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Carrier-free highly drug-loaded biomimetic Nanosuspensions encapsulated by cancer cell membrane based on homology and active targeting for the treatment of glioma

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Bioactive Materials 2021年第12期6卷 4402-4414页

作者： Yueyue Fan Yuexin Cui Wenyan Hao Mengyu Chen Qianqian Liu Yuli Wang Meiyan Yang Zhiping Li Wei Gong Shiyong Song Yang Yang Chunsheng Gao College of Pharmacy Henan UniversityKaifeng475000PR China State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing100850PR China

Nanosuspensions,as a new drug delivery system for insoluble drugs,are only composed of a drug and a small amount of stabilizer,which is dispersed in an aqueous solution with high drug-loading,small particle size,high dispersion,and large specific surface area.It can significantly improve the dissolution,bioavailability,and efficacy of insoluble drugs.In this study,paclitaxel Nanosuspensions((PTX)NS)were prepared by an ultrasonic precipitation method,with the characteristics of simple preparation and easy repetition.With the help of a homologous targeting mechanism,a kind of glioma C6 cancer cell membrane(CCM)-coated(PTX)NS was developed and modified with DWSW peptide to obtain DWSW-CCM-(PTX)NS with the functions of BBB penetration and tumor targeting.The results showed that the cancer cell membrane could effectively camouflage the Nanosuspensions so that it was not cleared by the immune system and could cross the blood-brain-barrier(BBB)and selectively target tumor tissues.Cell uptake experiments and in vivo imaging confirmed that the uptake of DWSW-CCM-(PTX)NS by tumor cells and the distribution in intracranial gliomas increased.Cytotoxicity test and in vivo anti-glioma studies showed that DWSW-CCM-(PTX)NS could significantly inhibit the growth of glioma cells and significantly prolong the survival time of glioma-bearing mice.Finally,the cancer cell membrane coating endowed the Nanosuspensions with the biological properties of homologous adhesion and immune escape.This study provides an integrated solution for improving the targeting of Nanosuspensions and demonstrates the encouraging potential of biomimetic Nanosuspensions applicable to tumor therapy.

关键词： Nanosuspensions Cancer cell membrane Biomimetic drug-delivery systems Gliomas Blood-brain barrier Paclitaxel

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Combined Nanosuspensions from two natural active ingredients for cancer therapy with reduced side effects

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Chinese Chemical Letters 2021年第9期32卷 2877-2881页

作者： Yonghui Qiao Zhihao Wei Tingting Qin Rufeng Song Zhiqiang Yu Qi Yuan Juan Du Qingbing Zeng Lanlan Zong Shaofeng Duan Xiaohui Pu Henan University of Chinese Medicine Zhengzhou 450046China Institute of Pharmacy School of PharmacyHenan UniversityKaifeng 475004China School of Pharmaceutics Sciences Southern Medical UniversityGuangzhou 510515China Department of Pharmacy The Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhou 450003China

Tumor drug resistance and systemic side effects of chemotherapeutic drugs are the main reasons for the failure of cancer treatment.In recent years,it was found that some natural active ingredients can reverse MDR and regulate body immunity to enhance the efficacy and reduce toxicity of chemotherapeutic drugs.In this paper,a new Nanosuspensions,HCPT and QUR hybrid Nanosuspensions(HQ-NPs),was prepared by the microprecipitation-high pressure homogenization method to reverse tumor drug resistance,reduce toxicity,and increase therapeutic efficacy.The in vitro investigation results showed that HQ-NPs had a unique shape(particle size was about 216.3±5.9 nm),changed crystalline,and different dissolution rates compared with HCPT-NPs and QUR-NPs,which is attributed to the strong intermolecular forces between HCPT and QUR as indicated by the results of the molecule dock.It was verified that the HQ-NPs could double the retention of HCPT in cells and enhance the cytotoxicity to A549/PTX cells in vitro tests compared with HCPT-NPs.We also found that HQ-NPs can significantly enhance the accumulation of HCPT in tumor sites,improve the antitumor activity of HCPT,and protect the immune organs and other normal tissues(PNanosuspensions can offer promising potential as the drug delivery system for HCPT and QUR to increase the therapeutic efficacy and reduce the toxicity of HCPT.

