pH响应型mPEG-PCL嵌段共聚物胶束用作药物运输

该文合成了一种具有pH敏感性,较低毒性的两亲性嵌段共聚物以用于药物运输。聚乙二醇-聚己内酯(mPEG-PCL)是以聚乙二醇单甲醚为引发剂,开环己内酯聚合而成,阿霉素则是通过顺乌头酸裂解键连在聚己内酯的末端。该嵌段聚合物通过核磁共振、红外光谱等进行表征。共轭阿霉素后的嵌段聚合物在水溶液中能够自组装形成胶束,胶束粒径约为45.4 nm,透射电镜显示胶束具有近似的球形结构。阿霉素在pH=4.0下的释放速率明显快于pH=7.4下的释放速率。mPEG-PCL在细胞培养中无细胞毒性,包载阿霉素的胶束在人类MCF-7乳腺癌细胞上表现出迟缓的细胞毒性。通过共聚焦显微镜观察游离阿霉素和mPEG-PCL-DOX胶束在MCF-7细胞内的定位说明载体能够携带阿霉素进入细胞。     

pH-responsive micelles based on (PCL)2(PDEA-b-PPEGMA)2 miktoarm polymer: controlled synthesis,characterization, and application as anticancer drug carrier

Amphiphilic A₂(BC)₂ miktoarm star polymers [poly(ϵ-caprolactone)]₂-[poly(2-(diethylamino)ethyl methacrylate)-b- poly(poly(ethylene glycol) methyl ether methacrylate)]₂ [(PCL)₂(PDEA-b-PPEGMA)₂] were developed by a combination of ring opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). The critical micelle concentration (CMC) values were extremely low (0.0024 to 0.0043 mg/mL), depending on the architecture of the polymers. The self-assembled empty and doxorubicin (DOX)-loaded micelles were spherical in morphologies, and the average sizes were about 63 and 110 nm. The release of DOX at pH 5.0 was much faster than that at pH 6.5 and pH 7.4. Moreover, DOX-loaded micelles could effectively inhibit the growth of cancer cells HepG2 with IC₅₀ of 2.0 μg/mL. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles. Therefore, the pH-sensitive (PCL)₂(PDEA-b-PPEGMA)₂ micelles could be a prospective candidate as anticancer drug carrier for hydrophobic drugs with sustained release behavior.     

Synthesis of glycopoly(pseudo amino acid)s and their interaction with lectins

In this study, we developed a novel bioeliminable amphiphilic glycopoly(pseudo amino acid), which was synthesized by the condensation polymerization of N-benzyloxycarbonyl-4-hydroxyl-l-proline (NZHpr) followed by the coupling of an alkynyl-functional sugar derivative to the azido-end group, P(NZHpr)_n. The glycosylated P(NZHpr)_n polymers formed micelles in the aqueous phase. Selective lectin binding experiments confirmed that the glycosylated P(NZHpr)_n can be used in biorecognition applications. The DOX-loaded micelles facilitated improved uptake of DOX by HeLa cells within 2 h and were primarily retained in the cytoplasm, whereas free DOX tended to accumulate in the nuclei. The DOX-loaded glucosylated P(NZHpr)_n micelles exhibited a substantially lower cytotoxicity compared to free DOX.     

Mesoporous silica nanoparticles loading doxorubicin reverse multidrug resistance: performance and mechanism

Multidrug resistance (MDR) is one of the major obstacles for successful chemotherapy in cancer. One of the effective approaches to overcome MDR is to use nanoparticle-mediated drug delivery to increase drug accumulation in drug resistant cancer cells. In this work, we first report that the performance and mechanism of an inorganic engineered delivery system based on mesoporous silica nanoparticles (MSNs) loading doxorubicin (DMNs) to overcome the MDR of MCF-7/ADR (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The experimental results showed that DMNs could enhance the cellular uptake of doxorubicin (DOX) and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells. The IC(50) of DMNs against MCF-7/ADR cells was 8-fold lower than that of free DOX. However, an improved effect of DOX in DMNs against MCF-7 cells (a DOX-sensitive cancer cell line) was not found. The increased cellular uptake and nuclear accumulation of DOX delivered by DMNs in MCF-7/ADR cells was confirmed by confocal laser scanning microscopy, and could result from the down-regulation of P-gp and bypassing the efflux action by MSNs themselves. The cellular uptake mechanism of DMNs indicated that the macropinocytosis was one of the pathways for the uptake of DMNs by MCF-7/ADR cells. The in vivo biodistribution showed that DMNs induced a higher accumulation of DOX in drug resistant tumors than free DOX. These results suggested that MSNs could be an effective delivery system to overcome multidrug resistance.     

