Novel thermosensitive poly (N-isopropylacrylamide-co-vinylpyrrolidone-co-methacrylic acid) nanosystems for delivery of natural products (original) (raw)
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Molecular design of biodegradable polymeric micelles for temperature-responsive drug release
Journal of Controlled Release, 2006
We designed thermo-responsive and biodegradable polymeric micelles for an ideal drug delivery system whose target sites are where external stimuli selectively release drugs from the polymeric micelles. The thermo-responsive micelles formed from block copolymers that were composed both of a hydrophobic block and a thermo-responsive block. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) showing a lower critical solution temperature (LCST) around 40°C was synthesized for the thermo-responsive block, while biodegradable poly(D,L-lactide), poly(εcaprolactone), or poly(D,L-lactide-co-ε-caprolactone) was used for the hydrophobic block. By changing both the block lengths of the poly(D,Llactide)-containing block copolymers, physical parameters such as micelle diameter and critical micelle concentration were varied. On the other hand, the choice of the hydrophobic block was revealed to be critical in relation to both on the thermo-responsive release of the incorporated anticancer drug, doxorubicin, and the temperature-dependent change of the hydrophobicity of the micelles' inner core. One polymeric micelle composition successfully exhibited rapid and thermo-responsive drug release while possessing a biodegradable character.
Self-assembled thermoresponsive micelles of poly( N-isopropylacrylamide- b-methyl methacrylate
Biomaterials, 2006
To achieve a combination of spatial specificity in a passive manner with a stimuli-response targeting mechanism, a temperatureresponsive polymeric micelle was prepared using block copolymers of poly(N-isopropylacrylamide-b-methyl methacrylate) (PNIPAAmb-PMMA). The critical micelle concentration of amphiphilic block copolymers in aqueous solution was determined by fluorescence spectroscopy using pyrene as a fluorescence probe. Transmission electron microscopy images showed that these nanoparticles were regularly spherical in shape. Micelle size determined by size analysis was around 190 nm. The micelles showed reversible dispersion/ aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST) for PNIPAAm at around 33 1C, observed by optical absorbance measurements and dynamic light scattering (DLS). The anti-inflammation drug prednisone acetate was loaded as the model drug in the polymeric nanoparticles. In vitro release behavior of prednisone acetate was investigated, which showed a dramatic thermoresponsive fast/slow switching behavior according to the temperature-responsive structural changes of a micellar shell structure. The reversible and sensitive thermoresponse of this micelle might provide opportunities to construct a novel drug delivery system in conjunction with localized hyperthermia. r
Journal of Controlled Release, 1999
To achieve a combination of spatial specificity in a passive manner with a stimuli-responsive targeting mechanism, a temperature-responsive polymeric micelle is prepared using block copolymers of (poly(N-isopropylacrylamide-bbutylmethacrylate) (PIPAAm-PBMA)). The micelle inner core formed by self-aggregates of PBMA segments successfully loaded with a drug (adriamycin), and the outer shell of PIPAAm chains played a role of stabilization and initiation of micellar thermo-response. Optimum conditions were investigated for the micelle formation and drug loading into the inner cores in a view of micellar stability and function as drug carriers. Outer shell hydrophilicity that prevents inner core interaction with biocomponents and other micelles can be suddenly switched to hydrophobic at a specific site by local temperature increase beyond the LCST (lower critical solution temperature) (32.58C). These micelles showed reversible structural changes allowing drug release upon heating / cooling thermal fluctuations through the LCST. Polymeric micelles incorporated with adriamycin showed a dramatic thermo-responsive on / off switching behavior for both drug release and in vitro cytotoxicity according to the temperature responsive structural changes of a micellar shell structure. The reversible and sensitive thermo-response of the micelle opens up opportunities to construct a novel drug delivery system in conjunction with localized hyperthermia.
