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Development Of Novel Liposome-Encapsulated Combretastatin A4 Acylated Derivatives: Prodrug Approach For Improving Antitumor Efficacy
In: info:eu-repo/semantics/altIdentifier/doi/10.2147/IJN.S210938
Yongwei Gu,1,2,* Juanjuan Ma,2,* Zhiqin Fu,1,2,* Youfa Xu,1,2 Baoan Gao,1,2 Jianzhong Yao,3 Wei Xu,1 Kedan Chu,1 Jianming Chen1,2 1Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian 350108, People's Republic of China; 2Shanghai Wei Er Biopharmaceutical Technology Co., Ltd., Shanghai 201707, People's Republic of China; 3School of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China*These authors contributed equally to this workCorrespondence: Wei Xu; Jianming ChenDepartment of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian 350108, People's Republic of ChinaTel/fax +86-591-22861693; +86-21-31198900-8949Email 2000017@fjtcm.edu.cn; chenjm0711@163.comPurpose: The objective of the present study was to develop a liposomal drug delivery system based on combretastatin A4 (CA4) prodrugs modified with varying alkyl chains and investigate the in vitro drug conversion from prodrug and in vivo antitumor effect.Methods: The prodrug of CA4 was synthesized with stearyl chloride (18-carbon chain), palmitoyl chloride (16-carbon chain), myristoyl chloride (14-carbon chain), decanoyl chloride (10-carbon chain), and hexanoyl chloride (6-carbon chain) at the 3′-position of the CA4. Subsequently, it was encapsulated with liposomes through the thin-film evaporation method. Furthermore, the characteristics of prodrug-liposome were evaluated using in vitro drug release, conversion, and cytotoxicity assays, as well as in vivo pharmacokinetic, antitumor, and biodistribution studies.Results: The liposome system with loaded CA4 derivatives was successfully developed with nano-size and electronegative particles. The rate of in vitro drug release and conversion was reduced as the fatty acid carbon chain lengthened. On the contrary, in vivo antitumor effects were improved with the enlargement of the fatty acid carbon chain. The results of the in vivo pharmacokinetic and tissue distribution studies indicated that the reduced rate of CA4 release with a long carbon chain could prolong the circulation time and increase the drug concentration in the tumor tissue.Conclusion: These results suggested that the release or hydrolysis of the parent drug from the prodrug was closely related with the in vitro and in vivo properties. The slow drug release of CA4 modified with longer acyl chain could prolong the circulation time and increase the concentration of the drug in the tumor tissue. These effects play a critical role in increasing the antitumor efficacy.Keywords: combretastatin A4, liposome, prodrug, drug release, anticancer
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A MSLN-targeted multifunctional nanoimmunoliposome for MRI and targeting therapy in pancreatic cancer
In: info:eu-repo/semantics/altIdentifier/doi/10.2147/IJN.S34801
Li Deng,1,# Xingfa Ke,4,# Zhiying He,3,# Daoqiu Yang,5 Hai Gong,6 Yingying Zhang,1 Xiaolong Jing,4 Jianzhong Yao,2 Jianming Chen11Department of Pharmaceutics, 2Department of Medicinal Chemistry, School of Pharmacy, 3Department of Cell Biology, Second Military Medical University, Shanghai, People's Republic of China; 4Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian, People's Republic of China; 5Department of Dermatology, 107th Hospital of PLA, Yantai, People's Republic of China; 6Department of Radiation Oncology, General Hospital of Jinan Military Region, Jinan, People's Republic of China#These authors contributed equally to this workAbstract: Pancreatic cancer is a highly lethal disease with a 5-year survival rate less than 5% due to the lack of an early diagnosis method and effective therapy. To provide a novel early diagnostic method and targeted therapy for pancreatic cancer, a multifunctional nanoimmunoliposome with high loading of ultrasmall superparamagnetic iron oxides (USPIOs) and doxorubicin (DOX) was prepared by transient binding and reverse-phase evaporation method, and was conjugated with anti-mesothelin monoclonal antibody by post-insertion method to target anti-mesothelin-overexpressed pancreatic cancer cells. The in