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ABSTRACT: A multifunctional hybrid platinum(iv) prodrug, which consists of both the mitochondria-targeting drug DCA and the DNA-crosslinking drug cisplatin, was synthesized and tethered to a carrier polymer to further self-assemble into micelles for intracellular delivery.
Chemical Communications 09/2012; 48(87):10730-2. · 6.17 Impact Factor
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ABSTRACT: Multifunctional hybrid micelles are prepared from amphiphilic mal-PEG-b-PLA and mPEG-b-P(LA-co-DHC/RhB) block copolymers. A specific anti-transferrin receptor antibody, OX26, is linked onto the surface of the micelles. ELISA indicates that the conjugated antibody preserves its activity. OX26 conjugation can increase the uptake efficiency of micelles by target cell lines (C6). Pharmacokinetics and in vivo biodistribution experiments are carried out to investigate the ability of OX26-conjugated micelles (immunomicelles) to cross the blood-brain barrier. The data show that the brain uptake of OX26-conjugated micelles is much more than that of OX26-free ones. Therefore, OX26-conjugated micelles will be promising drug carriers to cross the blood-brain barrier.
Macromolecular Bioscience 07/2012; 12(9):1209-19. · 3.89 Impact Factor
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Haihua Xiao,
Haiqin Song,
Qiang Yang,
Haidong Cai,
Ruogu Qi,
Lesan Yan, Shi Liu,
Yonghui Zheng,
Yubin Huang,
Tongjun Liu,
Xiabin Jing
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ABSTRACT: A strategy of preparing composite micelles containing both cisplatin(IV) prodrug and paclitaxel was developed, i.e., synthesizing a cisplatin(IV) conjugate and a paclitaxel conjugate starting with the same biodegradable and amphiphilic block copolymer, and co-assembling the two conjugates. The composite micelles could release effective anticancer drug cisplatin(II) upon cellular reduction and PTX via acid hydrolysis once they came into the cancerous cells. Moreover, the composite micelles displayed synergistic effect in vitro and the combination therapy in micellar dosage-form led to reduced systematic toxicity and enhanced antitumor efficacy in vivo.
Biomaterials 06/2012; 33(27):6507-19. · 7.40 Impact Factor
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ABSTRACT: Biodegradable Y-shaped amphiphilic block copolymer mPEG-b-PLG-b-(PLA)2 was synthesized and characterized by 1HNMRand FTIR. The amphiphilic property of the copolymer with a mPEG-b-PLG segment as the hydrophilic arm and two PLA segments as the hydrophobic arms endows the copolymer with the ability to form core–shell nanoparticles in aqueous solution. Co-assembly of doxorubicin (Dox) and the block copolymer in selective solvent was carried out to prepare Dox-loaded micelles. The
inner-shell (PLG) of the micelle was crosslinked through a carbodiimide coupling method with cystamine as the crosslinker. The crosslinked micelles exhibit reduction-responsive release of Dox and the stability in vitro was much better than non-crosslinked micelles. In acidic release condition, the total amount of Dox released could be increased due to the increased solubility of Dox. The blood clearance of Dox in different form of micelles was studied and the results show that Dox loaded in the crosslinked micelles with PEG5K as the outer shell exhibit the longest blood circulation after intravenous injection.
Soft Matter 06/2012; 8(28):7426-7435. · 4.39 Impact Factor
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ABSTRACT: An oxaliplatin pro-drug (Oxa(IV)-COOH) with an axial carboxyl group was synthesized and conjugated to biodegradable polymers with pendant hydroxyl groups to prepare polymer-Oxa(IV) conjugates. A hydrophobic anthracycline-based drug, daunorubicin (DRB) was conjugated to similar biodegradable polymers with carboxyl groups to synthesize polymer-DRB conjugates. The two drug conjugates have the similar polymer backbone and are amphiphilic; thus, they can co-assemble into composite micelles. In the composite micelles, the polymer-Oxa(IV) conjugates can release clinically widely used water soluble anticancer drug oxaliplatin (Oxa(II)) upon reduction, while polymer-DRB conjugate is thought to release DRB via acid hydrolysis in the cancer cells. In this way, combination of the hydrophilic platinum drug Oxa(II) and hydrophobic drug DRB can be realized by delivering them in one platform. Moreover, the composite micelles showed reduced systematic toxicity and greater synergistic effect than combination of small molecules of the two anticancer drugs both in vitro and in vivo; thus, this polymer based combination therapy can be useful in future clinic application.
