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Targeted anti-cancer therapy: Co-delivery of VEGF siRNA and Phenethyl isothiocyanate (PEITC) via cRGD-modified lipid nanoparticles for enhanced anti-angiogenic efficacy

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 170-187页

作者： Bao Li Haoran Niu Xiaoyun Zhao Xiaoyu Huang Yu ding Ke Dang Tianzhi Yang Yongfeng Chen Jizhuang Ma Xiaohong Liu Keda Zhang Huichao Xie pingtian ding School of Pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China School of Life Science and Biopharmaceutics Shenyang Pharmaceutical University Shenyang 110016 China Department of Basic Pharmaceutical Sciences School of Pharmacy Husson University Bangor ME 04401USA College of Pharmacy Shenzhen Technology UniversityShenzhen 518118China

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvβ3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.

关键词： Anti-angiogenesis Tumor apoptosis Nanoparticles VEGF siRNA Hypoxia inducible factor(HIF)-1 protein Phenethyl isothi ocyanate(PEITC)

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Predatory bacterial hydrogels for topical treatment of infected wounds

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Acta Pharmaceutica Sinica B 2023年第1期13卷 315-326页

作者： Yan Liu Bo Zhuang Bochuan Yuan Hui Zhang Jingfei Li Wanmei Wang Ruiteng Li Lina Du pingtian ding Yiguang Jin Department of Pharmaceutics School of PharmacyShenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmaceutical Sciences Beijing Institute of Radiation MedicineBeijing 0850China Department of Chemical Defense Institute of NBC DefenseBeijing 102205China

Wound infection is becoming a considerable healthcare crisis due to the abuse of antibiotics and the substantial production of multidrug-resistant bacteria.Seawater immersion wounds usually become a mortal trouble because of the infection of Vibrio vulnificus.Bdellovibrio bacteriovorus,one kind of natural predatory bacteria,is recognized as a promising biological therapy against intractable bacteria.Here,we prepared a B.bacteriovorus-loaded polyvinyl alcohol/alginate hydrogel for the topical treatment of the seawater immersion wounds infected by V.vulnificus.The B.bacteriovorus-loaded hydrogel(BG)owned highly microporous structures with the mean pore size of 90μm,improving the rapid release of B.bacteriovorus from BG when contacting the aqueous surroundings.BG showed high biosafety with no L929 cell toxicity or hemolysis.More importantly,BG exhibited excellent in vitro anti-V.vulnificus effect.The highly effective infected wound treatment effect of BG was evaluated on mouse models,revealing significant reduction of local V.vulnificus,accelerated wound contraction,and alleviated inflammation.Besides the high bacterial inhibition of BG,BG remarkably reduced inflammatory response,promoted collagen deposition,neovascularization and re-epithelization,contributing to wound healing.BG is a promising topical biological formulation against infected wounds.

关键词： Bacterial predator Bdellovibrio bacteriovorus Hydrogel Infected wound Polyvinyl alcohol Sodium alginate Vibrio vulnificus Wound healing

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Opportunities and challenges of three-dimensional printing technology in pharmaceutical formulation development

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Acta Pharmaceutica Sinica B 2021年第8期11卷 2488-2504页

作者： Mengsuo Cui Hao Pan Yupei Su Dongyang Fang Sen Qiao pingtian ding Weisan Pan Department of Pharmaceutics School of PharmacyShenyang Pharmaceutical UniversityShenyang 110016China School of Pharmacy Liaoning University66 Chongshan Middle RoadShenyang 110036China

Three-dimensional printing is a technology that prints the products layer-by-layer,in which materials are deposited according to the digital model designed by computer aided design(CAD)software.This technology has competitive advantages regarding product design complexity,product personalization,and on-demand manufacturing.The emergence of 3 D technology provides innovative strategies and new ways to develop novel drug delivery systems.This review summarizes the application of 3 D printing technologies in the pharmaceutical field,with an emphasis on the advantages of 3 D printing technologies for achieving rapid drug delivery,personalized drug delivery,compound drug delivery and customized drug delivery.In addition,this article illustrates the limitations and challenges of 3 D printing technologies in the field of pharmaceutical formulation development.