关键词： Combination therapy Multidrug resistance Nanosuspensions Antitumor activity Immunomodulatory

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Improved stability and oral bioavailability of Ganneng dropping pills following transforming lignans of herpeto- spermum caudigerum into Nanosuspensions

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Chinese Journal of Natural Medicines 2018年第1期16卷 70-80页

作者： LI Juan-Juan CHENG Ling SHEN Gang QIU Ling SHEN Cheng-Ying ZHENG Juan XU Rong YUAN Hai-Long Department of Pharmacy Air Force General Hospital of PLA Beijing 100142 China Department of Pharmacy Guangyuan Central Hospital Guanyuan 628000 China Department of Pharmacy Shuangliu District Maternal and Child Health Hospital Chengdu 610075 China Chengdu Institute of Chinese Herbal Medicine Chengdu 610045 China

The present study was designed to improve storage stability and oral bioavailability of Ganneng dropping pills(GNDP) by transforming lignans of Herpetospermum caudigerum(HL) composed of herpetrione(HPE) and herpetin(HPN) into nanosuspension(HL-NS), the main active ingredient of GNDP, HL-NS was prepared by high pressure homogenization and lyophilized to transform into solid nanoparticles(HL nanoparticles), and then the formulated HL nanoparticles were perfused into matrix to obtain NS-GNDP by melting method. For a period of 3 months, the content uniformity, storage stability and pharmacokinetics test in vivo of NS-GNDP were evaluated and compared with regular GNDP at room temperature. The results demonstrated that uniformity of dosage units of NS-GNDP was acceptable according to the criteria of Chinese Pharmacopoeia 2015 J. Physical stability of NS-GNDP was investigated systemically using photon correlation spectroscopy(PCS), zeta potential measurement, and scanning electron microscopy(SEM). There was a slight increase in particles and PI of HL-NS re-dispersed from NS-GNDP after storage for 3 months, compared with new formulated NS-GNDP, which indicated a good redispersibility of the NS-GNDP containing HL-NS after storage. Besides, chemical stability of NS-GNDP was studied and the results revealed that HPE and HPN degradation was less when compared with that of GNDP, providing more than 99% of drug residue after storage for 3 months. In the dissolution test in vitro, NS-GNDP remarkably exhibited an increased dissolution velocity compared with GNDP and no distinct dissolution difference existed within 3 months. The pharmacokinetic study showed that HPE and HPN in NS-GNDP exhibited a significant increase in AUC0–t, Cmax and decrease in Tmax when compared with regular GNDP. These results indicated that NS-GNDP possessed superiority with improved storage stability and increased dissolution rate and oral bioavailability.

关键词： Ganneng dropping pills Lignans Herpetospermum caudigerum Nanosuspensions Stability Oral bioavailability

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Permeation into but not across the cornea:Bioimaging of intact nanoemulsions and Nanosuspensions using aggregation-caused quenching probes

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Chinese Chemical Letters 2018年第12期29卷 1834-1838页

作者： Dailei Liu Bo Wan Jianping Qi Xiaochun Dong Weili Zhao Wei Wu Yikang Dai Yi Lu Zhongjian Chen School of Pharmacy Fudan UniversityKey Laboratory of Smart Drug Delivery of MOE and PLAShanghai 201203China Shanghai Dermatology Hospital Shanghai 200443China Department of Ophthalmology Renji HospitalSchool of MedicineShanghai Jiaotong UniversityShanghai 200001China

Nanoemulsions(NEs) and Nanosuspensions(NSs) show great potential in enhancing the ocular bioavailability of therapeutics through topical delivery. However, transocular fate of intact NEs and NSs is still inconclusive. In this study, an aggregation-caused quenching fluorescent probe is used to track precorneal retention and transocular transportation of intact NEs and NSs, while coumarin 6 is used to mimick the cargo. NEs show superior precorneal retention to NSs. Both the two types of nanocarriers can permeate into but not across the cornea. The smaller NEs(100 nm) permeate better into the cornea than the bigger ones(210 nm). Nanocarriers in the cornea serves as depots. The released cargo molecules can penetrate across the cornea and diffuse into the lens. Moreover, the conjunctiva-scleral route may be potential to deliver drugs to the back of the eye, In conclusion, the study provides useful tools and information in the field of transocular transportation of nanoparticles.

