Can Zhang

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Name: 张灿

Organization: China Pharmaceutical University , China

Department: Center of Drug Discovery

Title: (PhD)

TOPICS

Organic Chemistry

Chemicals
References

Performance of Doxorubicin-Conjugated Gold Nanoparticles: Regulation of Drug Location

Co-reporter:Teng Cui, Juan-Juan Liang, Huan Chen, Dong-Dong Geng, Lei Jiao, Jian-Yong Yang, Hai Qian, Can Zhang, and Ya Ding

ACS Applied Materials & Interfaces March 15, 2017 Volume 9(Issue 10) pp:8569-8569

Publication Date(Web):February 20, 2017

DOI:10.1021/acsami.6b16669

Drug-conjugated gold nanoparticles (GNPs), which are generally constructed with many molecules of thiol-terminated polyethylene glycol (PEG)-drug decorated on their surfaces via a thiol-Au covalent bond, are promising and efficient nanoprodrugs. However, because of the exposure of the hydrophobic drug molecules on the surface of the conjugate, in vivo stability, opsonization, and subsequent inefficient therapy become the main issues of this system. To solve these problems without complicating the structures of gold conjugates, herein we propose a method to change the relative position of PEG and the drug. A novel gold conjugate (GNP-NHN═Dox-mPEG) with doxorubicin (Dox) shielded by PEGylation on the surface of GNPs is designed. It demonstrates improved solubility, stability, and dispersion and achieves a two-step stimulus-responsive drug release in response to an acidic environment in lysosomes and then esterase in the cytoplasm. This unique manner of release enables the cytoplasm to act as a reservoir for sustained drug delivery into the nucleus to improve antitumor efficacy in vivo. The intratumoral drug concentrations of the conjugate reach 14.4 ± 1.4 μg/g at 8 h, a two-fold increase in the drug concentration compared with that of the doxorubicin hydrochloride group. This molecular design and regulation approach is facile but important in modulating the in vivo performance of nanovehicles and demonstrates its vital potential in developing effective nanoparticle-based drug delivery agents.Keywords: Doxorubicin-conjugated gold nanoparticles; drug location; lysosomal escape; treatment efficacy improvement; two-step drug release;

Apigenin, a modulator of PPARγ, attenuates HFD-induced NAFLD by regulating hepatocyte lipid metabolism and oxidative stress via Nrf2 activation

Co-reporter:Xiujing Feng, Wen Yu, Xinda Li, Feifei Zhou, ... Pingping Shen

Biochemical Pharmacology 2017 Volume 136(Volume 136) pp:

Publication Date(Web):15 July 2017

DOI:10.1016/j.bcp.2017.04.014

Lipid metabolic disorders and oxidative stress in the liver are key steps in the progression of nonalcoholic fatty liver disease (NAFLD), which is a major risk factor for the development of metabolic syndrome. To date, no pharmacological treatment for this condition has been approved. Our previous study has found that the food-derived compound apigenin (Api) significantly attenuates obesity-induced metabolic syndrome by acting as a peroxisome proliferator-activated receptor gamma modulator (PPARM). Herein, a high fat diet (HFD) induced NAFLD model was used to dig out whether Api had the effect on NAFLD. The results showed that Api had obvious effect in restraining NAFLD progression, including attenuating HFD induced lipid accumulation and oxidative stress in vivo. As a PPARM, although Api did significantly inhibit the expression of PPARγ target genes encoding the protein associated with lipid metabolism, it had no obvious activating effect on PPARγ. Interestingly, we found that Api promoted Nrf2 into the nucleus, thereby markedly activating Nrf2 to inhibit the lipid metabolism related genes and increase the oxidative stress related genes. Further Nrf2 knockdown/knockout and overexpression experiments showed that Api regulating PPARγ target genes was dependent on Nrf2 activation and the activation of Nrf2 counteracted the activation effect of PPARγ by Api. Importantly, we also found that Api might bind with Nrf2 via auto dock and ITC assay. Therefore, our results indicate that Api ameliorates NAFLD by a novel regulating mode of Nrf2 and PPARγ in inhibiting lipid metabolism and oxidative stress abnormity.Download high-res image (133KB)Download full-size image

Co-delivery of paclitaxel and anti-survivin siRNA via redox-sensitive oligopeptide liposomes for the synergistic treatment of breast cancer and metastasis