Journal of Controlled Release 06/2012; 163(3):304-314. · 5.73 Impact Factor
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ABSTRACT: As the transport protein for iron, transferrin can trigger cellular endocytosis once binding to its receptor (TfR) on the cell membrane. Using this property, we conjugated transferrin onto the surface of biodegradable polymeric micelles constructed from amphiphilic block copolymers. The core of micelle was either labeled with a near-infrared dye (NIR) or conjugated with a chemotherapeutic drug paclitaxel (PTX) to study the biodistribution or antitumor effect in nude mice bearing subcutaneous TfR-overexpressing cancers. DLS and TEM showed that the sizes of Tf-conjugated and Tf-free micelles were in the range of 85-110 nm. Confocal laser scanning microscopy and flow cytometry experiments indicated that the uptake efficiency of the micelles by the TfR-overexpressing cells was enhanced by Tf conjugation. Semiquantitative analysis of the NIR signals collected from the tumor site showed that the maximum accumulation was achieved at 28 h in the M(NIR) group, while at 22 h in Tf-M(NIR) groups; and the area under the intensity curve in the Tf-M(NIR) groups was more than that in M(NIR) group. Finally, the tumor inhibition effects of targeting micelles were studied with the gastric carcinoma model which overexpressed TfR. The analysis of tumor volumes and the observation of H&E-stained tumor sections showed that Tf-M(PTX) had the best antitumor effect compared with the control groups (saline, PTX, and M(PTX)). The results of this study demonstrated the potential application of Tf-conjugated polymeric micelles in the treatment of TfR-overexpressing cancers.
Molecular Pharmaceutics 05/2012; 9(7):1919–1931. · 4.78 Impact Factor
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ABSTRACT: It is still a great challenge to apply therapeutic concentration of anti-cancer drugs to the tumor site with low system toxicity. An in situ administration strategy was applied to reverse the aerobic glycolysis of tumor in vivo for the first time. Controlled release of therapeutic concentration of dichloroacetate (DCA) from polylactide (PLA) electrospun mats covering the solid tumor locally was designed to suppress the cervical carcinoma in vivo. A dramatic decrease in the volume and weight of tumors was observed for 19 days in tumor-bearing mice, and a totally 96% of the tumor suppression degree was obtained even the initial tumor volume was around 200 mm(3). Half of the mice recovered in less than 3 weeks. Necrosis was examined rather than apoptosis on the tumor cells as the main process of cell death induced by the DCA-loaded electrospun mats. A proposed necroptosis mechanism was presented to explain the signal pathways that were induced by the metabolic remodeling of DCA. It provided support for this strategy that target the bio-energy metabolism of the cervical carcinoma locally is a quick and effective pathway to cure the advanced-carcinoma of cervical.