Enhanced loading of doxorubicin into polymeric micelles by a combination of ionic bonding and hydrophobic effect,and the pH-sensitive and ligand-mediated delivery of loaded drug

Folate-conjugated micelles were fabricated from amphiphilic diblock copolymers with poly(ethylene glycol) as the hydrophilic block and a random copolymer of n-butyl methacrylate and methacrylic acid as the hydrophobic block. Doxorubicin (DOX), a model drug that contains an amine group and hydrophobic moiety, was loaded with a high loading capacity into micelles by a combination of ionic bonding and hydrophobic effect. The combined interactions imparted a pH-sensitive delivery property to the system. The release rate of loaded DOX was slow at pH 7.4 (i.e., mimicking the plasma environment) but increased significantly at acidic pH (i.e., mimicking endosome/lysosome conditions). Acid-triggered drug release resulted from the carboxylate protonation of poly(methacrylic acid), which dissociated the ionic bonding between the micelles and DOX. Cellular uptake by folate receptor-overexpressing HeLa cells of the DOX-loaded folate-conjugated micelles was higher than that of micelles without folate conjugation. Thus, the DOX-loaded folate-conjugated micelles displayed higher cytotoxicity to HeLa cells.     

Thermoresponsive core-shell-corona micelles of poly(ethyleneglycol)-b-poly(N-isopropylacrylamide)-b-polystyrene

Core-shell-corona micelles with a thermoresponsive shell self-assembled by triblock copolymer of poly(ethyleneglycol)-b-poly(N-isopropylacrylamide)-b-polystyrene (PEG₄₅-b-PNIPAM₁₆₈-b-PS₄₆) are studied by ¹H NMR, light scattering and atomic force microscopy. The thermoresponsive triblock copolymer, which has a relatively short hydrophobic PS block, can disperse in water at room temperature to form core-shell-corona micelles with the hydrophobic PS block as core, the thermoresponsive PNIPAM block as shell and the hydrophilic PEG block as corona. At temperature above lower critical solution temperature (LCST) of the PNIPAM block, the PNIPAM chains gradually collapse on the PS core to shrink the size and change the structure of the resultant core-shell-corona micelles with temperature increasing. It is found that there possibly exists an interface between the PNIPAM shell and PEG corona of the core-shell-corona micelles at temperature above LCST of the PNIPAM block.     

透明质酸自组装聚合物胶束的制备及表征

为了增强抗肿瘤药物的靶向性与抗肿瘤活性,本文制备了透明质酸-十八烷聚合物,用其对阿霉素进行包载,考察其理化性质及体外细胞毒性。合成两亲性透明质酸-十八烷聚合物,利用核磁对其结构进行确证。选择超声法制备载阿霉素的聚合物胶束,考察胶束的粒径、电位、包封率、载药量以及体外释放行为。选择乳腺癌细胞MCF-7为肿瘤细胞模型,考察载药胶束的体外抗肿瘤活性。成功合成了透明质酸-十八烷聚合物。制备的空白胶束和载药的胶束的粒径分别为（180.7±1.25）nm和（178.3±2.24）nm,Zeta电位分别为（-21.3±0.25）mV和（-18.1±0.31）mV。载阿霉素聚合物胶束的包封率为（96.1%±0.72%）,载药量为16.1%±1.18%,体外释放行为表明在72h的累计药物释放率仅为40%左右,具有明显的缓释行为。体外细胞毒性结果表明,空白聚合物胶束对肿瘤细胞几乎没有毒性,而载阿霉素的聚合物胶束具有较好的抗肿瘤活性。结论：透明质酸-十八烷聚合物胶束可以有效地包载抗肿瘤药物阿霉素,具有良好的缓释特性和抗肿瘤活性。     