Co-reporter:Xinyan Chen, Yidi Zhang, Chunming Tang, Chunli Tian, Qiong Sun, Zhigui Su, Lingjing Xue, Yifan Yin, Caoyun Ju, Can Zhang

International Journal of Pharmaceutics 2017 Volume 529, Issues 1–2(Issue 1) pp:

Publication Date(Web):30 August 2017

DOI:10.1016/j.ijpharm.2017.06.071

The overexpression of survivin in breast cancer cells is an important factor of paclitaxel (PTX) resistance in breast cancer. To overcome PTX resistance and improve the antitumor effect of PTX, we developed a novel liposome-based nanosystem (PTX/siRNA/SS-L), composed of a redox-sensitive cationic oligopeptide lipid (LHSSG2C14) with a proton sponge effect, natural soybean phosphatidylcholine (SPC), and cholesterol for co-delivery of PTX and anti-survivin siRNA, which could specifically downregulate survivin overexpression. PTX/siRNA/SS-L exhibited high encapsulation efficiency and rapid redox-responsive release of both PTX and siRNA. Moreover, in vitro studies on the 4T1 breast cancer cells revealed that PTX/siRNA/SS-L offered significant advantages over other experimental groups, such as higher cellular uptake, successful endolysosomal escape, reduced survivin expression, the lowest cell viability and wound healing rate, as well as the highest apoptosis rate. In particular, in vivo evaluation of 4T1 tumor-bearing mice showed that PTX/siRNA/SS-L had lower toxicity and induced a synergistic inhibitory effect on tumor growth and pulmonary metastasis. Collectively, the collaboration of anti-survivin siRNA and PTX via redox-sensitive oligopeptide liposomes provides a promising strategy for the treatment of breast cancer and metastasis.Download high-res image (224KB)Download full-size image

Reversing Cancer Multidrug Resistance in Xenograft Models via Orchestrating Multiple Actions of Functional Mesoporous Silica Nanoparticles

Co-reporter:Debin Yang, Tingfang Wang, Zhigui Su, Lingjing Xue, Ran Mo, and Can Zhang

ACS Applied Materials & Interfaces 2016 Volume 8(Issue 34) pp:22431

Publication Date(Web):July 15, 2016

DOI:10.1021/acsami.6b04885

A multistimuli responsive drug delivery system (DDS) based on sulfhydryl and amino-cofunctionalized mesoporous silica nanoparticles (SH/NH2-MSNs) has been developed, in which the multifunctional hyaluronic acid (HA) derivatives were grafted onto the SH/NH2-MSNs by disulfide bonds for targeting delivery, controlling drug release and reversing multidrug resistance (MDR). The doxorubicin (Dox) loaded multifunctional HA derivatives modified mesoporous silica nanoparticles (Dox/HHS-MSNs) were enzyme and redox sensitive, which could respond to the intracellular stimuli of hyaluronidase (HAase) and glutathione (GSH) successively and prevent drug leakage before reaching the tumor tissues. The cellular uptake experiments showed that Dox/HHS-MSNs were vulnerable to be endocytosed into the Dox-resistant human breast adenocarcinoma (MCF-7/ADR) cells, efficiently realized the endolysosomal escape and remained in the cytoplasm. Because of orchestrating multiple actions above including active targeting, endolysosomal escape and efficient multilevel drug release, Dox/HHS-MSNs could induce the strongest apoptosis and cytotoxicity of MCF-7/ADR cells. Furthermore, a series of in vivo studies on MCF-7/ADR tumor-bearing xenograft mouse models demonstrated that Dox/HHS-MSNs possessed the enhanced tumor-targeting capacity and the best therapeutic efficacy to reverse cancer MDR.Keywords: active targeting; endolysosomal escape; enzyme and redox sensitive; mesoporous silica nanoparticles; multidrug resistance; multilevel drug release

Co-delivery of erlotinib and doxorubicin by pH-sensitive charge conversion nanocarrier for synergistic therapy