vitro and in vivo properties of this anti-mesothelin antibody-conjugated PEGlyated liposomal DOX and USPIOs (M-PLDU; and PEGlyated nanoimmunoliposome without antibody conjugation [PLDU]) were evaluated both in human pancreatic cancer cell line Panc-1 cell and in a pancreatic cancer xenograft animal model. Results showed that M-PLDUs were spherical and uniform with a diameter about ~180 nm, with a zeta potential of about −28~−30 mV, and had good efficacy encapsulating DOX and USPIOs. The in vitro study demonstrated that M-PLDUs possessed good magnetic resonance imaging (MRI) capability with a transverse relaxivity (r2) of about 58.5 mM–1 • s–1. Confocal microscopy showed more efficient uptake of M-PLDU in Panc-1 cells by antibody-mediated targeting. Methyl thiazolyl tetrazolium assay results showed significant inhibitory effect of M-PLDU against Panc-1 cells (half-maximal inhibitory concentration, 1.95 µM). The in vivo imaging study showed that the tumor signal intensity (SI) dropped significantly about 4 hours after intravenous injection of M-PLDU. The decrease in tumor SI induced by M-PLDUs (∆ SI = 145.98 ± 20.45) or PLDUs (∆ SI = 75.69 ± 14.53) was much more significant than that by free USPIOs (∆ SI = 42.78 ± 22.12; P < 0.01). The in vivo antitumor study demonstrated that compared with FD (free DOX) and PLDU, M-PLDU possessed higher inhibitory effect on tumor growth and the tissue distribution assay further proved that M-PLDUs could selectively accumulate in the tumor xenograft. These results indicated that M-PLDU not only well retained the inherent MRI capability of USPIOs, but significantly improved the targeting distribution of USPIOs and therapeutic agents in pancreatic tumor tissues. They may serve as a promising theranostic nanomedicine not only for early detection but also for MRI-monitored targeting therapy of human pancreatic cancer.Keywords: theranostic nanomedicine, nanoimmunoliposome, mesothelin, USPIO, doxorubicin, pancreatic cancer
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Comparison of anti-EGFR-Fab' conjugated immunoliposomes modified with two different conjugation linkers for siRNA delivery in SMMC-7721 cells
In: info:eu-repo/semantics/altIdentifier/doi/10.2147/IJN.S47597
Li Deng,1,* Yingying Zhang,1,* Lulu Ma,1,5,* Xiaolong Jing,1,3 Xingfa Ke,1,3 Jianhao Lian,1,3 Qiang Zhao,1,3 Bo Yan,1,3 Jinfeng Zhang,4 Jianzhong Yao,2 Jianming Chen1 1Department of Pharmaceutical Science, 2Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; 3Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian, People's Republic of China; 4Shanghai TCM Integrated Hospital, Shanghai, People's Republic of China; 5Department of Pharmacy, First Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China *These authors contributed equally to this paper Background: Targeted liposome-polycation-DNA complex (LPD), mainly conjugated with antibodies using functionalized PEG derivatives, is an effective nanovector for systemic delivery of small interference RNA (siRNA). However, there are few studies reporting the effect of different conjugation linkers on LPD for gene silencing. To clarify the influence of antibody conjugation linkers on LPD, we prepared two different immunoliposomes to deliver siRNA in which DSPE-PEG-COOH and DSPE-PEG-MAL, the commonly used PEG derivative linkers, were used to conjugate anti-EGFR Fab' with the liposome. Methods: First, 600 µg of anti-EGFR Fab' was conjugated with 28.35 µL of a micelle solution containing DSPE-PEG-MAL or DSPE-PEG-COOH, and then post inserted into the prepared LPD. Various liposome parameters, including particle size, zeta potential, stability, and encapsulation efficiency were evaluated, and the targeting ability and gene silencing activity of TLPD-FPC (DSPE-PEG-COOH conjugated with Fab') was compared with that of TLPD-FPM (DSPE-PEG-MAL conjugated with Fab') in SMMC-7721 hepatocellular carcinoma cells. Results: There was no significant difference in particle size between the two TLPDs, but the zeta potential was significantly different. Further, although there was no significant difference in siRNA encapsulation efficiency, cell viability, or serum stability between TLPD-FPM and TLPD-FPC, cellular uptake of TLPD-FPM was significantly greater than that of