Degradable micelles based on hydrolytically degradable amphiphilic graft copolymers for doxorubicin delivery

Micelles based on a low-toxic and hydrolytically degradable poly(β-amino ester)-g-octadecyl acrylate (PAE-g-ODA) amphiphilic copolymer were developed for doxorubicin (DOX) delivery. A two-step reaction pathway was used to synthesize PAE-g-ODA copolymers with poly(ethylene glycol) segments in the backbone via Michael-type addition reaction. Copolymers with various grafting degrees were obtained by tuning the feeding molar ratios of acrylate/formed secondary amine and the grafting reaction time. Among this series of copolymers, PAE-g-ODA-2 (PAE-g-ODA with 45% ODA side chains) were found to form spherical micelles with an average size of 72.5 nm, as determined by dynamic light scattering (DLS) and transmission electron microscope (TEM), whereas the other PAE-g-ODA copolymers fail to form stable micelles with a narrow size distribution in an aqueous solution. The titration curve illustrated that PAE-g-ODA-2 has a high buffer capacity in the pH range of 7.5-5. The hydrolytic degradation of PAE-g-ODA-2 copolymer in PBS buffer (pH 7.4, 37 °C) was monitored by ¹H NMR. It was found that up to 70% ester groups in the backbones were hydrolyzed in 48 h. The DOX-loaded micelles release about 70% trapped DOX within 48 h in physiological condition. Cytotoxicity assay showed a low cytotoxicity of PAE-g-ODA-2 micelles as well as a higher inhibition against HepG2 tumor cells of DOX-loaded micelles than free DOX.     

Multifunctional and thermoresponsive unimolecular micelles for tumor-targeted delivery and site-specifically release of anticancer drugs

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(?-caprolactone)-b-poly(N-isopropylacrylamide-co-acrylamide)-fluorescein methyl ester/b′-methoxy poly(ethylene glycol)/poly(ethylene glycol)-folate (i.e., H40-PCL-b-P(NIPAAm-co-AAm)-FL/b′-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.     

Synthesis of thermoresponsive polymeric micelles of PNIPAAm‐b‐OMMA as a drug carrier for loading and controlled release of prednisolone

We synthesized a drug delivery system of poly(N‐isopropylacrylamide)‐b‐oligo(methyl methacrylate) (PNIPAAm‐b‐OMMA) via polycondensation of two homopolymers in 1,4‐dioxane. The products are characterized by FT‐IR and ¹H‐NMR spectra and TEM. The PNIPAAm‐b‐OMMA copolymer micelles in aqueous solution present the same lower critical solution temperature (LCST) as the unmodified PNIPAAm, owing to the formation of a core–shell micellar structure that the hydrophilic shell shields the hydrophobic inner OMMA core from interacting with water. The micelle carriers exhibit two heterogeneous microdomains: a hydrophobic inner core capable of highly solubilizing hydrophobic prednisolone molecules, plus a hydrated outer shell that stabilizes this micellar structure below its LCST. Moreover, the micelle carriers show reversible thermoresponsive aggregation/dispersion in response to temperature cycles through the LCST. By using the antiinflammation drug prednisolone as model drug, it is found that the PNIPAAm‐b‐OMMA drug carrier could prolong the release time and control the release amount by changing the temperature. Accordingly, this copolymer micelle may provide as an effective drug carrier for drug control and release. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Bioinspired photo-degradable amphiphilic hyperbranched poly(amino ester)s: Facile synthesis and intracellular drug delivery

