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Meidong Lang - One of the best experts on this subject based on the ideXlab platform.
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fine tuning Micellar core forming block of poly ethylene glycol block poly e caprolactone amphiphilic copolymers based on chemical modification for the solubilization and delivery of doxorubicin
Biomacromolecules, 2011Co-Authors: Mi Che, Zhanzha Liu, Ya Xiao, Ya Zhang, Ya Zhou, Meidong LangAbstract:This study aimed to optimize poly(ethylene glycol)-b-poly(e-caprolactone) (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 Flory–Huggins interaction parameters between DOX and the core-forming segments [i.e., poly(e-caprolactone) (PCL) and poly[(e-caprolactone-co-γ-(carbamic acid benzyl ester)-e-caprolactone] (P(CL-co-CABCL))] was calculated to assess the Drug–polymer 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[(e-caprolactone-co-γ-(carbamic acid benzyl ester)-e-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 1H NMR, FT-IR, GP...
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fine tuning Micellar core forming block of poly ethylene glycol block poly e caprolactone amphiphilic copolymers based on chemical modification for the solubilization and delivery of doxorubicin
Biomacromolecules, 2011Co-Authors: Jinliang Yan, Yan Xiao, Yan Zhang, Min Chen, Zhanzhan Liu, Yan Zhou, Wensong Tan, Meidong LangAbstract:This study aimed to optimize poly(ethylene glycol)-b-poly(e-caprolactone) (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 Flory-Huggins interaction parameters between DOX and the core-forming segments [i.e., poly(e-caprolactone) (PCL) and poly[(e-caprolactone-co-γ-(carbamic acid benzyl ester)-e-caprolactone] (P(CL-co-CABCL))] was calculated to assess the Drug-polymer 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[(e-caprolactone-co-γ-(carbamic acid benzyl ester)-e-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. mPEG-b-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 Drug-core 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.
Natalya Rapoport - One of the best experts on this subject based on the ideXlab platform.
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ultrasound mediated Micellar Drug delivery
International Journal of Hyperthermia, 2012Co-Authors: Natalya RapoportAbstract:During the last decade, nanomedicine has emerged as a new field of medicine that utilises nanoscale materials for delivery of Drugs, genes and imaging agents. The efficiency of Drug delivery may be enhanced by the application of directed energy, which provides for Drug targeting and enhanced intracellular uptake. In this paper, we present a review of recent advances in the ultrasound-mediated Drug delivery with the emphasis on polymeric micelles as tumour-targeted Drug carriers. This new modality of Drug targeting to tumours is based on the Drug encapsulation in polymeric micelles followed by a localised release at the tumour site triggered by focused ultrasound. The rationale behind this approach is that Drug encapsulation in micelles decreases systemic concentration of free Drug and provides for a passive Drug targeting to tumours via the enhanced permeability and retention (EPR) effect, therefore reducing unwanted Drug interactions with healthy tissues. Ultrasound affects Micellar Drug delivery on various levels. Mild hyperthermia induced by ultrasound may enhance micelle extravasation into tumour tissue; mechanical action of ultrasound results in Drug release from micelles and enhances the intracellular uptake of both released and encapsulated Drug. In addition, polymeric micelles sensitise multiDrug resistant (MDR) cells to the action of Drugs.
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ultrasound enhanced tumor targeting of polymeric Micellar Drug carriers
Molecular Pharmaceutics, 2004Co-Authors: Zhonggao Gao, Heidi D Fain, Natalya RapoportAbstract:Cancer chemotherapy is often complicated by toxic side effects of anticancer Drugs. We are developing a new modality of tumor chemotherapy aimed at circumventing side effects of treatment via Drug targeting to tumors. The technique is based on Drug encapsulation in polymeric micelles followed by a controlled Drug release at a target site triggered by ultrasonic irradiation. The encouraging in vitro results of previous years warranted animal experiments for verification of the in vivo feasibility of the proposed technique. We report here on the effect of ultrasound on a biodistribution of a Micellar Drug carrier (fluorescently labeled Pluronic micelles) in ovarian cancer-bearing nu/nu mice. The degree of carrier accumulation in the cells of various organs was characterized by flow cytometry. Polymeric micelles were formed in either pure Pluronic P-105 solutions (unstabilized micelles) or 1:1 (weight) mixtures of Pluronic P-105 with PEG-diacylphospholipid (stabilized micelles). Intraperitoneal (ip) and intravenous (iv) injections were compared. The data showed that a 30 s ultrasonic irradiation by 1 or 3 MHz ultrasound applied locally to the tumor significantly enhanced accumulation of Pluronic in the tumor cells, which was observed for both ip and iv injections and for unstabilized and stabilized micelles. The data indicated targeting of Pluronic micelles to the tumors; the degree of targeting was enhanced by a local tumor sonication.