TLPD-FPC in EGFR-overexpressing SMMC-7721 cells. The luciferase gene silencing efficiency of TLPD-FPM was approximately three-fold high than that of TLPD-FPC. Conclusion: Different conjugation linkers whereby antibodies are conjugated with LPD can affect the physicochemical properties of LPD and antibody conjugation efficiency, thus directly affecting the gene silencing effect of TLPD. Immunoliposomes prepared by DSPE-PEG-MAL conjugation with anti-EGFR Fab' are more effective than TLPD containing DSPE-PEG-COOH in targeting hepatocellular carcinoma cells for siRNA delivery. Keywords: liposome-polycation-DNA, anti-EGFR Fab', immunoliposomes, small interfering RNA delivery, conjugation technology, hepatocellular carcinoma
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Folate-mediated and pH-responsive chidamide-bound micelles encapsulating photosensitizers for tumor-targeting photodynamic therapy
In: info:eu-repo/semantics/altIdentifier/doi/10.2147/IJN.S208649
Zhiqiang Ma,*,1 Pengwei Hu,*,2 Changyong Guo,2 Dan Wang,3 Xingjie Zhang,1 Min Chen,1 Qirong Wang,1 Miao Sun,1 Peiyu Zeng,1 Fengkun Lu,1,2 Linhong Sun,1 Lan She,1 Hongtao Zhang,4 Jianzhong Yao,1 Feng Yang1,21School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; 2Department of Pharmacy, Hebei North University, Zhangjiakou, People's Republic of China; 3Department of Obstetrics and Gynecology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China; 4Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, People's Republic China*These authors contributed equally to this workBackground: Nonspecific tumor targeting, potential relapse and metastasis of tumor after treatment are the main barriers in clinical photodynamic therapy (PDT) for cancer, hence, inhibiting relapse and metastasis of tumor is significant issues in clinic.Purpose: In this work, chidamide as a histone deacetylases inhibitor (HADCi) was bound onto a pH-responsive block polymer folate polyethylene glycol-b-poly(aspartic acid) (PEG-b-PAsp) grafted folate (FA-PEG-b-PAsp) to obtain the block polymer folate polyethylene glycol-b-poly(asparaginyl-chidamide) (FA-PEG-b-PAsp-chidamide, FPPC) as multimodal tumor-targeting drug-delivery carrier to inhibiting tumor cell proliferation and tumor metastasis in mice.Methods: Model photosensitizer pyropheophorbide-a (Pha) was encapsulated by FPPC in PBS to form the polymer micelles Pha@FPPC [folate polyethylene glycol-b-poly(asparaginyl-chidamide) micelles encapsulating Pha]. Pha@FPPC was characterized by transmission electron microscope and dynamic light scattering; also, antitumor activity in vivo and in vitro were investigated by determination of cellular ROS level, detection of cell apoptosis and cell cycle arrest, PDT antitumor activity in vivo and histological analysis.Results: With favorable and stable sphere morphology under transmission electron microscope (TEM) (∼93.0 nm), Pha@FPPC greatly enhanced the cellular uptake due to its folate-mediated effective endocytosis by mouse melanoma B16-F10 cells and the yield of ROS in tumor cells induced by PDT, and mainly caused necrocytosis and blocked cell growth cycle not only in G2 phase but also in G1/G0 phase after PDT. Pha@FPPC exhibited lower dark cytotoxicity in vitro and a better therapeutic index because of its higher dark cytotoxicity/photocytotoxicity ratio. Moreover, Pha@FPPC not only significantly inhibited the growth of implanted tumor and prolonged the survival time of melanoma-bearing mice due to both its folate-mediated tumor-targeting and selectively accumulation at tumor site by EPR (enhanced permeability and retention)effect as micelle nanoparticles but also remarkably prevented pulmonary metastasis of mice melanoma after PDT compared to free Pha, demonstrating its dual antitumor characteristics of PDT and HDACi.Conclusion: As a folate-mediated and acid-activated chidamide-grafted drug-delivery carrier, FPPC may have great potential to inhibit tumor metastasis in clinical photodynamic treatment for cancer because of its effective and multimodal tumor-targeting performance as photosensitizer vehicle.Keywords: photodynamic therapy, PDT, histone deacetylase inhibitor, HDACi, micelles, folate, pH-responsive, photosensitizer
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