关键词： Transocular transportation Topical administration Aggregation-caused quenching probe Nanoemulsions Nanosuspensions

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Preparation and Characterization of Paclitaxel/Chitosan Nanosuspensions for Drug Delivery System and Cytotoxicity Evaluation In Vitro

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Advanced Fiber Materials 2019年第2期1卷 152-162页

作者： Yongjia Liu Fengren Wu Yongle Ding Bangshang Zhu Yue Su Xinyuan Zhu Instrumental Analysis Center National Infrastructures for Translation Medicine(Shanghai)State Key Laboratory of Metal Matrix CompositesSchool of Chemistry and Chemical EngineeringShanghai Jiao Tong UniversityShanghai 200240China State Key Laboratory for Modification of Chemical Fibers and Polymer Materials Donghua UniversityShanghai 201620China

In this study,we prepared paclitaxel/chitosan(PTX/CS)Nanosuspensions(NSs)with different mass ratios of PTX and CS(1.5:2,2:2,and 2.5:2),for controlled drug delivery purposes.For attachment and dispersion in water medium,a simple ultrasonic disruption technique was employed.The water-dispersed PTX/CS NSs exhibited a rod-shape morphology with an average diameter of 170-210 nm and average length of about 1-10μm.Transmission electron microscopy,differential scan-ning calorimetry and X-ray diffraction indicated that the obtained PTX/CS NSs contain a nanocrystalline PTX phase.It was also inferred that presence of CS can promotes the crystalline nature of PTX up to 80%.In addition,efficiency of PTX loading reached over 85%in freeze-dried PTX/CS NSs,showing a slow rate of drug release in vitro for 8 days.The MTT and LDH assessments revealed that PTX/CS NSs significantly inhibit the growth of tumor cells(HeLa),while it is slightly toxic for the normal cells(NIH/3T3).Therefore,PTX/CS NSs is suggested as a potential nanodrug delivery system for cancer therapy.

关键词： Paclitaxel Chitosan Nanosuspensions Drug release Cytotoxicity in vitro

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Nanosuspensions of Poorly Water Soluble Drugs Prepared by Precipitation-Combined Homogenization Technology based on Acid-Base Neutralization Reactions

Nanosuspensions of Poorly Water Soluble Drugs Prepared by Pr...

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2015年中国药学大会暨第十五届中国药师周

作者： Gang Shen Ling Cheng Lihong Zhang Baode shen Juanjuan Li Juan Zhen Rong Xu Hailong Yuan Pharmacy College Chengdu University of Traditional Chinese Medicine Department of Pharmacy Air Force General Hospital of PLA

Herpetospermum caudigerum lignans（HTL）, one of the potential drugs with the treatment of anti-hepatitis B virus and hepatoprotective effects, have been limited in clinical applications because of poor saturation solubility, resulting in low bioavailability. Both herpetrione（HPE） and herpetin（HPN） are considered as the most abundant ingredient in HTL and exhibit weak acidity. The purpose of this study was to produce dried preparations of HTL（composed of HPE and HPN） nosuspensions with high redispersibility using lyophilization. The HTL-NS was prepared by utilizing precipitation-combined homogenization technology based on acid-base neutralization reactions, and variously critical formulation and process parameters affecting the characteristics of HTL-NS were optimized. The resultant products were characterized by particle size analysis, SEM, XRD, physical stability, solubility, dissolution and bioavailability. The dried preparations with a mean redispersed particle size of 286 nm was produced by using 4%（w/v） mannitol as cryoprotectants and possessed good physical stability at 4 oC or 25 oC for two months. Meanwhile, in vitro evaluation showed dried preparations could significantly increase saturation solubility and dissolution rate along with improving in vivo oral bioavailability, when compared with raw drug. This study provides a feasible drug delivery system for poorly water-soluble ingredients with pH-dependent solubility.

