolysis performance similar to TG pre-uptake. Subsequently, TMCMS showed a serious of TG-mimetic transport features across intestinal epithelial cells: hydrolysis–re-esterification–chylomicron assembly, participating into such a biochemical process and self-assembling to a chylomicron-associated TMCMS（namely TMCMS@CM） in enterocytes. As a result, TMCMS brought 10.6 folds oral bioavailability through circumventing first-pass metabolism through lymphatic transport pathway. Our study provides evidences of using the bio-selfassembling TMCMS nanocarrier to facilitate bioavailability and efficacy via lymphatic transport of oral drugs.

关键词： lymphatic transport antiretroviral therapy oral bioavailability first-pass metabolism lymphatic target mesoporous silica nanocarrier lopinavir

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药学学报:英文版 2023年第6期13卷 2544-2558页

作者： Yuehong Ren Wei Wu Xingwang Zhang Department of Pharmaceutics College of PharmacyJinan UniversityGuangzhou 511443China Center for Medical Research and Innovation Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghai 201399China Key Laboratory of Smart Drug Delivery of MOE School of PharmacyFudan UniversityShanghai 201203China

Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration(oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake.

关键词： Oral targeted drug delivery Biological barriers In vivo fate Nanoparticles transport mechanisms Delivery strategies lymphatic transport Feasibility

Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 188-203页

作者： Mingyang Zhang Yifan Miao Can Zhao Tong Liu Xiyan Wang Zixuan Wang Wenxin Zhong Zhonggui He Chutong Tian Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province Hangzhou 310058China Joint International Research Laboratory of Intelligent Drug Delivery Systems Ministry of EducationShenyang 110016China Liaoning Provincial Institute of Drug Inspection and Testing Shenyang 110036China

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

关键词： Steric disulfide bond Triglyceride-like pr odrugs Cabazitaxel lymphatic transport Oral chemotherapy

Advanced delivery strategies facilitating oral absorption of heparins

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Asian Journal of Pharmaceutical Sciences 2020年第4期15卷 449-460页

作者： Guihua Fang Bo Tang School of Pharmacy Nantong University19 Qixiu RoadNantong 226001China

Heparins show great anticoagulant effect with few side effects,and are administered by subcutaneous or intravenous route in clinics.To improve patient compliance,oral administration is an alternative route.Nonetheless,oral administration of heparins still faces enormous challenges due to the multiple obstacles.This review briefly analyzes a series of barriers ranging from poorly physicochemical properties of heparins,to harsh biological barriers including gastrointestinal degradation and pre-systemic metabolism.Moreover,several approaches have been developed to overcome these obstacles,such as improving stability of heparins in the gastrointestinal tract,enhancing the intestinal epithelia permeability and facilitating lymphatic delivery of heparins.Overall,this review aims to provide insights concerning advanced delivery strategies facilitating oral absorption of heparins.

关键词： Heparins Oral delivery Multiple obstacles Stability Intestinal epithelia permeability lymphatic transport

Self-microemulsifying drug delivery system for improving the bioavailability of huperzine A by lymphatic uptake

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Acta Pharmaceutica Sinica B 2017年第3期7卷 353-360页

作者： Fang Li Rongfeng Hu Bin Wang Yun Gui Gang Cheng Song Gao Lei Ye Jihui Tang Anhui University of Chinese Medicine Hefei 230038China National Chinese Medicinal Materials Products Quality Supervision and Inspection Center(Anhui) Bozhou 236800China Key Laboratory of Xin'an Medicine Ministry of Education Hefei 230038China Anhui“115”Xin'an Traditional Chinese Medical Research&Development Innovation Team Hefei 230038China Anhui Province Key Laboratory of R&D of Chinese Medicine Hefei 230038China School of Pharmacy Anhui Medical UniversityHefei 230022China

Huperzine A(Hup-A) is a poorly water-soluble drug with low oral bioavailability. A selfmicroemulsifying drug delivery system(SMEDDS) was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion(SPIP) technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration–time curve(AUC) of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension(P transport mechanism, and the values of K_a and P_(app) of Hup-A SMEDDS in the ileum were much higher than those in other intestinal segments. The determination of Hup-A concentration in mesenteric lymph nodes can be used to explain the intestinal lymphatic absorption of Hup-A SMEDDS. For Hup-A SMEDDS, the values of AUC and maximum plasma concentration(C_(max)) of the blocking model were significantly lower than those of the control model(Plymphatic transport of Hup-A SMEDDS and Hup-A suspension were about 40% and 5%,respectively, suggesting that SMEDDS can significantly improve the intestinal lymphatic uptake and transport of Hup-A.

关键词： Huperzine A Self-microemulsion Drug delivery systems SMEDDS Bioavailability Single-pass intestinal perfusion lymphatic transport