Biomaterials 03/2012; 33(17):4362-9. · 7.40 Impact Factor
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ABSTRACT: Pirarubicin (THP) was conjugated onto the pendant carboxyl groups of poly(ethylene glycol)-block-poly(l-lactide-co-2-methyl-2-carboxyl-propylene carbonate) [PEG-b-P(LA-co-MCC)] through hydrazone, ester, and amide bonds, respectively, and the conjugates were assembled into micelles with diameters between 30 and 60 nm. The in vitro THP release of the three conjugate micelles was conducted in pH 7.4 and 5.0 buffer solutions, and conjugate micelles with hydrazone linkage had the fastest THP release rate. Their in vitro cytotoxicity was tested using mouse mammary adenocarcinoma EMT6 cells and in vivo anti-tumor activity in Balb/c mice models bearing EMT6 tumors were compared with free THP and with each other. The results showed that the polymer-THP conjugates displayed higher cell-uptakes and better anti-tumor activities than free THP at 4h, and among the three micelles, those with hydrazone linkage had the highest anti-tumor activity in vivo, while those with amide linkage were the lowest.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 03/2012; 46(5):329-35. · 2.61 Impact Factor
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ABSTRACT: The biodegradable cationic copolymers monomethoxy poly(ethylene glycol)-block-poly(ε-caprolactone)-block-poly(L-lysine) (mPEG-b-PCL-b-PLL, further abbr. as "M") with a PCL block of different lengths and with a triazole linkage between the PCL and PLL blocks were synthesized via ring-opening polymerization of ε-caprolactone and L-lysine N-carboxyanhydride and click reactions. With the copolymer without the PCL block (mPEG-b-PLL, further abbr. as "P") as a control, self-assembling and complexation of these copolymers with siRNA were studied. siRNA-loading capacity, siRNA delivery performance and cellular uptake of the complexation products, namely complex from P (P-complex) and complexes from M1 and M2 (M1-complex and M2-complex), were further examined and correlated to their block-copolymer compositions. The results showed the block copolymers P, M1 and M2 have strong enough binding ability so that the complexes formed can resist the heparin displacement and RNase degradation. Compared to P-complex, M-complexes have smaller size and higher particle density so that they can be internalized via endocytosis more easily than free siRNA or P-complex and they display higher siRNA delivery efficiency and higher gene silencing efficiency than P-complex. The silencing efficiency of micellar complex is close to that of Lipofectamine(TM) 2000 and much better than PEI-25kDa. Therefore, mPEG-b-PCL-b-PLL is expected to be a promising siRNA carrier.
Journal of Controlled Release 01/2012; 159(2):251-60. · 5.73 Impact Factor
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ABSTRACT: A biodegradable and amphiphilic copolymer, MPEG-b-P(LA-co-MCC), which contains pendant carboxyl groups was chosen as a drug carrier for active anticancer part (DACH-Pt) of oxaliplatin to form an MPEG-b-P(LA-co-MCC/Pt) complex. It could self-assemble into micelles with a mean diameter of 30−40 nm, and a surface potential near −10 mV. The typical platinum content was 10 wt%. The micelles showed acid responsive drug release kinetics which is beneficial to the drug release under the intracellular environment. The Pt(II) species were released mainly in the form of DACH-Pt-Cl2 in 150 mM NaCl solution and DACH-Pt2+-(H2O)2 in pure water according to the results obtained by HPLC-ICP-MS and XPS. In vitro evaluation showed that the micelles displayed the same or higher cytotoxicities against SKOV-3, HeLa, and EC-109 cancer cells compared with oxaliplatin. The enhanced cytotoxicity against SKOV-3 cells is attributed to effective internalization of the micelles by the cells via endocytosis mechanism and the sensitivity of SKOV-3 cells to platinum drugs. This novel biodegradable and amphiphilic copolymer based platinum drugs will have great potential application in clinic.
Acta biomaterialia 01/2012; · 3.98 Impact Factor
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Journal of controlled release. 01/2012;
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ABSTRACT: Esophageal cancer is recognized as one of the most refractory pernicious diseases. In addition, it is an aggressive malignancy with a propensity for local progression and distant dissemination. Because of the poor long-term prognosis for patients with esophageal cancer, increasing attention has focused on the integration of targeted agents into current therapeutics. Nevertheless, there have been few studies reported concerning the therapeutic efficacy of paclitaxel-conjugated polymeric micelles in human esophageal cancer in vivo. Therefore, the aim of this research was to investigate the tumor inhibition effect of composite micelles containing folic acid and paclitaxel on the human esophageal EC9706 cancer cell line.
