Co-reporter:Nida El Islem Guissi, Huipeng Li, Yurui Xu, Farouk Semcheddine, Minglei Chen, Zhigui Su, and Qineng Ping
Molecular Pharmaceutics April 3, 2017 Volume 14(Issue 4) pp:1082-1082
Publication Date(Web):February 13, 2017
DOI:10.1021/acs.molpharmaceut.6b01009
Mitoxantrone (MTO) is a potent drug used to treat breast cancer; however, efforts to expand its clinical applicability have been restricted because of its high risk for cardiotoxicity. In this study, we successfully conjugated MTO or folic acid (FA) to a synthesized D-α-tocopheryl polyethylene glycol 2000 succinate (TPGS2k), herein, shortened to MCT and FCT, respectively. The two produced conjugates could self-assemble to form MCT micelles or MCT/FCT mixed micelles (FMCT) aiming to lower systemic toxicity, enhance entrapment efficiency, and provide a platform for targeted delivery. Moreover, these micellar materials showed a significantly low CMC and could be used to load MTO. The diameters of MTO-loaded micelles (MTO-MCT and MTO-FMCT) were less than 100 nm with a negative zeta potential. We further characterized the pH-responsive drug release of MTO-MCT and MTO-FMCT and then assessed their cellular uptake and antitumor efficacy in human breast cancer cell lines (MCF-7) via confocal microscopy, flow cytometry, and cytotoxicity studies. All the results revealed that both MTO-MCT and MTO-FMCT increased drug loading and entrapment efficiency and possessed sufficient pH-sensitive release. Additionally, MTO-FMCT displayed an improved uptake through folate-mediated endocytosis, resulting in a higher cytotoxic effect on MCF-7 cells compared with that of MTO-MCT. Meanwhile, both MTO-MCT and MTO-FMCT exhibited a low toxicity on hCMEC/D3 normal cells. More importantly, pharmacokinetic study demonstrated that, in comparison with free MTO injection, MTO-MCT and MTO-FMCT, respectively, achieved half-lives 11.5 and 13 times longer and a 9.7- and 5.8-fold increase in AUC. In vivo, both MTO-MCT and MTO-FMCT formulations significantly prolonged the survival time of MCF-7 tumor-bearing mice and had a better efficacy/toxicity ratio. Promisingly, MTO-FMCT micelles remarkably increased MTO accumulation in tumors in vivo, induced higher tumor cell apoptosis, and showed lower toxicity toward major organs. These results imply that MTO-FMCT may be used as a potential drug delivery system for breast cancer targeted therapy.Keywords: breast cancer therapy; folate targeting; mitoxantrone; self-assembled micelle; TPGS2k;
Co-reporter:Minjie Sun;Jing Li;Cuiting Zhang;Ying Xie;Hongzhi Qiao;Zhigui Su;David Oupický
Advanced Healthcare Materials 2017 Volume 6(Issue 8) pp:
Publication Date(Web):2017/04/01
DOI:10.1002/adhm.201600693
The ability to escape endo/lysosomal trafficking is critically important to prevent entrapment of nanomedicines in lysosomes and to achieve maximum therapeutic efficacy of drugs delivered to cells through endocytosis. In this study, a novel pH-sensitive chitosan carrier with the ability to reverse its charge during endo/lysosomal trafficking is developed as a way of improving lysosomal disruption. N-Arginine-N-octyl chitosan (AOCS) is synthesized by grafting l-arginine onto carboxymethyl chitosan. The AOCS is used to modify the surface of nanostructured lipid carriers (NLC) to prepare pH-sensitive charge-reversal lysosomolytic nanocarriers (ANLC). The ANLC is loaded with 10-hydroxycamptothecin (HCPT). The results show that ANLC is able to reverse surface zeta potential from negative to positive at lysosomal pH, which contributes to improved release of encapsulated drugs into cytoplasm. The lysosomolytic capability of ANLC is confirmed by confocal microscopy and transmission electron microscopy. In vitro studies demonstrate that the anticancer activity of HCPT-loaded ANLC is improved when compared with HCPT-NLC and free HCPT. In vivo pharmacokinetics and tissue distribution analysis show improved delivery of HCPT-ANLC to subcutaneous Heps mouse liver tumors and greatly improved antitumor activity. The results present ANLC as a promising drug delivery carrier for improved antitumor therapy.