关键词： Three-dimensional printing technology Drug delivery system Pharmaceutical Personalized medicine Additive manufacturing On-demand manufacturing Advantages Limitations and challenges

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Molecular weight determination of a newly synthesized guanidinylated disulfide-containing poly(amido amine) by gel permeation chromatography

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Asian Journal of Pharmaceutical Sciences 2017年第3期12卷 292-298页

作者： Haonan Xing Mei Lu Lei Xian Jinmin Zhang Tianzhi Yang Li Yang pingtian ding School of Pharmacy Shenyang Pharmaceutical UniversityShenyangChina Department of Basic Pharmaceutical Sciences School of PharmacyHusson UniversityBangorMEUSA

A cationic gene delivery vector, guanidinylated disulfide-containing poly(amido amine)(CARCBA), was synthesized by Michael addition reaction between N,N′-cystaminebisacrylamide(CBA) and guanidine hydrochloride(CAR). Gel permeation chromatography(GPC) was used to evaluate the molecular weight of synthesized CAR-CBA. Polyethyleneimine(PEI) with molecular weight of 25 kDa was adopted as a reference, and polyethylene glycols(PEG) with different molecular weights were used to establish a standard curve for determining the molecular weight of CAR-CBA. The effects of two critical factors, namely columns and eluents,on the molecular weight measurement of CAR-CBA were investigated to optimize the GPC quantitative method. The results showed that Ultrahydrogel columns(120, 250) and HAc–NaAc(0.5 M, pH 4.5) buffer solution were the optimal column and GPC eluent, respectively.The molecular weight of the synthesized CAR-CBA was analyzed by the optimized GPC method and determined to be 24.66 kDa.

关键词： Guanidinylated disulfide-containing poly(amido amine) Synthesis Cationic gene delivery vector Molecular weight determination Gel permeation chromatography

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Liquisolid technique and its applications in pharmaceutics

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Asian Journal of Pharmaceutical Sciences 2017年第2期12卷 115-123页

作者： Mei Lu Haonan Xing Jingzheng Jiang Xiao Chen Tianzhi Yang Dongkai Wang pingtian ding School of Pharmacy Shenyang Pharmaceutical UniversityShenyangChina Department of Basic Pharmaceutical Sciences School of PharmacyHusson UniversityBangorMEUSA

Most of the newly developed drug candidates are lipophilic and poorly water-soluble. Enhancing the dissolution and bioavailability of these drugs is a major challenge for the pharmaceutical industry. Liquisolid technique, which is based on the conversion of the drug in liquid state into an apparently dry, non-adherent, free flowing and compressible powder,is a novel and advanced approach to tackle the issue. The objective of this article is to present an overview of liquisolid technique and summarize the progress of its applications in pharmaceutics. Low cost, simple processing and great potentials in industrial production are main advantages of this approach. In addition to the enhancement of dissolution rate of poorly water-soluble drugs, this technique is also a fairly new technique to effectively retard drug release. Furthermore, liquisolid technique has been investigated as a tool to minimize the effect of pH variation on drug release and as a promising alternative to conventional coating for the improvement of drug photostability in solid dosage forms. Overall, liquisolid technique is a newly developed and promising tool for enhancing drug dissolution and sustaining drug release, and its potential applications in pharmaceutics are still being broadened.

关键词： Liquisolid technique Dissolution enhancement Poorly water-soluble drugs Sustained release pH variation Photostability

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Exosome-based small RNA delivery:Progress and prospects

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Asian Journal of Pharmaceutical Sciences 2018年第1期13卷 1-11页

作者： Mei Lu Haonan Xing Zhe Xun Tianzhi Yang pingtian ding Cuifang Cai Dongkai Wang Xiaoyun Zhao School of Pharmacy Shenyang Pharmaceutical University Institute of Metabolic Disease Research and Drug Development China Medical University Department of Basic Pharmaceutical Sciences School of Pharmacy Husson University School of Life Science and Biopharmaceutics Shenyang Pharmaceutical University