Co-reporter:Yongju He, Zhigui Su, Lingjing Xue, Hui Xu, Can Zhang

Journal of Controlled Release 2016 Volume 229() pp:80-92

Publication Date(Web):10 May 2016

DOI:10.1016/j.jconrel.2016.03.001

Pretreatment of lung cancer cells with epidermal growth factor receptor (EGFR) inhibitor erlotinib has been recently reported that could dramatically synergize their apoptotic response to DNA damage agent doxorubicin (DOX). To translate this synergistic therapy into in vivo anticancer therapy and clinical practice, we designed a novel pH-sensitive charge conversion nanocarrier (M-HHG2C18-L) that contained erlotinib/DOX combination and produced a sequential staggered drug release for synergistic lung cancer therapy. In this study, a synthetic zwitterionic oligopeptide lipid (1,5-dioctadecyl-l-glutamyl2-histidyl-hexahydrobenzoic acid, HHG2C18) was used to construct a pH-sensitive lipid bilayer (HHG2C18-L), which was subsequently applied to coat amino-functionalized mesoporous silica nanoparticles (MSN-NH2). Erlotinib and DOX were separately incorporated into HHG2C18-L and MSN-NH2 respectively to obtain pH-sensitive charge conversion erlotinib/DOX co-delivery nanoparticles (M-HHG2C18-L(E + D)). We confirmed that M-HHG2C18-L(E + D) were able to reverse surface zeta potential from negative to positive at tumor extracellular pH, thus facilitating the targeted cancer cell internalization. Furthermore, as erlotinib was sequestered in the exterior lipid bilayer and the controlled release ability of MSN-NH2, erlotinib released faster than DOX during the cellular transport. Additionally, HHG2C18-L became more positive at tumor intracellular pH and enhanced Coulombic repulsion with MSN-NH2, leading to increased sequential staggered release of erlotinib and DOX. Due to the pretreatment and time-staggered inhibition of EGFR with erlotinib and the enhanced intracellular release of DOX to the nucleus, the maximized synergistic cell killing effect was achieved. Compared to non-sensitive erlotinib/DOX co-delivery nanoparticles (M-SPC-L(E + D)) and simultaneous DRUG coadministration. M-HHG2C18-L(E + D) with sequential staggered drug release and pH-sensitive charge conversional properties showed great synergistic effects in antiproliferation and apoptosis of A549 human cancer cells in vitro. The in vivo study demonstrated that M-HHG2C18-L(E + D) exhibited considerable tumor accumulation and potent suppression of tumor growth in Lewis lung carcinoma tumor bearing mice. It was also demonstrated that M-HHG2C18-L(E + D) showed no systemic toxicity and possessed distinguished effect on extending survival period. These results suggested that M-HHG2C18-L(E + D) had great potential application in cancer treatment.

Novel nonsecosteroidal VDR ligands with phenyl-pyrrolyl pentane skeleton for cancer therapy

Co-reporter:Zhixin Ge, Meixi Hao, Meng Xu, Zhigui Su, Zisheng Kang, Lingjing Xue, Can Zhang

European Journal of Medicinal Chemistry 2016 Volume 107() pp:48-62

Publication Date(Web):1 January 2016

DOI:10.1016/j.ejmech.2015.10.042

•A series of nonsecosteroidal VDR ligands were synthesized for cancer therapy.•Compound 5k and 5i have display excellent inhibition activity.•Compounds we synthesized showed no significant effect on serum calcium in rats.A series of nonsecosteroidal vitamin D3 receptor (VDR) ligands with phenyl-pyrrolyl pentane skeleton were synthesized for cancer therapy. In contrast to 1α,25-dihydroxyvitamin D3 (Calcitriol), these VDR ligands exhibited anti-proliferative activity without inducing hypercalcemia. These compounds were evaluated for vitamin D3-agonistic ability and anti-proliferative activity in vitro. Among them, compounds 5k and 5i exhibited equivalent vitamin D3-agonistic activity compared with Calcitriol. Meanwhile, compound 5k displayed promising inhibiting profile against MCF-7, HepG-2 and Caco-2 with IC50 values of 0.00586 μM, 0.176 μM, and 1.01 μM (Calcitriol: 5.58 μM, 80.83 μM and 4.46 μM) respectively. Compound 5i inhibited proliferation of PC-3 with IC50 value of 0.00798 μM (Calcitriol: 17.25 μM). Additionally, neither of these compounds significantly elevated serum calcium in rats.

