PEG-PE/clay composite carriers for doxorubicin: Effect of composite structure on release, cell interaction and cytotoxicity (original) (raw)
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Polymer Bulletin
The synthesized heterocyclic compound: 5-[4-bromobenzylidene amino)-1, 3, 4-thiadiazole-2-thiol abbreviated as BATT possessed good antibacterial activity for various Gram-negative and Gram-positive bacteria. In addition to potent antitumor activity to breast cancer, for the first time, the novelty of this study is facile low-cost formulation of safe antitumor drug delivery system (DDS) for breast cancer from such simple heterocyclic compound. Heterocyclic compound is efficiently and spontaneously incorporated into MMT clay polymer matrix forming novel therapeutic nanocomposite DDS for breast cancer. BATT successfully intercalates MMT clay polymer matrix. Electron donation ability of nanocomposites is confirmed by cyclic voltammetry in terms of small peak-to-peak redox potential \Delta E_{{{\text{peak}}}}$$ Δ E peak . Adsorption of BATT on clay is carried out by batch adsorption method. Better adsorption strength at low pH 2 decreased with increasing pH. Adsorption data are analyze...
European Journal of Pharmaceutics and Biopharmaceutics, 2008
Novel micelle-forming poly(ethylene oxide)-block-poly(e-caprolactone) (PEO-b-PCL) block copolymers bearing doxorubicin (DOX) side groups (PEO-b-P(CL-DOX)) on the PCL block were synthesized. Prepared block copolymers were characterized, assembled to polymeric micellar drug conjugates and assessed for the level of DOX release at pH 7.4 and pH 5.0 using a dialysis membrane to separate released and conjugated drug. The possibility for the degradation of PCL backbone for PEO-b-P(CL-DOX) micelles was investigated using gel permeation chromatography. Micelle-forming DOX conjugate did not show any signs of DOX release at 37°C within 72 h of incubation at both pHs, but revealed signs of poly(ester) core degradation at pH 5.0. In further studies, PEO-b-PCL micelles bearing benzyl, carboxyl or DOX groups in the core were also used as micellar nano-containers for the physical encapsulation of DOX, where maximum level of drug-loading and control over the rate of DOX release was achieved by polymeric micelles containing benzyl groups in their core, i.e., PEO-b-poly(a-benzylcarboxylate-e-caprolactone) (PEO-b-PBCL) micelles. The in vitro cytotoxicity of chemically conjugated DOX as part of PEO-b-P(CL-DOX) and physically encapsulated DOX in PEO-b-PBCL against B16F10 murine melanoma cells was assessed and compared to that of free DOX. Consistent with the results of in vitro release study, cytotoxicity of micellar PEO-b-P(CL-DOX) conjugate (IC 50 of 3.65 lg/mL) was lower than that of free and physically encapsulated DOX in PEO-b-PBCL (IC 50 of 0.09 and 3.07 lg/mL, respectively) after 24 h of incubation. After 48 h of incubation, the cytotoxicity of conjugated DOX (IC 50 of 0.50 lg/mL) was still lower than the cytotoxicity of free DOX (IC 50 of 0.03 lg/mL), but surpassed that of physically encapsulated DOX in PEO-b-PBCL (IC 50 of 1.54 lg/mL). The results point to a potential for PEO-b-P(CL-DOX) and PEO-b-PBCL as novel polymeric micellar drug conjugates and nano-containers bearing hydrolyzable cores for DOX delivery.
Journal of Controlled Release, 2004
Diblock copolymers of poly(q-caprolactone) (PCL) and monomethoxy poly(ethylene glycol) (MPEG) with various compositions were synthesized. The amphiphilic block copolymers self-assembled into nanoscopic micelles and their hydrophobic cores encapsulated doxorubicin (DOX) in aqueous solutions. The micelle diameter increased from 22.9 to 104.9 nm with the increasing PCL block length (2.5-24.7 kDa) in the copolymer composition. Hemolytic studies showed that free DOX caused 11% hemolysis at 200 Ag ml À 1 , while no hemolysis was detected with DOX-loaded micelles at the same drug concentration. An in vitro study at 37 jC demonstrated that DOX-release from micelles at pH 5.0 was much faster than that at pH 7.4. Confocal laser scanning microscopy (CLSM) demonstrated that DOX-loaded micelles accumulated mostly in cytoplasm instead of cell nuclei, in contrast to free DOX. Consistent with the in vitro release and CLSM results, a cytotoxicity study demonstrated that DOX-loaded micelles exhibited time-delayed cytotoxicity in human MCF-7 breast cancer cells.