A novel amphiphilic photo-degradable hyperbranched polymer was reported at the first time. The hyperbranched o-nitrobenzyl containing poly(amino ester)s (HPAE) were prepared by one-pot Michael addition polymerization. The photo-induced degradation of hyperbranched poly(amino ester)s was confirmed by gel permeation chromatography (GPC) and UV-vis spectra. Bioinspired phosphorylcholine grafted HPAE (HPAE-PC) was synthesized via thiol-ene click chemistry. HPAE-PC can self-assemble to micelles and the micelles could be disassembled under UV irradiation because of the photo-degradation of HPAE. HPAE-PC micelles were used to load anticancer drug Doxorubicin (DOX). In vitro drug release studies showed that the release of DOX was much faster in the presence of UV irradiation than that without UV irradiation. The fluorescence microscope results indicated that DOX-loaded micelles exhibited faster drug release in A549 cells after UV irradiation. Moreover, the DOX-loaded HPAE-PC micelles under UV irradiation exhibited better anticancer activity against A549 cells than that of the nonirradiated ones. The novel amphiphilic photo-degradable hyperbranched polymers can be used to construct spatiotemporal on-demand drug delivery system for cancer therapy.     

TPE‐conjugated biomimetic and biodegradable polymeric micelle for AIE active cell imaging and cancer therapy

Smart nanocarrier for simultaneous drug delivery and cellular imaging is ideal for both cancer therapy and diagnosis. In this work, polymeric micelles based on the tetraphenylethene (TPE) conjugated poly(N6‐carbobenzyloxy‐l ‐lysine)‐block‐poly(2‐methacryloyloxyethyl phosphorylcholine) (TPE‐PLys‐b‐PMPC) copolymer are successfully prepared. Such biomimetic and biodegradable TPE‐PLys‐b‐PMPC micelles exhibit remarkable aggregation‐induced emission (AIE) feature and great biocompatibility, showing great potential for bioimaging application. In addition, anticancer drug doxorubicin (DOX) can be incorporated into the core of micelles and the intracellular release of DOX can be furthermore traced through the fluorescent imaging of these AIE micelles. As expected, this DOX‐loading polymeric micelle shows significant growth inhibition against HeLa cells and 4T1 cells and such TPE‐PLys‐b‐PMPC micelles would be a promising drug carrier for potential cancer therapy and bioimaging. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 45651.     

A thermo/pH/magnetic-responsive nanogel based on sodium alginate by modifying magnetic graphene oxide: Preparation,characterization, and drug delivery

A novel thermo/pH/magnetic-triple-responsive nanogel was synthesized by grafting N-isopropylacrylamide and acrylic acid onto sodium alginate to modify magnetic graphene oxide as a drug delivery system. The synthesized nanogel was characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), vibrating sample magnetometer (VSM), atomic force micrographs (AFM), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). The obtained nanogel displayed excellent reversible transmittance changes in response to pH, temperature, and magnetic field. The performance of the nanogels to load doxorubicin (DOX) drug and to sustain doxorubicin release was tested upon exposure to pH, temperature, and magnetic field variations. The mechanism of drug release was proposed in this paper by different kinetic models. In addition, the effects of nanogels and DOX-loaded nanogels on MCF-7 cells were examined and results were compared with free DOX drug. The in vitro results demonstrated that this triple-responsive nanogel can be an appropriate candidate for applications in cancer therapy.     

Thermosensitive biotinylated hydroxypropyl cellulose-based polymer micelles as a nano-carrier for cancer-targeted drug delivery

In this article, we report the synthesis of a novel amphiphilic hydroxypropyl cellulose-based polymer (HPC-PEG-Chol) that contained poly (ethylene glycol) and cholesterol-containing moieties with specific degrees of substitution. The resulting polymer was subsequently converted to a biotin conjugate (HPC-PEG-Chol-biotin), to develop a new potential cancer-targeted drug delivery system. The biotin conjugate was used to prepare micelles via the dialysis method. The polymeric micelles in aqueous solution presented a lower critical solution temperature (LCST) of 39.8 ^oC. The critical micelle concentration (CMC) values of the polymeric micelles at 25 and 45 °C were evaluated to be about 0.32 and 0. 25 g/L, respectively. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses of the micelles revealed the spherical shapes of the micelles, with 84 nm mean diameters that increased with the increase of the temperature above LCST. The hydrophobic anticancer drug paclitaxel (PTX) was loaded in the micelles and the in vitro release behaviors of PTX were investigated at different temperatures. The release profile of PTX from the polymeric micelles revealed a thermosensitivity, since its release rate was higher at 41 °C than at 37 °C. Fluorescent microscopy analyses confirm that the PTX-loaded HPC-PEG-Chol-biotin is superior in cellular uptake, with very strong adsorption to both HeLa and MDA-MB-231 cancer cell lines. MTT assay in normal cells indicated that HPC-PEG-Chol-biotin micelles have great potential to be safely used in tumor-targeting chemotherapy.     