Design, synthesis and evaluation of pyrrolo[2,3-d]pyrimidine-phenylamide hybrids as potent Janus kinase 2 inhibitors

Co-reporter:Tingfang Wang, Xiaofei Liu, Meixi Hao, Jianan Qiao, Caoyun Ju, Lingjing Xue, Can Zhang

Bioorganic & Medicinal Chemistry Letters 2016 Volume 26(Issue 12) pp:2936-2941

Publication Date(Web):15 June 2016

DOI:10.1016/j.bmcl.2016.04.027

Janus kinase 2 (JAK2) plays an essential role in the signaling of hormone-like cytokines and growth factors, which has been convinced as an important target of myeloproliferative neoplasms (MPNs) therapy. In this study, a series of novel pyrrolo[2,3-d]pyrimidine-phenylamide hybrids were designed and synthesized as potential JAK2 inhibitors through hybridization strategy. In vitro biological studies showed that most of these compounds exhibited potent activity against JAK2. Especially, compound 16c was identified as a suitable lead compound, which showed favorable pharmacokinetic profiles in rats (F = 73.57%), excellent in vitro efficacy against erythroleukemic cells (TF-1, IC50 = 0.14 μM), and high selectivity for JAK2 (IC50 = 6 nM with >97-fold selectivity vs JAK3).A series of novel pyrrolo[2,3-d]pyrimidine-phenylamide hybrids were designed using the hybridization strategy and synthesized as potential JAK2 inhibitors.

A Collaborative Assembly Strategy for Tumor-Targeted siRNA Delivery

Co-reporter:Qiong Sun; Zisheng Kang; Lingjing Xue; Yunkai Shang; Zhigui Su; Hongbin Sun; Qineng Ping; Ran Mo

Journal of the American Chemical Society 2015 Volume 137(Issue 18) pp:6000-6010

Publication Date(Web):April 14, 2015

DOI:10.1021/jacs.5b01435

A novel “collaborative assembly” approach was reported for the synthesis of an siRNA delivery system via a combination of an electrostatically driven physical assembly and a facile click reaction-mediated chemical assembly, which showed various advantages of more safety, efficiency, and flexibility over the conventional approach that is only based on the physical assembly. This strategy remained a high cationic property of lipid-based complex for high siRNA loading capacity. The direct chemical modification of a model polyanion, hyaluronic acid (HA) on the cationic complex via click chemistry shielded the positive charge of complex without affecting the siRNA binding, which reduced the toxicity and enhanced the blood stability of the complex. In addition, the incorporated polyanion might be prefunctionalized, which endued the carrier with better biological characteristics such as long circulating or tumor targeting. We demonstrated that the obtained lipid-polymer hybrid nanoparticle (RSC-HA) using collaborative assembly presented greater in vivo stability in the blood for efficient tumor targeting than the physically assembled RSC/HA in which HA was physically adsorbed on the complex. After endocytosis into the cells, the protection of RSC-HA on siRNA turned off, while the release of siRNA induced by the intracellular signals for enhanced gene-silencing capacity. This combination of physical and chemical assemblies provides an efficient strategy for the exploitation of safe, stable, and functionalized siRNA delivery systems.

Sequential intra-intercellular nanoparticle delivery system for localized delivery of doxorubicin

Co-reporter:Caoyun Ju, Ran Mo, Can Zhang

Journal of Controlled Release 2015 Volume 213() pp:e15

Publication Date(Web):10 September 2015

DOI:10.1016/j.jconrel.2015.05.021

Extracellular pH-sensitive mixed micelles for prostate tumor targeted anticancer drug delivery

Co-reporter:Ding Qu, Jing-Wei Xue, Ran Mo, Cao-Yun Ju, Xiang Jin, Can Zhang

Journal of Controlled Release 2015 Volume 213() pp:e14

Publication Date(Web):10 September 2015

DOI:10.1016/j.jconrel.2015.05.019

Acid/redox dual-activated liposomes for tumor-targeted drug delivery and enhanced therapeutic efficacy

Co-reporter:Xuefan Xu, Lei Zhang, Assogba G. Assanhou, Lu Wang, Yidi Zhang, Wenyuan Li, Lingjing Xue, Ran Mo and Can Zhang

RSC Advances 2015 vol. 5(Issue 83) pp:67803-67808

Publication Date(Web):07 Aug 2015

DOI:10.1039/C5RA06445G

Acid/redox dual-activated liposomes consisting of a synthetic functional lipid were developed to overcome the multiple barriers to the intravenous delivery of an anticancer drug from the injection site to the target site. The liposome exhibited tumor pH-promoted cellular uptake, endocytic pH-responsive endo-lysosomal escape and redox-triggered intracellular drug release, thereby yielding enhanced antitumor activity.