International Journal of Applied Pharmaceutics, 2019
Objective: The purpose of the present study was a characterization of chitosan (CS)-polypyrrole (PPY) nanocomposites for controlled release of anticancer drug doxorubicin (DOX). Methods: Chitosan crosslink with PPY with montmorillonite (MMT) called as (CS-PPY/MMT) were formulated using the solvent casting method. The prepared nanocomposites were characterized by X-Ray Diffraction Analysis (XRD), tensile strength, scanning electronic microscope (SEM). Results: The XRD result confirmed that the CS-PPY/MMT possessed crystal structure. The nanocomposites CS-PPY/MMT-4 were showed a homogenous morphology. The Water uptake and swelling ratio of the CS-PPY and CS-PPY/MMT were found to decrease with increase in the concentration of clay. Mechanical properties of the CS-PPY and CS-PPY/MMT were assessed in terms of tensile strength and extensibility using texture analyzer. Increase in tensile strength and reduction in extensibility was reported with an increase in the nanoclay content. In vitr...
Journal of Controlled Release, 2000
Doxorubicin (DOX) was physically loaded into micelles prepared from poly(ethylene glycol)-poly(b-benzyl-L-aspartate) block copolymer (PEG-PBLA) by an o / w emulsion method with a substantial drug loading level (15 to 20 w / w%). DOX-loaded micelles were narrowly distributed in size with diameters of approximately 50-70 nm. Dimer derivatives of DOX as well as DOX itself were revealed to be entrapped in the micelle, the former seems to improve micelle stability due to its low water solubility and possible interaction with benzyl residues of PBLA segments through p-p stacking. Release of DOX compounds from the micelles proceeded in two stages: an initial rapid release was followed by a stage of slow and long-lasting release of DOX. Acceleration of DOX release can be obtained by lowering the surrounding pH from 7.4 to 5.0, suggesting a pH-sensitive release of DOX from the micelles. A remarkable improvement in blood circulation of DOX was achieved by use of PEG-PBLA micelle as a carrier presumably due to the reduced reticuloendothelial system uptake of the micelles through a steric stabilization mechanism. Finally, DOX loaded in the micelle showed a considerably higher antitumor activity compared to free DOX against mouse C26 tumor by i.v. injection, indicating a promising feature for PEG-PBLA micelle as a long-circulating carrier system useful in modulated drug delivery.
Journal of Materials Chemistry, 2012
Two kinds of reduction and pH responsive disulfide-cross-linked poly(ethylene glycol)-polypeptide copolymers were prepared through one-step ring-opening polymerization of g-benzyl-L-glutamate N-carboxyanhydride (BLG NCA) or 3-benzyloxycarbonyl-L-lysine N-carboxyanhydride (ZLL NCA) and L-cystine N-carboxyanhydride (LC NCA) with amino group terminated monomethoxy poly(ethylene glycol) (mPEG-NH 2 ) as macroinitiator. Then, the copolymers were deprotected and dispersed in phosphate buffered saline, yielding PEG-polypeptide nanogels. Doxorubicin (DOX), a model anticancer drug, was effectively loaded into nanogels via electrostatic and hydrophobic interactions. The DOX release from all DOX-loaded nanogels was accelerated in intracellular reductive and acidic conditions, which controlled by Fickian diffusion and nanogels swelling. The enhanced intracellular DOX release was observed in glutathione monoester (GSH-OEt) pretreated HeLa cells. DOX-loaded nanogels showed higher cellular proliferation inhibition towards GSH-OEt pretreated HeLa and HepG2 cells than to unpretreated or buthionine sulfoximine (BSO) pretreated cells. Hemolysis tests indicated that nanogels were hemocompatible, and the presence of nanogels could reduce the hemolysis ratio (HR) of DOX significantly. These features suggest that the nanogels can efficiently load and deliver DOX into tumor cells and enhance the inhibition of cellular proliferation in vitro, providing a favorable platform to construct an efficient drug delivery system for cancer therapy.
Biomaterials, 2010
The purpose of this study was to develop polymeric nano-carriers of doxorubicin (DOX) that can increase the therapeutic efficacy of DOX for sensitive and resistant cancers. Towards this goal, two polymeric DOX nano-conjugates were developed, for which the design was based on the use of multi-functionalized poly(ethylene oxide)-block-poly(3-caprolactone) (PEO-b-PCL) micelles decorated with avb3 integrintargeting ligand (i.e. RGD4C) on the micellar surface. In the first formulation, DOX was conjugated to the degradable PEO-b-PCL core using the pH-sensitive hydrazone bonds, namely RGD4C-PEO-b-P(CL-Hyd-DOX). In the second formulation, DOX was conjugated to the core using the more stable amide bonds, namely RGD4C-PEO-b-P(CL-Ami-DOX). The pH-triggered drug release, cellular uptake, intracellular distribution, and cytotoxicity against MDA-435/LCC6 WT (a DOX-sensitive cancer cell line) and MDA-435/ LCC6 MDR (a DOX-resistant clone expressing a high level of P-glycoprotein) were evaluated. Following earlier in vitro results, SCID mice bearing MDA-435/LCC6 WT and MDA-435/LCC6 MDR tumors were treated with RGD4C-PEO-b-P(CL-Hyd-DOX) and RGD4C-PEO-b-P(CL-Ami-DOX), respectively. In both formulations, surface decoration with RGD4C significantly increased the cellular uptake of DOX in MDA-435/ LCC6 WT and MDA-435/LCC6 MDR cells. In MDA-435/LCC6 WT , the best cytotoxic response was achieved using RGD4C-PEO-b-P(CL-Hyd-DOX), that correlated with the highest cellular uptake and preferential nuclear accumulation of DOX. In MDA-435/LCC6 MDR , RGD4C-PEO-b-P(CL-Ami-DOX) was the most cytotoxic, and this effect correlated with the accumulation of DOX in the mitochondria. Studies using a xenograft mouse model yielded results parallel to those of the in vitro studies. Our study showed that RGD4C-decorated PEO-b-P(CL-Hyd-DOX) and PEO-b-P(CL-Ami-DOX) can effectively improve the therapeutic efficacy of DOX in human MDA-435/LCC6 sensitive and resistant cancer, respectively, pointing to the potential of these polymeric micelles as the custom-designed drug carriers for clinical cancer therapy.