Polymer Science, Series B, 2020
A thermal-responsive Y-shaped amphiphilic block copolymer, namely poly(N-isopropylacrylamide-block-[poly(ε-caprolactone)] 2 (PNIPAAm-b-PCL 2), was synthesized through the combination of atom transfer radical polymerization (ATRP) and ring-opening polymerization (ROP) techniques, and its potential as smart anti-cancer drug delivery system was investigated preliminary. The fabricated polymers were characterized using FTIR and 1 H NMR spectroscopy, and GPC analysis. The self-assembly behavior of the fabricated PNIPAAm-b-PCL 2 copolymer under thermal stimuli was investigated using dynamic light scattering and UV-Vis spectroscopy. The lower critical solution temperature of the synthesized PNIPAAmb-PCL 2 was found to be 39-41°C. The doxorubicin hydrochloride loading and encapsulation capacities of the fabricated PNIPAAm-b-PCL 2 were calculated to be 62 ± 3%, and 75 ± 4%, respectively; the drug release value was up to 46.5% during 40 h at 37°C and up to 88% at 40°C.
Journal of Biomedical Materials Research Part A, 2009
Thermosensitive and biotinylated biotin-poly (N-isopropylacrylamide-coN -hydroxymethylacrylamide)block-poly(methyl methacrylate) (biotin-P(NIPAAm-co-HMAAm)-b-PMMA) block copolymers were designed and synthesized. The conjugation of biotin molecule with the copolymer as well as the capability of easily functionalizing with ligands for pretargeting approach of the biotinylated multifunctional drug carrier was confirmed by a novel method called capillary electrophoresis immunoassay (CEIA) based on enhanced chemiluminescence (CL) detection. The biotin-P(NIPAAm-co-HMAAm)-b-PMMA copolymer was capable of self-assembling into nanometersized micelle. The anticancer drug methotrexate (MTX), used as a model drug, was loaded in the self-assembled micelles and the thermo-triggered release behavior of MTX was investigated.
Polymer, 2012
Considering the fact that tumors have a lower pH value and a higher temperature than a normal tissue, a new type of thermoresponsive and biodegradable micelles, based on the H40-poly(3-caprolactone)-bpoly(N-isopropylacrylamide-co-acrylamide)-fluorescein methyl ester/b 0-methoxy poly(ethylene glycol)/ poly(ethylene glycol)-folate (i.e., H40-PCL-b-P(NIPAAm-co-AAm)-FL/b 0-MPEG/PEG-FA (HPPNAP-FA)) with imaging and targeting moieties on the periphery were developed for the tumor-targeted delivery and temperature-induced site-specifically release of hydrophobic anticancer drugs. The amphiphilic HPPNAP-FA copolymer was able to self-assemble into unimolecular micelles in aqueous solution with an average diameter of 65 nm. The lower critical solution temperature (LCST) of micelles was around 39.5 C. The anticancer drug, paclitaxel (PTX), was encapsulated into the multifunctional micelles. In vitro release studies demonstrated that the drug-loaded delivery system is relatively stable at physiologic conditions but susceptible to mild acidic environments and temperatures above LCST which would trigger the release of encapsulated drugs. Both flow cytometry and fluorescent microscopy showed that the cellular uptake of the PTX-loaded HPPNAP-FA micelles is higher than that of the PTX-loaded HPPNAP because of the folate receptor mediated endocytosis. The efficacy of this thermoresponsive drug delivery system was also evaluated at temperatures above the LCST (40 C); the results demonstrated that the cellular uptake and the cytotoxicity of PTX-loaded micelles increase prominently. These results indicate that these multifunctional and thermoresponsive unimolecular micelles are promising biomaterials to improve the delivery efficiency and cancer specificity of hydrophobic chemotherapeutic drugs.
Thermoresponsive Polymer Micelles as Potential Nanosized Cancerostatics
Biomacromolecules, 2015
An effective chemotherapy for neoplastic diseases requires the use of drugs that can reach the site of action at a therapeutically efficacious concentration and maintain it at a constant level over a sufficient period of time with minimal side effects. Currently, conjugates of highmolecular-weight hydrophilic polymers or biocompatible nanoparticles with stimuli-releasable anti-cancer drugs are considered to be some of the most promising systems capable of fulfilling these criteria. In this work, conjugates of thermo-responsive di-block copolymers with the covalently bound cancerostatic drug pirarubicin (PIR) were synthesized as a reversible micelleforming drug delivery system combining the benefits of the above mentioned carriers. The diblock copolymer carriers were composed of hydrophilic poly[N-(2-Page 1 of 43 ACS Paragon Plus Environment Biomacromolecules 2 hydroxypropyl)methacrylamide]-based block containing a small amount (~ 5 mol. %) of comonomer units with reactive hydrazide groups and a thermo-responsive poly[2-(2methoxyethoxy)ethyl methacrylate] block. PIR was attached to the hydrophilic block of the copolymer through the pH-sensitive hydrazone bond designed to be stable in the blood stream at pH 7.4 but to be degraded in the intratumoral/intracellular environment at pH 5-6. The temperature-induced conformation change of the thermo-responsive block (coil-globule transition), followed by self-assembly of the copolymer into a micellar structure, was controlled by the thermo-responsive block length and PIR content. The cytotoxicity and intracellular transport of the conjugates as well as the release of PIR from the conjugates inside the cells, followed by its accumulation in the cell nuclei, were evaluated in vitro using human colon adenocarcinoma (DLD-1) cell lines. It was demonstrated that the studied conjugates have a great potential to become efficacious in vivo pharmaceuticals.