关键词： Herpetospermum caudigerum lignans Nanosuspensions acid–base neutralization saturation solubility dissolution oral bioavailability

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Preparation and evaluation of silymarin Nanosuspensions for protective effects on stress-induced liver injury

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中国药理学与毒理学杂志 2017年第5期31卷 473-473页

作者： WANG Xiao-dan HAO Ji-fu CHEN Wei WANG Hao WANG De-cai ZHANG Han-ting Institute of Pharmacology Taishan Medical University School of Pharmaccutical Sciences Taishan Medical University Departments of Behavioral Medicine & Psychiatry and Physiology & Pharmacology West Virginia University Health Sciences Center

OBJECTIVE To fabricate Silymarin(SM) Nanosuspensions(NSs) and evaluate their protective effect on stress-induced liver injury. METHODS SM Nanosuspensions were tailored by combination of the anti-solvent precipitation and high pressure homogenization(HPH); the formulations were optimized by central composite design. The pharmacokinetics and pharmacodynamics of SM-NSs were also performed.RESULTS In light of the quadratic mathematical equations derived from the Design of Expert Software,the optimal formulation of SM-NSs consisted of PVP 0.34% and F188 0.36%. The morphology of NSs was found to be spherical with a diameter of about 150 nm using transmission electron microscope(TEM)observation. The pharmacokinetics experiment demonstrated that oral administration of SM-NSs significantly increased its bioavailability compared to the coarse powder(Cmax: 9.03 ± 2.39 mg · L^(-1);AUMC_(0→∞):3757.35±227.19 mg·L^(-1)·h; AUC_(0→∞):171.84±26.61 mg·L^(-1)·h). In pharmacodynamics,it was found that restraint stress produced oxidative effects and increased serum AST and ALT levels in mice,both of which were significantly inhibited by SM and SM-NSs; in addition,administration of SM-NSs showed more effective prevention against acute liver injury than SM coarse suspensions(r^2=0.986,0.984,P<0.05). CONCLUSION The results suggest that fabricated SM-NSs exert potent hepatoprotective effects and attenuate restraint stress-induced liver injury. The study provides an effective approach to improving the property of SM,which can be used for treatment of liver diseases.

关键词： silymarin Nanosuspensions pharmcokinetics stress-induced liver injury

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Fast dissolving film containing nanoparticles:a novel solidified strategy for drug Nanosuspensions

Fast dissolving film containing nanoparticles:a novel solidi...

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“好医生杯”中药制剂创新与发展论坛

作者： Bao-de Shen Cheng-ying Shen Xu-dong Yuan Jin-xia Bai Qing-yuan Lv He Xu Ling Dai Chao Yu Jin Han Hai-long Yuan 302 Hospital of PLA&PLA Institute of Chinese Materia Medica School of Science Monmouth UniversityWest Long Branch

In this study,a novel fast dissolving film containing drug nanoparticles was developed with the goal of transforming drug Nanosuspensions into a solid dosage.Nanosuspensions wereprepared by high pressure homogenization and then transformed into fast dissolving film containing drug nanoparticles by film casting.Herpetrione(HPE),a novel and potent antiviral agent with poor water solubility that extracted from Herpetospermum caudigerum,was chosen as a model drug and studied systematically.The uniformity of dosage units of the preparation was acceptable according to the criteria of Chinese Pharmacopoeia 2010.The fast dissolving film was disintegrated in water within 30 s with reconstituted Nanosuspensions particle size of 280.69±11.57 nm,which was similar to that of drug Nanosuspensions,indicating a good redispersibility of the fast dissolving film.Result of X-ray diffraction showed that HPE in the fast dissolving film was in the amorphous state.In the in vitro dissolution test,the fast dissolving film containing HPE nanoparticles showed an increased dissolution velocity markedly.The result revealed that the fast dissolving film containing drug nanoparticles may provide a potential opportunity in transforming drug Nanosuspensions into a solid dosage form as well as enhancing the dissolution rate of poorly water-soluble drugs.

关键词： Nanosuspensions High pressure homogenization Fast dissolving films Film casting

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Studies on pharmacokinetics and acute toxicity of paclitaxel Nanosuspensions

Studies on pharmacokinetics and acute toxicity of paclitaxel...