Design, synthesis and biological activities of novel oxazolo[4,5-g]quinazolin-2(1H)-one derivatives as EGFR inhibitors

Co-reporter:Siyuan Yin, Liliang Zhou, Jinsheng Lin, Lingjing Xue, Can Zhang

European Journal of Medicinal Chemistry 2015 101() pp: 462-475

Publication Date(Web):

DOI:10.1016/j.ejmech.2015.07.008

Sequential Intra-Intercellular Nanoparticle Delivery System for Deep Tumor Penetration

Co-reporter:Dr. Caoyun Ju;Dr. Ran Mo;Jingwei Xue;Lei Zhang;Zekai Zhao;Dr. Lingjing Xue; Qineng Ping ;Dr. Can Zhang

Angewandte Chemie International Edition 2014 Volume 53( Issue 24) pp:6253-6258

Publication Date(Web):

DOI:10.1002/anie.201311227

Abstract

To achieve deep tumor penetration of large-sized nanoparticles (NPs), we have developed a reversible swelling–shrinking nanogel in response to pH variation for a sequential intra-intercellular NP delivery. The nanogel had a crosslinked polyelectrolyte core, consisting of N-lysinal-N′-succinyl chitosan and poly(N-isopropylacrylamide), and a crosslinked bovine serum albumin shell, which was able to swell in an acidic environment and shrink back under neutral conditions. The swelling resulted in a rapid release of the encapsulated chemotherapeutics in the cancer cells for efficient cytotoxicity. After being liberated from the dead cells, the contractive nanogel could infect neighboring cancer cells closer to the center of the tumor tissue.

Back Cover: Sequential Intra-Intercellular Nanoparticle Delivery System for Deep Tumor Penetration (Angew. Chem. Int. Ed. 24/2014)

Co-reporter:Dr. Caoyun Ju;Dr. Ran Mo;Jingwei Xue;Lei Zhang;Zekai Zhao;Dr. Lingjing Xue; Qineng Ping ;Dr. Can Zhang

Angewandte Chemie International Edition 2014 Volume 53( Issue 24) pp:

Publication Date(Web):

DOI:10.1002/anie.201401142

In vitro evaluation on novel modified chitosan for targeted antitumor drug delivery

Co-reporter:Ding Qu, Haijiao Lin, Nan Zhang, Jingwei Xue, Can Zhang

Carbohydrate Polymers 2013 Volume 92(Issue 1) pp:545-554

Publication Date(Web):30 January 2013

DOI:10.1016/j.carbpol.2012.08.112

In this study, a novel amphiphilic copolymer designed as N-octyl-N-phthalyl-3,6-O-(2-hydroxypropyl) chitosan (OPHPC) were synthesized and then conjugated with folic acid (FA-OPHPC) to produce a targeted drug carrier for tumor-specific drug delivery. OPHPC and FA-OPHPC were characterized by FT-IR, 1H NMR, 13C NMR and elemental analysis. Paclitaxel (PTX) loaded OPHPC micelles (PTX-OPHPC) with well-defined spherical shape and homogeneous distribution exhibited drug-loading rate ranging from 33.6% to 45.3% and entrapment efficiency from 50.5% to 82.8%. In the cellular uptake studies, PTX-OPHPC brought about a significantly higher amount of PTX accumulated in human breast adenocarcinoma cell line (MCF-7 cells) compared with Taxol®. Moreover, the cellular uptake of PTX in PTX loaded FA-OPHPC micelles (PTX-FA-OPHPC) was 3.2-fold improved in comparison with that of PTX-OPHPC. The results revealed that OPHPC micelle might be a promising drug carrier for promoting PTX cellular uptake and FA-OPHPC micelle could be used as a potential tumor-targeted drug vector.Highlights► Synthesis and characterization of novel amphiphilic chitosan derivates as drug delivery system. ► Introduction of phthalyl groups could lower CMC and improve solubility in aqueous and organic system. ► Drug-loaded micelles with small particle size, narrow distribution and high drug loading efficiency. ► Enhancement on cellular uptake by active tumor targeting. ► Mechanism of cellular uptake varied from different surface properties.