Intravenous administration of folate-targeted, paclitaxel-loaded micelles was demonstrated to be more efficient in inhibiting subcutaneous xenograft tumors and extending the survival rate of tumor-bearing nude mice than free paclitaxel and plain paclitaxel micelles at an equivalent paclitaxel dose of 20 mg/kg, which was further backed up by flow cytometry, TUNEL, and expression of apoptosis-related proteins, including Bax, Bcl2, and caspase 3 in this study.
The folate-mediated paclitaxel-loaded polymeric micelle is a promising agent for the treatment of human esophageal cancer.
International Journal of Nanomedicine 01/2012; 7:3487-502. · 3.13 Impact Factor
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ABSTRACT: A biodegradable and amphiphilic copolymer, mPEG-b-P(LA-co-MAC/TMA) that contains pendant 1,2-bidentate carboxyl groups is synthesized by thiol-ene radical addition and is further used to chelate with the active anticancer species (DACH-Pt) of oxaliplatin to form an mPEG-b-P(LA-co-MAC/TMA-Pt-DACH) complex. The polymer platinum complex can self-assemble into micelles. In vitro studies show that the DACH-Pt micelles display enhanced or comparable cytotoxicity against SKOV-3 and MCF-7 cancer cells, while they show reduced toxicity to HeLa cells compared with oxaliplatin.
Macromolecular Bioscience 12/2011; 12(3):367-73. · 3.89 Impact Factor
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Journal of Controlled Release 11/2011; 152 Suppl 1:e103-4. · 5.73 Impact Factor
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Journal of Controlled Release 11/2011; 152 Suppl 1:e258-60. · 5.73 Impact Factor
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Journal of Controlled Release 11/2011; 152 Suppl 1:e123-4. · 5.73 Impact Factor
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ABSTRACT: A Pt(IV) complex was covalently conjugated to a new biodegradable amphiphilic tri-block copolymer, MPEG-b-PCL-b-PLL, which contains pendant amino groups, to form a polymeric pro-drug of cisplatin(II), MPEG-b-PCL-b-PLL/Pt(IV). The conjugate was assembled into nano-micelles. The Pt(IV) complex, the polymer carrier and the conjugate were characterized systematically. In vitro release experiments showed that drug release from the polymer-Pt(IV) micelles follows an acid responsive and oxidation-reduction sensitive kinetics. HPLC-ICP-MS analysis revealed that cisplatin(II) can be released from the conjugate under an acidic plus a reductive condition which is available inside a cancerous cell. In vitro MTT assay demonstrated that the polymer-Pt(IV) micelles display higher cytotoxicity against SKOV-3 tumor cells than both cisplatin(II) and Pt(IV) complex. This enhanced cytotoxicity is attributed to effective internalization of the micelles by the cells via endocytosis mechanism, which was observed by fluorescence imaging and by direct determination of the platinum uptake by the cells. This polymer-Pt(IV) conjugate is a promising polymeric pro-drug of cisplatin in micellar form. It can protect the Pt(IV) complex against blood clearance. It can enter cancerous cells via endocytosis mechanism and then cisplatin(II) can be released. Therefore, this polymeric pro-drug of cisplatin is expected to find clinical applications in the future.
Biomaterials 10/2011; 32(30):7732-9. · 7.40 Impact Factor
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ABSTRACT: Doxorubicin (Dox) was conjugated onto a biodegradable block copolymer methoxy-poly(ethylene glycol)-block-poly(lactide-co-2,2-dihydroxymethylpropylene carbonate (mPEG-b-P(LA-co-DHP)) via a carbamate linkage and an acid-labile hydrazone linkage, respectively. Mutifunctional mixed micelles consisting of Dox-containing copolymer mPEG-b-P(LA-co-DHP/Dox) and folic acid-containing copolymer mPEG-b-P(LA-co-DHP/FA) were successfully prepared by coassembling the two component copolymers. The mixed micelles had well-defined core shell structure and their diameters were in the range of 70-100 nm. Both Dox-conjugates (via carbamate or hydrazone linkage) showed pH-dependent release behavior, and the micelles with hydrazone linkage showed more pH-sensitivity compared to those with carbamate linkage. The in vitro cell uptake experiment by CLSM and flow cytometry showed preferential internalization of FA-containing micelles by human ovarian cancer cell line SKOV-3 than that without FA. Flow cytometric analysis was conducted to reveal the enhanced cell apoptosis caused by the FA-containing micelles. These results suggested that these micelles containing both chemotherapeutic and targeting ligand could be a promising nanocarrier for targeting the drugs to cancer cells and releasing the drug molecules inside the cancer cells.