Synthesis and physicochemical characterization of amphiphilic block copolymers bearing acid-sensitive orthoester linkage as the drug carrier

Amphiphilic block copolymers bearing an acid-sensitive orthoester linkage, composed of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic poly(γ-benzyl L-glutamate) (PBLG), were prepared as the carrier capable of selectively releasing the hydrophobic drug at the mildly acidic condition. Diblock copolymers with various lengths of PBLG were synthesized via ring opening polymerization of benzyl glutamate NCA in the presence of the acid-labile PEG as a macroinitiator. Owing to their amphiphilicities, the copolymers formed spherical micelles in aqueous conditions, and their particle sizes (22-106 nm in diameter) were dependent on the block length of PBLG. These nanoparticles were stable in the physiological buffer (pH 7.4), whereas they were readily decomposed under the acidic condition. In particular, the block copolymer with a smaller hydrophobic portion was rapidly disassembled under the acidic condition. Doxorubicin (DOX), chosen as the model anti-cancer drug, was effectively encapsulated into the hydrophobic core of the micelles using the solvent casting method. The loading efficiency depended on the hydrophobic block length of the copolymer; i.e., the longer hydrophobic block allowed for loading of larger amounts of the drug. In vitro release studies demonstrated that DOX was slowly released from the pH-sensitive micelles in the physiological buffer (pH 7.4), whereas the release rate of DOX significantly increased under the acidic condition (pH 5.0). From the in vitro cytotoxicity test, it was found that DOX-loaded pH-sensitive micelles showed higher toxicity to SCC7 cancer cells than DOX-loaded micelles without the orthoester linker. These results suggest that the amphiphilic block copolymer bearing the orthoester linkage is useful for pH-triggered delivery of the hydrophobic drug.     

Self-Assembled Polymeric Micelles Based on Hyaluronic Acid-g-Poly(d,l-lactide-co-glycolide) Copolymer for Tumor Targeting

Graft copolymer composed hyaluronic acid (HA) and poly(d,l-lactide-co-glycolide) (PLGA) (HAgLG) was synthesized for antitumor targeting via CD44 receptor of tumor cells. The carboxylic end of PLGA was conjugated with hexamethylenediamine (HMDA) to have amine end group in the end of chain (PLGA-amine). PLGA-amine was coupled with carboxylic acid of HA. Self-assembled polymeric micelles of HAgLG have spherical morphologies and their sizes were around 50–200 nm. Doxorubicin (DOX)-incorporated polymeric micelles were prepared by dialysis procedure. DOX was released over 4 days and its release rate was accelerated by the tumoric enzyme hyaluronidase. To assess targetability of polymeric micelles, CD44-positive HepG2 cells were employed treated with fluorescein isothiocyanate (FITC)-labeled polymeric micelles. HepG2 cells strongly expressed green fluorescence at the cell membrane and cytosol. However, internalization of polymeric micelles were significantly decreased when free HA was pretreated to block the CD44 receptor. Furthermore, the CD44-specific anticancer activity of HAgLG polymeric micelles was confirmed using CD44-negative CT26 cells and CD44-positive HepG2 cells. These results indicated that polymeric micelles of HaLG polymeric micelles have targetability against CD44 receptor of tumor cells. We suggest HAgLG polymeric micelles as a promising candidate for specific drug targeting.     