Polymeric Micelles: Potential Drug Delivery Devices
INDONESIAN JOURNAL OF PHARMACY, 2013
Polymeric micelles (PMs) have been the most popular and promising topic of many researches in the field of drug delivery and targeting for the past two decades. Polymeric micelles are the selfassembled nano-sized colloidal particles which are made up of amphiphilic block copolymers i.e. polymers consisting of hydrophobic block and hydrophilic block. In this highlight, we give an overview of the structure of micelles and polymeric micelles followed by a summary of the methods used for their preparation. We then focus on several kinds of PMs based on intermolecular forces such as polyion complex micelles (PICMs), non-covalently connected micelles (NCCMs) and recently developed smart polymeric assemblies which can respond to the application of external stimuli such as a change in temperature, pH, redox and light to afford novel nanomaterials. The types of polymers used in the preparation of PMs have also been highlighted so as to facilitate its use in drug delivery and targeting. These...
Iranian Polymer Journal, 2012
The thermosensitive micelles based on the two series of cholesteryl-modified hydroxypropyl cellulose (series 1 and 2, respectively) were used as a promising drug carrier. The polymers 1a and 2a with side chain substitution degrees D Chol = 0.7 and 2.1 mol% were selected for micelle preparation, respectively. Polymeric micelles were prepared by the co-solvent evaporation method. The aqueous self-assembly of the polymers was studied using fluorescence analysis and transmission electron microscopy (TEM). The critical micelle concentrations (CMCs) values of the various D Chol of polymers were evaluated in the range of ca. 0.13-0.29 g/L which decreased with the increase of D Chol in both series. Furthermore, the CMC values displayed a downtrend profile, with increasing the temperature. The polymer 1a with less D Chol had lower CMC than that of polymer 2a. By using the naproxen as a hydrophobic model drug, the drug-loaded micelles were prepared. The TEM image of naproxen-loaded micelles of polymer 1a with 40 % drug-loading efficiency and 8 % loading capacity showed that micelles were regularly spherical in shape with a mean diameter of 70 nm. The unmodified HPC exhibited a lower critical solution temperature (LCST) of more than 41°C in water, while polymeric micelles in aqueous solution presented an LCST of 38.7°C. A drug release study was performed by dialysis method in phosphate-buffered solution at 25, 37 and 40°C, respectively. The release kinetics of naproxen from the polymeric micelles revealed a thermosensitivity, since its release rate was higher at 40°C than at 25°C.
Polymeric micelles as drug delivery vehicles
Though much progress has been made in drug delivery systems, the design of a suitable carrier for the delivery of hydrophobic drugs is still a major challenge for researchers. The use of micellar solutions of low molecular weight surfactants has been one of the popular methods for the solubilization of hydrophobic drugs; however, such surfactants suffer from high critical micelle concentration and concomitant low stabilities. In contrast to surfactants of low molecular masses, polymeric micelles are associated with general advantages like higher stability, tailorability, greater cargo capacity, non-toxicity and controlled drug release. Therefore, the current review article is focused on the engineering of the core of polymeric micelles for maximum therapeutic effect. For enhanced drug encapsulation capacity and getting useful insights into the controlled release mechanism we have reviewed the effects of temperature and pH on responsive polymeric micelles. The article also presents important research outcomes about mixed polymeric micelles as better drug carriers in comparison to single polymeric micelles.