Biomacromolecules 08/2010; 11(8):2094-102. · 5.48 Impact Factor
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ABSTRACT: Two kinds of paclitaxel (PTX) conjugate nanomicelles were prepared for cell apoptosis and anti-tumor activity evaluation on Lewis lung cancer mice models. One (PTX micelles) was prepared by self-assembling the PTX-conjugate co-polymer, poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2-carboxyl-propylene carbonate/PTX), and the other (FA-PTX micelles) was by co-assembling a mixture of the folic acid (FA)-carrying co-polymer poly(ethylene glycol)-b-poly(L-lactide-co-2,2-dihydroxylmethyl-propylene carbonate/FA) (PEG-b-P(LA-co-DHP/FA)), and the PTX-conjugate co-polymer. At 7 and 14 days after tail intravenous injection, the mice were killed. The inhibition rates of tumor growth for PTX and FA-PTX micelles were 50 and 90%, respectively, on the day 7, and 33 and 71%, respectively, on the day 14 after drug injection. Flow cytometry analysis showed that the cell apoptosis rates were 43, 54 and 72% for the control group, PTX micelles group and FA-PTX micelles group, respectively, on the day 7, and 16, 25 and 42 on the day 14. With the TUNEL assay, the grey values of PTX micelles and FA-PTX micelles groups were determined to be 61-62% and 43-44%, of that of the control group, on day 7 or day 14, respectively. Therefore, the PTX micelles and the FA-PTX composite micelles significantly inhibited the subcutaneously inoculated Lewis lung cancer and effectively induced the cell apoptosis, and the FA-PTX composite micelles displayed a better efficacy than the PTX-micelles, implying the contribution of the folate-mediated targeting and endocytosis effect.
Journal of Biomaterials Science Polymer Edition 06/2010; · 1.69 Impact Factor
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ABSTRACT: Two kinds of micelles containing Rhodamine B were prepared by a solvent evaporation method. One (Lac-f-micelles: lactose-free micelles) was from a Rhodamine-containing copolymer, poly(ethylene glycol)-b-poly(l-lactide-co-2,2-dihydroxylmethyl-propylene carbonate/Rhodamine) [PEG(5000)-b-P(LA(4000)-co-DHP(600)/Rhodamine)], and the other (Lac+micelles lactose-containing micelles) was from a mixture of the targeting copolymer lactose-poly(ethylene glycol)-poly (l-Lactide) [Lac-PEG(4600)-PLA(4500)] and the Rhodamine-containing copolymer PEG(5000)-b-P(LA(4000)-co-DHP(600)/Rhodamine). ESEM and DLS measurements showed that the two kinds of micelles have similar size (in the range of 60-100 nm) and size distribution. Cellular uptake studies in vitro revealed that the Lac+micelles showed stronger endocytosis ability than Lac-f-micelles in SMMC7221 human liver cancer cells, but the Lac+micelles were rarely internalized by Vero cells. The micelle solutions were administrated into mice via tail intravenous injection. Then, five visceral organs were isolated from the mice at specified time intervals and relative fluorescent intensities of the ex vivo organs and their homogenates were examined by CRI Maestro 500FL in vivo imaging system. The results showed that the Lac+micelles showed more remarkable liver-targeting effect than the Lac-f-micelles. And the liver-targeting effect could be established in ca. 12 h after tail i.v. injection.
Biomaterials 03/2010; 31(9):2646-54. · 7.40 Impact Factor