RNA interfering(RNAi), mediated by small interfering RNAs and microRNAs, is currently one of the most promising tools of gene therapy. Small RNAs are capable of inducing specific post-transcriptional gene silencing, providing a potentially effective platform for the treatment of a wide array of diseases. However, similar to other nucleic acid-based drugs,the major hurdle of RNAi therapy is lack of efficient and non-immunogenic delivery vehicles. Currently, viruses, synthetic polymers, and lipid-based carriers are among the most widely studied vehicles for small RNA delivery. However, many drawbacks are reported to be associated with these delivery vehicles. There is a pressing need to replace them with more efficient and better-tolerated approaches. Exosomes secreted from the endocytic compartment of live cells, are a subtype of endogenous extracellular vesicles that transfer genetic and biochemical information among different cells, thus playing an important role in cellcell communication. Recently, accumulating attention has been focused on harnessing exosomes as nanaocarriers for small RNAs delivery. Due to their natural role in shuttling endogenous nucleic acid in our body, exosomes may exhibit higher delivery efficiency, lower immunogenicity, and better compatibility than existing foreign RNA carriers. Importantly,exosomes own intrinsic homing capacity that can guide small RNAs across natural membranous barriers. Moreover, such a capacity can be further improved by adding appropriate targeting moieties. In this manuscript, we briefly review the progress and challenges of RNAi therapy, and discuss the potential of exosomes' applications in small RNA delivery with focus on the most recent advances in exosome-based small RNA delivery for disease therapy.

关键词： Exosomes RNA interfering Small RNAs Delivery Neurological disorders Tumors

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Advance in bioequivalence assessment of topica dermatological products

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Asian Journal of Pharmaceutical Sciences 2016年第6期11卷 700-707页

作者： Mei Lu Haonan Xing Xiao Chen Lei Xian Jingzheng Jiang Tianzhi Yang pingtian ding School of Pharmacy Shenyang Pharmaceutical UniversityShenyangChina Department of Basic Pharmaceutical Sciences School of PharmacyHusson UniversityBangorMEUSA

Bioequivalence(BE) assessment of topical dermatological products is a long standing challenge. The development of generic topical dermatological products has often been hampered due to the limited number of acceptable approaches, which are capable of determining the BE between generic products and reference list products. The aim of this manuscript is to review different BE assessment approaches of topical dermatological products. Besides, the advances in BE evaluation and biowaivers are also provided. Currently, except in the case of dermatological corticosteroids, the golden rule to establish the BE of most topical dermatological products still heavily relied on clinical endpoint trials,which are often unreliable, time-consuming and expensive. The regulatory agencies and pharmaceutical industries are forging ahead to the development of new surrogate BE assessment approaches for other topical dermatological products. These promising approaches include dermatopharmacokinetic study(DPK), dermal microdialysis(DMD), in vitro studies, pharmacokinetic study(PK), near-infrared spectrometry(NIR), and confocal Raman spectroscopy(CRS). In addition, the expansion of biowaivers for topical dermatological products has been explored by pharmaceutical scientists. In conclusion, to accelerate the development and approval of topical dermatological products, emphasis should be put on the following areas, i.e., optimizing and standardizing the existing BE assessment methods, exploring novel alternatives of BE assessment approaches, and expanding biowaivers for topical dermatological products.

关键词： Bioequivalence assessment Generic Topical dermatological products Biowaiver

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The development of polycarbophil as a bioadhesive material in pharmacy

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Asian Journal of Pharmaceutical Sciences 2013年第4期8卷 218-227页

作者： Zhaolu Zhu Yinglei Zhai Ning Zhang Donglei Leng pingtian ding School of Pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China School of Medical Devices Shenyang Pharmaceutical UniversityShenyang 110016China

Polycarbophil(PCP),a kind of pharmaceutical polymers with superior bioadhesive properties has been widely used in the field of controlled drug delivery systems.It could be used as a highly efficient thickener,bioadhesive agent,suspending aid and emulsion stabilizer when dispersed in water or other polar solvents.These exceptional utilities of the polymers result from their hydrophilic nature.Hydrogen bonding plays an important role in most adhesion behaviours and becomes the main adhesion force.This paper reviews the applications of PCP in pharmacy over the past decades,and clarifies its unique advantages in the bioadhesive formulations.After an introduction discussing its structural characteristics and action mechanism,the focus turned to the description of its available applications in detail with particular emphasis on the ocular,nasal,vagina and oral drug delivery systems.The other less developed formulations are also described,including the buccal and the transdermal delivery systems.