Co-reporter:Zhigui Su, Minglei Chen, Yanyu Xiao, Minjie Sun, Li Zong, Sajid Asghar, Mei Dong, Huipeng Li, Qineng Ping, Can Zhang
Journal of Controlled Release 2014 Volume 196() pp:370-383
Publication Date(Web):28 December 2014
DOI:10.1016/j.jconrel.2014.09.020
Drug delivery strategies utilizing tumor microenvironment are recognized as a critical doorway to overcome multidrug resistance (MDR). However, the variability of tumor microenvironment at different disease stages would definitely minimize stimuli generation and eventually the therapeutic effects of these stimuli sensitive systems. Herein, we report a unique reactive oxygen species (ROS) triggered nanosystem that can replenish the ROS upon disassembly to maintain its high level. This was accomplished by a new amphiphilic polymer (TBH) composed of D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), hyaluronic acid (HA) and arylboronic ester. As a linker of TPGS to HA, arylboronic ester could efficiently degrade in response to ROS resulting in dismantling of nanosystem followed by rapid release of TPGS. Owing to ROS inducing activity of TPGS with mitochondrial respiratory complex II, ROS regeneration was observed for TBH nanosystem both in MCF-7/ADR cells and tumor tissues xenografted with MCF-7/ADR cells. Furthermore, doxorubicin-loaded TBH nanosystem (DOX-TBH) revealed higher drug cytotoxicity due to enhanced retention effect on account of ROS triggered DOX release and P-gp inhibitory mechanism of TPGS. Moreover, HA significantly improved tumor targeting capability of DOX-TBH, while ROS based triggering and regenerating mechanism lead to marked inhibition of the tumor growth in the xenograft MCF-7/ADR tumor-bearing nude mice.Schematic presentation of ROS-triggered and regenerating anticancer nanosystem.
Co-reporter:Hongzhi Qiao, Minjie Sun, Zhigui Su, Ying Xie, Minglei Chen, Li Zong, Yahan Gao, Huipeng Li, Jianping Qi, Qun Zhao, Xiaochen Gu, Qineng Ping
Biomaterials 2014 35(25) pp: 7157-7171
Publication Date(Web):
DOI:10.1016/j.biomaterials.2014.04.106
Co-reporter:Zhigui Su, Jiangxiu Niu, Yanyu Xiao, Qineng Ping, Minjie Sun, Aiwen Huang, Weiliang You, Xiaoye Sang, and Dongfen Yuan
Molecular Pharmaceutics 2011 Volume 8(Issue 5) pp:1641-1651
Publication Date(Web):July 19, 2011
DOI:10.1021/mp100463n
A new conjugate, octreotide–polyethylene glycol(100) monostearate (OPMS), was developed for the enhancement of targeting delivery of hydroxycamptothecine (HCPT) loaded in nanostructured lipid carrier (NLC). 2 ×10–3 and 5 × 10–3 mmol of OPMS were respectively used to modify NLC so that the targeted nanocarriers with low and high ligand density were obtained. For comparison, the pegylated NLCs without octreotide were prepared by adding equal molar amounts of polyethylene glycol(100) monostearate (PGMS). The relation between the modification levels and properties of various NLCs were studied in vivo and in vitro. At a high modification level, a slower release rate of HCPT and the more stable nanocarriers was achieved. At the same time, the fixed aqueous layer thickness (FALT) and average surface density of PEG chains (SDPEG) was increased, but the distance (D) between two neighboring PEG grafting sites became narrower. The in vivo pharmacokinetic study in healthy rat indicated that the modified NLCs had a longer circulation than NLC (P < 0.05) due to pegylation effect and OPMS modified NLCs had larger MRT and AUC0–t than that of PGMS modified NLCs at the same modification level. Furthermore, the florescence microscopy observation also showed the targeting effect of octreotide modification on somatostatin receptors (SSTRs) of tumor cell (SMMC-7721). The uptake of SMMC-7721 was much more than that of normal liver cell (L02) for OPMS modified NLC, and the highest uptake was observed for 5 × 10–3 mmol of OPMS modified one. No obvious difference was found among the L02 uptake of OPMS modified NLCs and NLC, but their uptake was higher than that of PGMS modified NLCs. All the results indicated that the OPMS highly modified NLCs would improve the effect of antitumor therapy by inhibiting the degradation, evading RES and enhancing the drug uptake of tumor cells.Keywords: nanostructured lipid carrier; octreotide; polyethylene glycol(100) monostearate; somatostatin receptor;
Co-reporter:Can Zhang, Yao Cheng, Guowei Qu, Xiaoli Wu, Ya Ding, Zhihong Cheng, Liangli Yu, Qineng Ping
Carbohydrate Polymers 2008 Volume 72(Issue 3) pp:390-397
Publication Date(Web):16 May 2008
DOI:10.1016/j.carbpol.2007.09.004
In this paper, new sustained release microspheres with a surface coating of targeting moieties coating are presented. Bovine serum albumin (BSA) was used to prepare the microspheres loading with 5-fluorouracil (5-FU) by means of chemical crosslinking method and then the microspheres were coated with N-galactosylated chitosan by electrostatic interaction. The structure of coating layers on the surface of 5-FU-loaded BSA microspheres was characterized by attenuated total reflection Fourier (ATR-FTIR), electron spectroscopy for chemical analysis (ESCA), wide X-ray diffraction (WXRD) and transmission electron microscopy (TEM). The properties of the coated microspheres containing 5-FU were determined. The size was in the range of 0.60–0.65 μm, zeta potential was 16.6 mv, and the encapsulation efficiency, drug loading, and the content of galactosyl groups were 40.3% (w/w), 2.9% (w/w), and 5.4% (w/w), respectively. In comparison with uncoated microspheres, the coated microspheres showed delayed release and less burst release in vitro. All results suggested the BSA microspheres preparation with galactosyl chitosan coating could be a promising method for targeted delivery to the liver.