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2012年中国药学大会暨第十二届中国药师周

作者： Lei Gao a,,Guiyang Liu a,Jianli Ma a,Xiaoqing Wang a,Meng Niu a,Jiarui Kang ba Department of Pharmacy,The First Affiliated Hospital of General Hospital of PLA,No.51 Fucheng Road,Beijing 100048,Chinab Department of pathology,The First Affiliated Hospital of General Hospital of PLA,No.51 Fucheng Road,Beijing 100048,China

Object:In this study paclitaxel Nanosuspensions were successfullyprepared by using TPGS as the stabilizers,which can inhibit the efflux function ofP-glucoprotein.The pharmacokinetics and acute toxicity were evaluated in mice.Method:The paclitaxel Nanosuspensions were prepared by the evaporativeprecipitation into aqueous solution（EPAS） method,and the freeze-dried powders ofthe suspensions were obtained through lyophilization process.The morphology andparticle size of Nanosuspensions were determined.The pharmacokinetics and acutetoxicity of paclitaxel Nanosuspensions were studied after intravenous administrationusing Kunming mice as experimental animals.A marketed paclitaxel injectablesolution was studied parallelly.Results:The paclitaxel nanoparticles were rod shapeunder the transmission electron microscope,and the particle size was 135.4nm.Thepaclitaxel Nanosuspensions displayed a different pharmacokinetic property comparedwith the marketed injectable solution,including a decreased initial concentration,increased plasma half-life,AUC and MRT.The results of acute toxicity showed theLD50 of paclitaxel Nanosuspensions is 98.63mg/kg,two times more than that ofmarked injection（41.46mg/kg）.Conclusions:The paclitaxel Nanosuspensionsprepared in this study could markedly enhance the tolerance of mice,and manifested adifferent pharmacokinetic property.

关键词： paclitaxel Nanosuspensions pharmacokinetics acute toxicity

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Formulation of dried lignans nanosuspension with high redispersibility to enhance stability,dissolution,and oral bioavailability

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Chinese Journal of Natural Medicines 2016年第10期14卷 757-768页

作者： SHEN Gang CHENG Ling WANG Li-Qiang ZHANG Li-Hong SHEN Bao-De LIAO Wei-Bo LI Juan-Juan ZHENG Juan XU Rong YUAN Hai-Long Department of Pharmacy Air Force General Hospital of PLABeijing 100142China Pharmacy College Chengdu University of Traditional Chinese MedicineChengdu 611137China School of Biomedical Sciences Huaqiao UniversityQuanzhou 362021China

Herpetospermum caudigerum lignans(HTL), one of the potential drugs with anti-hepatitis B virus and hepatoprotective effects, has limited clinical applications because of poor aqueous solubility and low bioavailability. Both herpetrione(HPE) and herpetin(HPN) are the most abundant ingredients in HTL and exhibit weak acidity. The purpose of the present study was to produce dried preparations of HTL(composed of HPE and HPN) Nanosuspensions(HTL-NS) with high redispersibility using lyophilization technology. The HTL-NS was prepared by utilizing precipitation-combined homogenization technology based on acid-base neutralization reactions, and critical formulation and process parameters affecting the characteristics of HTL-NS were optimized. The resultant products were characterized by particle size analysis, SEM, XRD, stability, solubility, dissolution and in vivo bioavailability. HTL-NS showed near-spherical-shaped morphology and the size was 243 nm with a narrow PDI value of 0.187. The dried preparations with a relatively large particle size of 286 nm and a PDI of 0.215 were achieved by using 4%(W/V) mannitol as cryoprotectants, and had a better stability at 4 or 25 oC for 2 months, compared to HTL-NS. In the in vitro test, the dried preparations showed markedly increased solubility and dissolution velocity. Besides, in the in vivo evaluation, it exhibited significant increases in AUC0–t, C_(max), MRT and a decrease in T_(max), compared to the raw drug.. In conclusion, our results provide a basis for the development of a drug delivery system for poorly water-soluble ingredients with p H-dependent solubility.

关键词： Herpetospermum caudigerum lignans Nanosuspensions Acid-base neutralization Saturation solubility Dissolution Oral bioavailability

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