关键词： Polycarbophil Bioadhesive Hydrogen bonding Bioavailability Drug delivery systems

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A simple method to improve the dissolution of repaglinide and exploration of its mechanism

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Asian Journal of Pharmaceutical Sciences 2014年第4期9卷 218-225页

作者： Zhaolu Zhu Tianzhi Yang Yanan Zhao Nannan Gao Donglei Leng pingtian ding School of Pharmacy Shenyang Pharmaceutical UniversityNo.103Wenhua RoadShenyang 110016China Department of Basic Pharmaceutical Sciences School of PharmacyHusson University1 College CircleBangorME 04401USA

In the present study,a simple and rapid method was developed to improve the in vitro dissolution of repaglinide,an oral antidiabetic drug,which was based on addition of meglumine in 50%(v/v)ethanol to dissolve repaglinide,and the drug dissolved in meglumine/50%ethanol was used directly with a binder to prepare tablets.The mechanism of solubilization of repaglinide by meglumine was studied by using infrared spectrum(IR),ultraviolet(UV)measurement through dual wavelength,differential scanning calorimetry(DSC)and X-ray powder diffraction methods.Dissolution tests of repaglinide tablets were performed in the media with different pH values and the repaglinide concentrations were analyzed by High Performance Liquid Chromatography(HPLC)method.The solubility data showed that with the meglumine concentration increasing,the solubility of repaglinide was increased.Meanwhile,tablets with the molar ratio of repaglinide and meglumine 1:2(n/n)resulted in a significant increase in dissolution compared to the repaglinide tablets without using meglumine,and nearly equal to the commercial preparations of Novo-Norm^(®),which concluded that meglumine had a great role in promoting the dissolution of repaglinide.The results of IR and UV dual wavelength methods suggested the formation of repaglinideemeglumine(REPeMEG)molecular complex.DSC results showed that the melting peak of repaglinide disappeared in the REPeMEG coprecipitate,which indicated that repaglinide was stable when existing at amorphous or molecular state.The experiment of X-ray powder diffraction showed that with the solubilization of meglumine,the crystal diffraction peak of repaglinide disappeared,which further inferred that repaglinide was formed complexes with meglumine.It was demonstrated that the method of improving repaglinide with meglumine was reliable and could be suitable for repaglinide tablets production in industry.This study also provides a feasible way to enhance the dissolution of drugs with low solubility,which will be leading to improved bioavailability

关键词： In vitro dissolution Repaglinide Meglumine Solubilization Molecular complex

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Comparative pharmacokinetics of tetramethylpyrazine phosphate in rat plasma and extracellular fluid of brain after intranasal,intragastric and intravenous administration

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Acta Pharmaceutica Sinica B 2014年第1期4卷 74-78页

作者： Dongmei Meng Haoyang Lu Shanshan Huang Minyan Wei pingtian ding Xianglin Xiao Yuehong Xu Chuanbin Wu School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China The First Affiliated Hospital of Guangzhou Medical College Guangzhou 510120China School of Pharmacy Shenyang Pharmaceutical UniversityShenyang110016China

The purpose of this study was to compare the pharmacokinetic profiles of tetramethylpyrazine phosphate(TMPP)in plasma and extracellular fluid of the cerebral cortex of rats via three delivery routes:intranasal(i.n.),intragastric(i.g.)and intravenous(i.v.)administration.After i.n.,i.***.and i.***.administration of a single-dose at 10 mg/kg,cerebral cortex dialysates and plasma samples drawn from the carotid artery were collected at timed intervals.The concentration of TMPP in the samples was analyzed by HPLC.The area under the concentration-time curve(AUC)and the ratio of the AUCbrain to the AUCplasma(drug targeting efficiency,DTE)was calculated to evaluate the brain targeting efficiency of the drug via these different routes of administration.After i.***.administration,TMPP was rapidly absorbed to reach its peak plasma concentration within 5 min and showed a delayed uptake into cerebral cortex(t_(max)=15 min).The ratio of the AUCbrain dialysates value between i.***.route and i.***.injection was 0.68,which was greater than that obtained after i.***.administration(0.43).The systemic bioavailability obtained with i.***.administration was greater than that obtained by the i.***.route(86.33%vs.50.39%),whereas the DTE of the nasal route was 78.89%,close to that of oral administration(85.69%).These results indicate that TMPP is rapidly absorbed from the nasal mucosa into the systemic circulation,and then crosses the blood-brain barrier(BBB)to reach the cerebral cortex.Intranasal administration of TMPP could be a promising alternative to intravenous and oral approaches.

关键词： Tetramethylpyrazine phosphate Intranasal delivery Pharmacokinetics Microdialysis Rat

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