Co-reporter:Hao Gao, Yueqing Gu, Qineng Ping
Journal of Controlled Release 2007 Volume 118(Issue 3) pp:325-332
Publication Date(Web):23 April 2007
DOI:10.1016/j.jconrel.2006.12.028
The paper introduced an improved fabrication technique, by which the hydrophobic polymer monofilament fiber loading hydrophilic drug was obtained. The micronized 5-Fu (5-fluorouracil) powders were homogeneously dispersed in PLLA (poly(l-lactic acid))–chloroform solution to form the suspension, and then the suspension was solidified in the nonsolvent to prepare the fibers by wet-spinning method under mild condition. The diameter of drug-loaded fiber was in the range of 50–250 μm. The hydrophilic drug powders were successfully encapsulated into the monofilament fiber with good stability, high drug loading content and efficacy. The MTT cytotoxicity assay in vitro revealed the satisfactory anticancer activity of the drug-loaded fibers. The long-term release characteristics of these fibers were also achieved. Furthermore, the drug release rate of the fibers could be regulated by the formulation and fabricating parameters, such as drug loading content, polymer concentration in suspension, nonsolvent composition and flow rate in wet-spinning. The release mechanism of the fibers was investigated and described by Fickian diffusion equation.
Co-reporter:Zhong Yao, Can Zhang, Qineng Ping, Liangli (Lucy) Yu
Carbohydrate Polymers 2007 Volume 68(Issue 4) pp:781-792
Publication Date(Web):23 April 2007
DOI:10.1016/j.carbpol.2006.08.023
A series of novel chitosan derivatives with octyl, sulfate and polyethylene glycol monomethyl ether (mPEG) groups as hydrophobic and hydrophilic moieties, respectively, were synthesized. These PEGylated amphiphilic chitosan derivatives were characterized with 1H NMR, 13C NMR, FTIR and elemental analysis. And their physical properties were measured by wide angle X-ray diffraction (WAXD) and thermogravimetric analysis (TG). The critical micelle concentrations (CMCs) of the modified chitosans determined by using pyrene as a hydrophobic probe in fluorescence spectroscopy were found to be 0.011–0.079 mg/ml, and the log CMC was linearly relative to four structure parameters, that is the degree of substitution (DS) of chitosan unit, sulfate group, PEG unit and octyl group by mole per kilogram. Paclitaxel, a water-insoluble anticancer drug, was solubilized into the polymeric micelles formed by these derivatives utilizing physical entrapment method, with micellar particle size around 100–130 nm, and the highest paclitaxel concentration of 3.94 mg/ml was found in N-mPEG-N-octyl-O-sulfate chitosan (mPEGOSC) micellar solution, which was much higher than that in water (less than 0.001 mg/ml). Therefore, N-mPEG-N-octyl-O-sulfate chitosan micelles may be useful as a prospective carrier for paclitaxel.
Co-reporter:Can Zhang, Ya Ding, Liangli (Lucy) Yu, Qineng Ping
Colloids and Surfaces B: Biointerfaces 2007 Volume 55(Issue 2) pp:192-199
Publication Date(Web):1 April 2007
DOI:10.1016/j.colsurfb.2006.11.031
This research investigated the possible utilization of amphiphilic N-octyl-N-trimethyl chitosan (OTMCS) derivatives in solublization and controlled release of 10-hydroxycamptothecin (10-HCPT), a hydrophobic anticancer drug. The release behavior of the 10-HCPT-OTMCS micelles was measured and compared to that of a commercial 10-HCPT lyophilized powder in vitro and in vivo. This research also examined the effects of chemical structure of the chitosan derivatives and the micellar preparation conditions on the encapsulation efficiency, drug loading content, and particle size of the polymeric micelles. The results showed that these chitosan derivatives were able to self-assemble and form spherical shape polymeric micelles with an average particle size range of 24–280 nm and a drug loading content of 4.1–32.5%, depending on the modified structures and loading procedures. The solubility of 10-HCPT in aqueous fluid was increased about 80,000-fold from 2 ng/ml in water to 1.9 mg/ml in OTMCS micellar (degree of octyl and trimethyl substitution is 8% and 54%, respectively) solution. In addition, OTMCS was able to modulate the in vitro release of 10-HCPT and improve its pharmacokinetic properties and lactone ring stability in vivo. These data suggested the possible utilization of the amphiphilic micellar chitosan derivatives as carriers for hydrophobic drugs for improving their delivery and release properties.