Thermosensitive micelleshydrogel hybrid system based on poloxamer 407 for localized delivery of paclitaxel

Co-reporter:Caoyun Ju;Juan Sun;Peng Zi;Xiang Jin

Journal of Pharmaceutical Sciences 2013 Volume 102( Issue 8) pp:2707-2717

Publication Date(Web):

DOI:10.1002/jps.23649

Abstract

A thermosensitive micelles–hydrogel hybrid system based on Poloxamer 407 (P407) was prepared to resolve the fast erosion and low loading capability of lipophilic drug of P407 gels for local chemotherapy. Different amounts of glutaraldehyde (GA) were applied to generate cross-linked networks with carboxymethyl chitosan (CMCS) interpenetrated in P407 gels, in which paclitaxel (PTX)-loaded N-octyl-O-sulfate chitosan micelles (PTX-M) were dispersed uniformly. The in vitro characteristics of CMCS-modified P407 gels (PTX-M-MG) were performed by examining the viscosity, swelling ratio, mechanical property, and drug release, while the in vivo evaluation included tissue distribution and anticancer efficacy through intratumoral administration in hepatoma solidity cell (Heps) tumor-bearing mice. The results showed that PTX-M-MG containing 0.05% (w/v) GA possessed lower viscosity, higher swelling ratio, stronger mechanical property, and longer term drug release, in which the loading efficiency of PTX was enlarged by the introduction of PTX-M. Moreover, PTX-M-MG revealed a prolonged retention at tumor sites, lasting for 20 days, and a superior tumor inhibition rate (64.27%) with reduced toxicity compared with Taxol^®, PTX-M, and PTX-M loaded unmodified P407 gels (PTX-M-P407). It can be concluded that PTX-M-MG is a promising local delivery system for hydrophobic drug in cancer therapy, providing both improved efficacy and relieved side effects. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2707–2717, 2013

Multistage pH-Responsive Liposomes for Mitochondrial-Targeted Anticancer Drug Delivery

Co-reporter:Ran Mo;Qiong Sun;Jingwei Xue;Nan Li;Wenyuan Li;Qineng Ping

Advanced Materials 2012 Volume 24( Issue 27) pp:3659-3665

Publication Date(Web):

DOI:10.1002/adma.201201498

Drug Delivery: Multistage pH-Responsive Liposomes for Mitochondrial-Targeted Anticancer Drug Delivery (Adv. Mater. 27/2012)

Co-reporter:Ran Mo;Qiong Sun;Jingwei Xue;Nan Li;Wenyuan Li;Qineng Ping

Advanced Materials 2012 Volume 24( Issue 27) pp:

Publication Date(Web):

DOI:10.1002/adma.201290167

PEG prodrug of gambogic acid: Amino acid and dipeptide spacer effects

Co-reporter:Ya Ding, Peng Zhang, Xiao-Yan Tang, Can Zhang, Song Ding, Hai Ye, Qi-Long Ding, Wen-Bin Shen, Qi-Neng Ping

Polymer 2012 Volume 53(Issue 8) pp:1694-1702

Publication Date(Web):3 April 2012

DOI:10.1016/j.polymer.2012.02.022

The clinical application of gambogic acid (GA), a natural component with promising antitumor activity, was limited due to its extremely poor aqueous solubility, rapid elimination in vivo, and wide biodistribution. To solve these problems, 30 poly(ethylene glycol)-amino acid (or dipeptide)-gambogic acid (PEG-spacer-GA) conjugates were synthesized. All polymeric prodrugs showed satisfactory aqueous solubility (1.2 × 103–4.5 × 105 times of GA solubility). It was found that the molecular weight of PEG and the choice of spacers played important role in controlling the drug percentage, water solubility, and drug release properties of PEG-GA conjugates with and without spacers. Studies of pharmacokinetics, biodistribution, and cell cytotoxicity revealed that, employing the polymeric conjugation strategy, the remarkably improved circulatory retention time and bioavailability, as well as reduced peripheral toxicity were obtained in comprising with GA and its Cremophor EL formulation. The liver target character of PEG-GA conjugates made them potential prodrugs for liver cancer treatment.