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mechanism of the ultrasonic activation of Micellar Drug delivery
Journal of Controlled Release, 2001Co-Authors: Alexander Marin, Natalya RapoportAbstract:The mechanism of the ultrasonic enhancement of the uptake of cytotoxic Drugs, doxorubicin (DOX) and ruboxyl (Rb) by HL-60 cells from Pluronic micelles was studied. DOX and Rb sorption from either PBS or Micellar Pluronic solutions is described by Langmuir-type isotherms characteristic of substrates with limited number of sorption centers. The sorption limits for Rb from PBS and Pluronic were considerably higher than those for DOX, presumably due to much higher Rb partitioning into cell membranes. The overall number of Drug sorption centers for both Drugs decreased in the presence of Pluronic implying the effect of Pluronic on the DNA conformation, which was confirmed by the electron paramagnetic resonance (EPR) experiments using Rb as a spin probe. Ultrasound increased Drug uptake by the cells from PBS and Pluronic solutions. The fluorescence microscopy and flow cytometry experiments using fluorescently-labeled Pluronic showed that ultrasound enhanced both the intracellular uptake of Pluronic micelles and Pluronic trafficking into cell nuclei. A scheme is suggested that describes various equilibria controlling Drug/cell interactions and effect of ultrasound on these equilibria. Under the action of ultrasound, the equilibrium between the Micellar-encapsulated and free Drug is shifted in the direction of free Drug due to micelle perturbation; the equilibrium between extracellular and internalized Drug is shifted to the intracellular Drug due to the ultrasound-induced cellular changes that enhance the accessibility of various cellular structures to Drug. An important advantage offered by ultrasound is that the same degree of the intracellular Drug uptake may be achieved at a substantially lower Drug concentration in the incubation medium.
Rana Sanyal - One of the best experts on this subject based on the ideXlab platform.
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Dendron–Polymer Conjugate Based Cross-Linked Micelles: A Robust and Versatile Nanosystem for Targeted Delivery
2019Co-Authors: Filiz Calik, Aysun Degirmenci, Melike Eceoglu, Amitav Sanyal, Rana SanyalAbstract:Among various nanomedicine platforms, biodegradable polymeric micelles offer a viable approach to targeted cancer therapy. Herein, we report fabrication of core-cross-linked micelles using dendron–polymer conjugates as building blocks. Hydrophobic polyester dendrons containing peripheral alkene groups are conjugated to a hydrophilic poly(ethylene glycol) based copolymer bearing activated ester groups for appending an amine-containing peptide based targeting group, namely, cRGDfK. Micellar constructs assembled in aqueous media were cross-linked using a tetra-thiol molecule via the photochemical thiol–ene reaction. Cross-linked and non-cross-linked micelles were compared in terms of their critical Micellar concentration, stability, Drug loading, and Drug release characteristics. It was observed that the cross-linked micelles were stable upon excessive dilution compared to their non-cross-linked counterparts. Importantly, the amount of passive Drug release in neutral pH was considerably lower for the cross-linked Micellar systems. Furthermore, treatment of MDA-MB-231 breast cancer cells with nontargeted and targeted cross-linked micelles demonstrated higher internalization of the targeted construct. In corroboration, in vitro assay revealed that Drug loaded targeted micelles possessed higher cytotoxicity than the nontargeted ones. Facile fabrication of this modular platform which can carry a desired therapeutic agent and be conjugated with appropriate targeting units, along with the attributes necessary to serve as a viable Drug delivery system, offers a platform with potential for addressing various challenges in the field of Micellar Drug delivery
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combretastatin a 4 conjugated antiangiogenic Micellar Drug delivery systems using dendron polymer conjugates
Molecular Pharmaceutics, 2016Co-Authors: Burcu Sumer Bolu, Ece Manavoglu Gecici, Rana SanyalAbstract:Employment of polymeric nanomaterials in cancer therapeutics is actively pursued since they often enable Drug administration with increased efficacy along with reduced toxic side effects. In this study, Drug conjugated Micellar constructs are fabricated using triblock dendron–linear polymer conjugates where a hydrophilic linear polyethylene glycol (PEG) chain is flanked by well-defined hydrophobic biodegradable polyester dendrons bearing an antiangiogenic Drug, combretastatin-A4 (CA4). Variation in dendron generation is utilized to obtain a library of Micellar constructs with varying sizes and Drug loadings. In particular, a family of Drug appended dendron–polymer conjugates based on polyester dendrons of generations ranging from G1 to G3 and 10 kDa linear PEG were obtained using [3 + 2] Huisgen type “click” chemistry. The final constructs benefit from PEG’s hydrophilicity and antibiofouling character, as well as biodegradable nature of the hydrophobic polyester dendrons. The hydrophobic–hydrophilic–hydro...