Co-reporter:Xiao Ming Xu;Yan Wang;Xian Yang Liu;Yun Mei Song;Qi Neng Ping
Journal of Applied Polymer Science 2006 Volume 102(Issue 4) pp:4066-4074
Publication Date(Web):29 AUG 2006
DOI:10.1002/app.24393
The focus of the present study is on the temperature-dependent behavior of hydroxypropyl methylcellulose (HPMC) solutions at various ionic strength levels. Such behavior is then introduced into the study of tablet dissolution with the aim of explaining why ionic strength could vary the dissolution rate or cause the tablets to disintegrate. The results show that increasing the concentration of solute in the dissolution media will affect the thermal property of hydrated HPMC and then have an effect on the matrix tablets dissolution process. Of the thermal property, reduction of the cloud point is believed to have some relationship with the decrease of the dissolution rate, and decline of the thermal gelation temperature (TGT) might be responsible for the disintegration of the matrix tablets. A “gel out” process concerning the mechanism of the disintegration has been put forward, and a rheological method to test the lower critical solution temperature (LCST) is also presented. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 4066–4074, 2006
Co-reporter:Can Zhang;Ya Ding
Journal of Applied Polymer Science 2005 Volume 97(Issue 5) pp:2161-2167
Publication Date(Web):28 JUN 2005
DOI:10.1002/app.21975
A series of water-soluble chitosan derivatives, carrying galactose residues, were synthesized by using an alternative method in which the galactose groups were introduced into amino groups of the derivatives. First, hydroxyethyl chitosan (HECS) and hydroxypropyl chitosan (HPCS) were synthesized under alkaline conditions by using chitosan and propylene or chitosan and ClCH2CH2OH as the starting materials, respectively. Then lactobionic acid was added into the systems so as to form galactosylated HECS (Gal-HECS) and galactosylated HPCS (Gal-HPCS) with substitution degrees of 53 and 47%, respectively. Lactosaminated HPCS (Lac-HPCS) and Lactosaminated HECS (Lac-HECS) were obtained with substitution degrees of 42 and 38%, respectively, by the reductive amination of the mixtures of lactose and HECS or lactose and HPCS with potassium borohydride present in the reaction. The chemical structures of new chitosan derivatives were characterized by FTIR, 1H NMR, 13C NMR, and elemental analysis. Some physical properties were also analyzed by wide angle X-ray diffraction (WAXD) and differential scanning calorimetry (DSC). The novel chitosan derivatives carrying galactose residues may be used as additives for hepatic targeting delivery. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 97: 2161–2167, 2005
Co-reporter:Jiangxiu Niu, Zhigui Su, Yanyu Xiao, Aiwen Huang, Hongying Li, Xiao Bao, Sai Li, Yinan Chen, Mingjie Sun, Qineng Ping
European Journal of Pharmaceutical Sciences (23 January 2012) Volume 45(Issues 1–2) pp:216-226
Publication Date(Web):23 January 2012
DOI:10.1016/j.ejps.2011.11.013
A multifunctional mixed micelle was assembled for drug targeting delivery by combining two newly synthesized amphiphilic polymers, which were octreotide-polyethylene glycol-monostearate (OPMS) and N-octyl-N-succinyl-O-carboxymethyl chitosan (OSCC), respectively. The mixed micelle was designed to be characterized with long circulation, somatostatin receptors (SSTR)-mediated endocytosis and pH sensitivity. A series of assembling proportions of OPMS and OSCC was tested to reveal the effect of compositions on the functions. The particle size, zeta potential, drug loading and critical micelle concentration were examined. The dialysis test indicated a pH-triggering release behavior of the doxorubicin-loaded mixed micelle (DLMM), and faster release in acidic media (pH 4.0–6.0) in response to the protonation of carboxyl group. In addition, the PEG segments could efficiently protect the mixed micelle from plasma protein adsorption in vitro, and the DLMM composed of 20% OPMS and 80% OSCC provided the longest residence time after intravenous injection in rats in vivo. Due to SSTR mediated endocytosis, the significantly higher uptake of DLMM was observed in the tumor cells (SMMC-7721), compared with that in the normal cells (CHO) without SSTR expression. All the results suggested that the mixed micelle with multifunctional characteristics could be used as an effective approach for tumor treatment.Schematic diagram of the multifunctional mixed micellesDownload full-size image
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