Biomacromolecules, 2011
This study aimed to optimize poly(ethylene glycol)-b-poly(εcaprolactone) (PEG-b-PCL)-based amphiphilic block copolymers for achieving a better micellar drug delivery system (DDS) with improved solubilization and delivery of doxorubicin (DOX). First, the FloryÀHuggins interaction parameters between DOX and the core-forming segments [i.e., poly(εcaprolactone) (PCL) and poly[(ε-caprolactone-co-γ-(carbamic acid benzyl ester)-ε-caprolactone] (P(CL-co-CABCL))] was calculated to assess the drugÀpolymer compatibility. The results indicated a better compatibility between DOX and P(CL-co-CABCL) than that between DOX and PCL, motivating the synthesis of monomethoxy-poly(ethylene glycol)-b-poly[(εcaprolactone-co-γ-(carbamic acid benzyl ester)-ε-caprolactone] (mPEG-b-P-(CL-co-CABCL)) block copolymer. Second, two novel block copolymers of mPEG-b-P(CL-co-CABCL) with different compositions were prepared via ring-opening polymerization of CL and CABCL using mPEG as a macroinitiator and characterized by 1 H NMR, FT-IR, GPC, WAXD, and DSC techniques. It was found that the introduction of CABCL decreased the crystallinity of mPEG-b-PCL copolymer. Micellar formation of the copolymers in aqueous solution was investigated with fluorescence spectroscopy, DLS and TEM. mPEGb-P(CL-co-CABCL) copolymers had a lower critical micelle concentration (CMC) than mPEG-b-PCL and subsequently led to an improved stability of prepared micelles. Furthermore, both higher loading capacity and slower in vitro release of DOX were observed for micelles of copolymers with increased content of CABCL, attributed to both improved drugÀcore compatibility and favorable amorphous core structure. Meanwhile, DOX-loaded micelles facilitated better uptake of DOX by HepG2 cells and were mainly retained in the cytosol, whereas free DOX accumulated more in the nuclei. However, possibly because of the slower intracellular release of DOX, DOX-loaded micelles were less potent in inhibiting cell proliferation than free DOX in vitro. Taken together, the introduction of CABCL in the core-forming block of mPEG-b-PCL resulted in micelles with superior properties, which hold great promise for drug delivery applications.
Chemistry & Chemical Technology
Novel comb-like polymeric and oligomeric drug carriers combining backbone-copolymers of 5-tertbutylperoxy-5-methyl-1-hexene-3-yne (VEP) and glycidyl methacrylate (GMA)-and side PEG chains of various lengths were synthesized. Nanosized delivery systems containing conjugates of water soluble anticancer drug Doxorubicin were developed. The structures of copolymers and their conjugates with drugs were confirmed by IR-spectroscopy. Structural and colloidalchemical properties of water drug delivery systems were studied using photoluminescent (PL), UV-spectroscopy techniques, surface tension measurements and dynamic light scattering. The scheme of the immobilization of water soluble doxorubicin on developed PEGylated polymeric carriers was assumed.
Journal of Materials Chemistry, 2012
A series of multiblock poly(ether carbonate urethane)s comprising poly(trimethylene carbonate), poly(ethylene glycol), and poly(propylene glycol) segments, with a molecular weight of 60 000 g mol À1 , were synthesized. Thermogelling behaviors of the aqueous copolymer solutions were observed at gelation concentrations as low as 2 wt%. Rheological characterizations on the thermogel were carried out as a function of temperature and strain. The gels showed good recovery characteristics after being subjected to high strain. A sustained and complete doxorubicin release over 50 days can be achieved with this system. The rate of release can be tuned by changing the gel concentration or by using a copolymer with a different composition. The doxorubicin-loaded gels were effective in controlling the growth of HeLa cells when compared with doxorubicin dissolved in solution. The results demonstrated that the copolymers could be potentially used in chemotherapeutic applications.