Embedded of Nanogel into Multi-responsive Hydrogel Nanocomposite for Anticancer Drug Delivery

Hydrogels, nanogels, and nanocomposites show increasing potential for application in drug delivery systems due to their good chemical and physical properties. Therefore, we were encouraged to combine them to produce a new compound with unique properties for drug release systems. To this aim, we first prepared poly [(N-isopropylacrylamide)-co-(2-dimethylamino ethyl methacrylate) nanogel by copolymerization processes and then added it into the solution of poly (2-dimethylamino ethyl methacrylate)] grafted onto salep. Through dropwise addition of mixed aqueous solution of iron salts into the prepared polymeric solution, a novel hydrogel nanocomposite with excellent pH, thermo, and magnetic responsive was fabricated. The obtained hydrogel nanocomposite were characterized by Fourier transform infrared spectroscopy, thermo gravimetric analysis, X-ray diffraction, scanning electron microscopy, vibrating sample magnetometer, and atomic force micrographs. The dependence of swelling properties of hydrogel nanocomposite on the temperature, pH, and magnetic field were investigated. The release behavior of doxorubicin hydrochloride (DOX) drug from DOX loaded into synthesized hydrogel nanocomposite was investigated at different pHs, temperatures, and magnetic field. In addition, the drug release behavior from obtained hydrogel nanocomposite was monitored via different kinetic models. Lastly, the toxicity of the DOX and DOX-loaded hydrogel nanocomposite were studied on MCF-7 cells at different times. These results suggested that the obtained hydrogel nanocomposite might have high potential applications in drug delivery systems.     

Thermosensitive nanosized micelles from cholesteryl-modified hydroxypropyl cellulose as a novel carrier of hydrophobic drugs

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?C0.29?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.     

A tumor-targeting nano doxorubicin delivery system built from amphiphilic polyrotaxane-based block copolymers

Amphiphilic polyrotaxane (PR)-based block copolymers are synthesized by end-capping polypseudorotaxanes (PPRs) formed from distal 2-bromopropionyl terminated Pluronic F68 and a varying amount of β-cyclodextrins (β-CDs) using hydrophilic polymeric blocks of poly(ethylene glycol) methyl ether methacrylate (PEGMA) yielded via the in situ ATRP. To gain a tumor-targeting nano doxorubicin (DOX) delivery system for cancer chemotherapy, an active tumor-targeting ligand, folic acid (FA), is conjugated to the two ends of the resulting copolymers through “azide-ethylene click chemistry”. The conjugated copolymers enable to self-assemble into unique core–shell structured micelles in aqueous solution and to load DOX into the hydrophobic core. The drug loading content is increased from 2.0 wt% to 25.5 wt% with respect to the blank block copolymer most likely due to the hydrogen bond interaction between DOX and β-CDs threaded. After drug loading, the size of the micelles is enlarged from 120 nm to 220 nm in diameter as determined by dynamic light scattering (DLS) analysis. Moreover, these tumor-targeted polymeric micelles exhibit a slower and sustained DOX release behavior. The cell uptake and distribution, as well as the cytotoxicity of the polymeric micelles are also evaluated toward the MDA-MB-231 cells. The FA-conjugated PR-based block copolymer micelles appear to be internalized by the cancer cells via FA receptor mediated endocytosis; thus, they present enhanced cytotoxicity to the selected breast cancer cells.     

Synthesis and characterization of PEG–PCL–PEG triblock copolymers as carriers of doxorubicin for the treatment of breast cancer

Triblock copolymers of monomethoxy poly(ethylene glycol) (mPEG) and ε‐caprolactone (CL) were prepared with varying lengths of poly(ε‐caprolactone) (PCL) compositions and a fixed length of mPEG segment. The molecular characteristics of triblock copolymers were characterized by ¹H NMR, gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FT‐IR), X‐ray diffraction (XRD), and differential scanning calorimetry (DSC). These amphiphilic linear copolymers based on PCL hydrophobic chain and hydrophilic mPEG ending, which can self‐assemble into nanoscopic micelles with their hydrophobic cores, encapsulated doxorubicin (DOX) in an aqueous solution. The particle size of prepared micelles was around 40–92 nm. The DOX loading content and DOX loading efficiency were from 3.7–7.4% to 26–49%, respectively. DOX‐released profile was pH‐dependent and faster at pH 5.4 than pH 7.4. Additionally, the cytotoxicity of DOX‐loaded micelles was found to be similar with free DOX in drug‐resistant cells (MCF‐7/adr). The great amounts of DOX and fast uptake accumulated into the MCF‐7/adr cells from DOX‐loaded micelles suggest a potential application in cancer chemotherapy. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010