Water-soluble poly(ethylene glycol) prodrug of pemetrexed: Synthesis, characterization, and preliminary cytotoxicity

Co-reporter:Tao Min;Hai Ye;Peng Zhang;Jun Liu;Wenbin Shen;Wan Wang;Longsheng Shen

Journal of Applied Polymer Science 2009 Volume 111( Issue 1) pp:444-451

Publication Date(Web):

DOI:10.1002/app.29047

Abstract

Pemetrexed is a novel antifolate of antimetabolite with multiple enzyme targets involved in both pyrimidine and purine synthesis. It has entered the clinical usage due to favorable profiles especially in the cancer treatment of mesothelioma and non–small-cell lung carcinoma. But it presents numerous challenges associated with poor water solubility and unstability in its original form of glutamic acid. The aim of this study is to solubilize pemetrexed by designing and synthesizing its aqueous-soluble prodrug using high aqueous-soluble polymeric carrier poly(ethylene glycol) (PEG). A new type of soluble pemetrexed prodrug was synthesized with dihydroxyl PEG and a single amino acid linkage, and was extensively characterized using ¹H-NMR, ¹³C-NMR, Fourier-transform infrared, and matrix-assisted laser desorption time of flight mass spectrometry. In addition, the prodrugs were evaluated for the drug loading capability, the aqueous solubility, and the preliminary in vitro cytotoxicity. The results indicate that the new PEGylated pemetrexed conjugates possess enhanced water solubility and stability, and provide another feasible choice of the pharmaceutical form of pemetrexed in the clinical application. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009

Novel furoxan NO-donor pemetrexed derivatives: design, synthesis, and preliminary biological evaluation

Co-reporter:Tao Min;Bixin Yi;Peng Zhang;Jun Liu

Medicinal Chemistry Research 2009 Volume 18( Issue 7) pp:495-510

Publication Date(Web):2009 September

DOI:10.1007/s00044-008-9144-x

Design and synthesis of a new class of potent hybrid compounds obtained by joining NO-donor furoxanyl moieties, through an appropriate spacer arm, to the pemetrexed segment, which was prepared in a modified simple route, are presented. Structures of all the target compounds were characterized by using Fourier-transform infrared (FT-IR), 1H-nuclear magnetic resonance (NMR), 13C-NMR, and electrospray ionization mass spectroscopy (ESI-MS). In addition, preliminary evaluation of antitumor activity using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay based on four different cancer cell lines (BGC-1, HL60-1, SMMC-1, and A549-1) was performed. The results suggested that different length of spacer arm in the hybrid compounds did have an impact on the molecules’ capability to inhibit cancer cell growth to various degrees, but without showing significant difference on regular pharmacological behaviors. Among all the synthesized hybrids, compound 1f showed the strongest inhibitory activity against all the tested cell lines and it is currently under our further investigation.

Water soluble poly(ethylene glycol) prodrug of silybin: Design, synthesis, and characterization

Co-reporter:Peng Zhang;Hai Ye;Tao Min

Journal of Applied Polymer Science 2008 Volume 107( Issue 5) pp:3230-3235

Publication Date(Web):

DOI:10.1002/app.27450

Abstract

Silybin, the main component of silymarin, is an antihepatotoxic agent. But it presents numerous challenges associated with its poor aqueous solubility which has been realized as the major problem in its dosage form development and clinical application. The objective of our study was to solubilize silybin by designing and synthesizing its aqueous soluble prodrug using high aqueous soluble polymeric carrier—poly(ethylene glycol) (PEG). A novel soluble silybin prodrug was synthesized with a linear PEG and succinic ester linkage, and was extensively characterized using proton NMR, FTIR, and TOF-MS. Furthermore, the prodrug was evaluated for its drug loading capability which was 6.65% and the solubility was 800 mg/mL. The results indicate significantly higher solubility of the prodrug in comparison with silybin. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

Use of polymer combinations in the preparation of solid dispersions of a thermally unstable drug by hot-melt extrusion

Co-reporter:Jia Liu, Feng Cao, Can Zhang, Qineng Ping

Acta Pharmaceutica Sinica B (July 2013) Volume 3(Issue 4) pp:

Publication Date(Web):1 July 2013

DOI:10.1016/j.apsb.2013.06.007

The objective of the study was to prepare solid dispersions containing a thermally unstable drug by hot-melt extrusion (HME). Carbamazepine (CBZ) was selected as model drug and combinations of Kollidon VA64 (VA64), Soluplus (SOL) and Eudragit EPO (EPO) were utilized as carriers. Preformulation was conducted to identify the suitability of polymer combinations based on solubility parameters, differential scanning calorimetry (DSC), hot stage microscopy and thermogravimetric analysis. Physicochemical properties of solid dispersions were determined by DSC, X-ray diffraction, fourier transform infrared spectroscopy, dissolution and accelerated stability testing. The results show that drug-polymer miscibility at temperatures below the melting point (Tm) of CBZ was improved by combining EPO with VA64 or SOL. With 30% drug loading in a solid dispersion in SOL:EPO (1:1, w/w), CBZ was mainly present in an amorphous form accompanied by a small amount of a microcrystalline form. The dissolution rate of the solid dispersion was significantly increased (approximately 90% within 5 min) compared to either the pure drug (approximately 85% within 60 min) or the corresponding physical mixture (approximately 80% within 60 min) before and after storage. The solid dispersion in SOL:EPO (1:1, w/w) was relatively stable at 40 °C/75% RH under CBZ tablet packaging conditions for at least 3 months. In conclusion, polymer combinations that improve drug-polymer miscibility at an HME processing temperature below the Tm of a drug appear to be beneficial in the preparation of solid dispersions containing thermally unstable drugs.By combining Eudragit EPO (EPO) with Kollidon VA64 (VA64) or Soluplus (SOL), the drug-polymer miscibility during preparation of solid dispersions of the thermally unstable and poorly water soluble drug, carbamazepine (CBZ), by hot-melt extrusion at a temperature below its melting point was improved.Download full-size image.

Thermosensitive Micelles–Hydrogel Hybrid System Based on Poloxamer 407 for Localized Delivery of Paclitaxel

Co-reporter:Caoyun Ju, Juan Sun, Peng Zi, Xiang Jin, Can Zhang

Journal of Pharmaceutical Sciences (August 2013) Volume 102(Issue 8) pp:2707-2717

Publication Date(Web):1 August 2013

DOI:10.1002/jps.23649

A thermosensitive micelles–hydrogel hybrid system based on Poloxamer 407 (P407) was prepared to resolve the fast erosion and low loading capability of lipophilic drug of P407 gels for local chemotherapy. Different amounts of glutaraldehyde (GA) were applied to generate cross-linked networks with carboxymethyl chitosan (CMCS) interpenetrated in P407 gels, in which paclitaxel (PTX)-loaded N-octyl-O-sulfate chitosan micelles (PTX-M) were dispersed uniformly. The in vitro characteristics of CMCS-modified P407 gels (PTX-M-MG) were performed by examining the viscosity, swelling ratio, mechanical property, and drug release, while the in vivo evaluation included tissue distribution and anticancer efficacy through in-tratumoral administration in hepatoma solidity cell (Heps) tumor-bearing mice. The results showed that PTX-M-MG containing 0.05% (w/v) GA possessed lower viscosity, higher swelling ratio, stronger mechanical property, and longer term drug release, in which the loading efficiency of PTX was enlarged by the introduction of PTX-M. Moreover, PTX-M-MG revealed a prolonged retention at tumor sites, lasting for 20 days, and a superior tumor inhibition rate (64.27%) with reduced toxicity compared with Taxol®, PTX-M, and PTX-M loaded unmodified P407 gels (PTX-M-P407). It can be concluded that PTX-M-MG is a promising local delivery system for hydrophobic drug in cancer therapy, providing both improved efficacy and relieved side effects. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2707–2717, 2013

Design, synthesis and biological evaluation of nonsecosteroidal vitamin D3 receptor ligands as anti-tumor agents

Co-reporter:Bin Wang, Meixi Hao, Can Zhang

Bioorganic & Medicinal Chemistry Letters (15 March 2017) Volume 27(Issue 6) pp:

Publication Date(Web):15 March 2017

DOI:10.1016/j.bmcl.2017.01.084

1α,25-dihydroxyvitamin D3 (1,25-(OH)2D3, also known as calcitriol), the active form of vitamin D3, is being increasingly recognized for cancer therapy. Our previous work showed that phenyl-pyrrolyl pentane analogs, which mimicked anti-proliferative activities against several cancer cell lines of the natural secosteroidal ligand 1,25-(OH)2D3. Here, in order to optimize the structural features and discover more potent derivative, a series of nonsecosteroidal vitamin D3 receptor (VDR) ligands bearing acetylene bond linker was designed, synthesized and evaluated. Most of them showed moderate to good binding affinities and agonistic activities. Especially, compound 19f displayed the most anti-proliferative activities against MCF-7 and PC-3 cells with the IC50 values of 1.80 and 5.35 μM, respectively, which was comparable to positive control 1,25-(OH)2D3. Moreover, compound 19f exhibited reduced toxicity against human normal liver cell line (L02) compared with the parental compound 7. Besides, the preliminary structure–activity relationships (SARs) were also analyzed.