Mihaela C Stefan - One of the best experts on this subject based on the ideXlab platform.
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thermoresponsive star like γ substituted poly caprolactone s for Micellar Drug delivery
Journal of Materials Chemistry B, 2017Co-Authors: Katherine E Washington, Michael C Biewer, Ruvanthi N Kularatne, Yixin Ren, Matthew J Gillings, Calvin X Geng, Mihaela C StefanAbstract:Temperature responsive Drug carriers are attractive due to their ability to provide controlled release of the encapsulated cargo based on the use of external stimuli. In this work, 4- and 6-arm thermoresponsive star-like block copolymers were synthesized through the ring-opening polymerization of γ-substituted e-caprolactone monomers γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-e-caprolactone (MEEECL) and γ-ethoxy-e-caprolactone (ECL) using pentaerythritol and myo-inositol as multifunctional initiators. These amphiphilic block copolymers were shown to self-assemble into micelles and were characterized in terms of their feasibility as Drug carriers. Both polymers were shown to be thermodynamically stable and demonstrated temperature responsivity in a desirable range for Drug delivery, with lower critical solution temperatures of 39.4 °C and 39.8 °C for the 4- and 6-arm polymers, respectively. It was shown that the 6-arm star polymer had a higher Drug loading capability and better stability in vitro, allowing it to function as a better vehicle for Drug delivery in cytotoxicity experiments. These star polymers show promise as Drug carriers due to their biocompatibility, biodegradability, and temperature controlled release of doxorubicin.
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recent developments in Micellar Drug carriers featuring substituted poly e caprolactone s
Polymer Chemistry, 2015Co-Authors: Elizabeth A Rainbolt, Katherine E Washington, Michael C Biewer, Mihaela C StefanAbstract:In the field of Drug delivery, synthetic polymers have been widely explored due to their range of properties and functions achievable by tuning their structures. Poly(e-caprolactone)s in particular have established themselves as excellent candidates for biomedical applications because of their biocompatibility, biodegradability, and synthetic versatility. In this review, applications of functional poly(e-caprolactone)s in Drug delivery systems are highlighted. Recent studies regarding the encapsulation or direct conjugation of Drugs, bioactive molecules and moieties for targeting are discussed. Also considered are advances in amphiphilic polymers with functional poly(e-caprolactone)s that exhibit stimuli-responsive behavior: pH-, thermo-, photo-, and reduction-sensitive. Ongoing research and development of functional poly(e-caprolactone)s continues to expand their potential for use in Micellar Drug delivery systems.
Yuan Huang - One of the best experts on this subject based on the ideXlab platform.
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tumor targeting by ph sensitive biodegradable cross linked n 2 hydroxypropyl methacrylamide copolymer micelles
Biomaterials, 2014Co-Authors: Zhou Zhou, Yang Yang, Yuan HuangAbstract:Increasing the molecular weight of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers by using Micellar structures could result in more pronounced enhanced permeability and retention effect, thus increase the tumor accumulation of Drug. However, most Micellar formulations are relatively unstable and release their Drug non-specifically. To improve on these disadvantages, we developed a Micellar Drug delivery system based on self-assembly of HPMA copolymers. Amphiphilic conjugates were synthesized by conjugating the hydrophobic Drug doxorubicin and hydrophobic β-sitosterol to the hydrophilic HPMA polymer backbone via pH-sensitive hydrazone linkages. This linkage is quite stable at physiological pH but hydrolyzes easily at acidic pH. After conjugates self-assembly into micelles, HPMA copolymer side chains were cross-linked through the hydrazone linkages to ensure micelle stability in the blood. Using this approach, cross-linked micelles were obtained with molecular weight of 1030 KD and diameter of 10-20 nm. These micelles remained stable with undetectable doxorubicin release at pH 7.4 or mouse plasma, whereas collapsed quickly with 80% of the Drug released at pH 5 which corresponds to the pH of lyso/endosome compartments of tumor cells. Both cross-linked and non-cross-linked micelles displayed similar in vitro anti-tumor activity as linear copolymer conjugates in Hep G2 and A549 cancer cell lines with internalization mechanism by caveolin, clathrin, and giant macropinocytosis. In vivo studies in an H22 mouse xenograft model of hepatocarcinoma showed the tumor accumulation (1633 μCi/L*h) and anti-tumor rate (71.8%) of cross-linked micelles were significantly higher than non-cross-linked ones (698 μCi/L*h, 64.3%). Neither type of micelle showed significant toxicity in heart, lung, liver, spleen or kidney. These results suggest that cross-linked HPMA copolymer micelles with pH-sensitivity and biodegradability show excellent potential as carriers of anti-cancer Drugs.