Mengtan Cai

Synthesis of an amphiphilic block copolymer containing zwitterionic sulfobetaine as a novel pH-sensitive drug carrier

pH-sensitive drug carriers offer promise for tumor targeted drug delivery. An amphiphilic triblock copolymer, poly(e-caprolactone)-block-poly(diethylaminoethyl methacrylate)-block-poly(sulfobetaine methacrylate) (PCL–PDEA–PSBMA), was synthesized through click reaction of alkyne end-functionalized poly(sulfobetaine methacrylate) (polySBMA–alkyne) onto azide end-functionalized PCL–PDEA (PCL–PDEA–N3) and was used as a pH-sensitive drug carrier in the form of micelles. In particular, the micelles exhibited pH dependency as a result of the protonation of the PDEA block. A hydrophobic drug, curcumin, was chosen as a model drug to investigate the potential application of this triblock copolymer in drug-controlled release. The results indicated that the release rate of curcumin-loaded micelles at pH 5.0 was faster than that at pH 7.4. Furthermore, the results of the pharmacokinetics of the curcumin-loaded micelles in vivo showed that the retention time of the curcumin-loaded micelles in blood could extend and the clearance of curcumin in the micelles was delayed, compared with the curcumin solution. This new pH-sensitive triblock copolymer PCL–PDEA–PSBMA has great potential as a hydrophobic anticancer drug carrier.

pH and redox-responsive mixed micelles for enhanced intracellular drug release

In order to prepare pH and redox sensitive micelles, amphiphilic copolymers of poly (epsilon-caprolactone)-b-poly(2-(diethylamino) ethyl methacrylate) (PCL-PDEA) and disulfide-linked poly(ethyl glycol)-poly(epsilon-caprolactone) (mPEG-SS-PCL) were synthesized. The double-sensitive micelles were prepared simply by solvent-evaporating method with the mixed two copolymers. The pH sensitivity of the mixed micelles was confirmed by the change of micelle diameter/diameter distribution measured by dynamic lighting scattering (DLS) and the redox sensitivity of the mixed micelles was testified by the change of micellar morphous observed by scanning electron microscope (SEM). In vitro drug release showed that drug-loaded mixed micelles (mass ratio 5:5) could achieve above 90% of drug release under low pH and reducing condition within 10h. Moreover, the drug-loaded mixed micelles (mass ratio 5:5) showed the largest cellular toxicity compared with other drug-loaded micelles, while blank mixed micelles exhibited no toxicity. These results meant that the mixed micelles composed by the two amphiphilic copolymers can enhance intracellular drug release. It is concluded that the newly developed mixed micelles can serve as a potential drug delivery system for anticancer drugs.

Effect of architecture on the micellar properties of poly (ɛ-caprolactone) containing sulfobetaines.

Linear and star-shape poly(ɛ-caprolactone)-b-poly(N-(3-sulfopropyl)-N-methacryloxyethyl-N,N-diethylammoniumbetaine) (L/sPCL-b-PDEAS) with 4 and 6 arms were synthesized with the combination of Ring Opening Polymerization (ROP) and Atom Transfer Radical Polymerization (ATRP). These copolymers self-assembled into micelles via solvent evaporation method. The critical micelle concentration (CMC), determined by fluorescence spectroscopy using pyrene as a probe, was lower than 10(-3)mg/mL and decreased with increasing arm numbers. Atom force microscopy (AFM) images showed that the micelles were spherical in shape with narrow size distribution. The hydrophobic drug model carotene was efficiently loaded in the polymeric micelles. The sizes and drug loading content (DLC) of the carotene-loaded micelles increased with increasing drug content in feed. In vitro drug release experiment demonstrated that the release rate of carotene from the micelles was closely related to the arm numbers and drug loading content. Linear copolymer micelles showed the fastest release rate, 4-arm star shape copolymer micelles exhibited the lowest release rate. The micelles with higher drug loading content showed lower release rate. The release kinetics of carotene from micelles fitted the Ritger-Peppas equation.

Synthesis of amphiphilic copolymers containing zwitterionic sulfobetaine as pH and redox responsive drug carriers.

Amphiphilic poly(ɛ-caprolactone)-SS-poly(N,N-diethylaminoethyl methacrylate)-r-poly(N-(3-sulfopropyl)-N-methacrylate-N,N-diethylammonium-betaine) (PCL-SS-PDEASB) was designed and synthesized successfully. pH and redox dually responsive micelles were prepared based on the obtained copolymers, with zwitterionic sulfobetaines as hydrophilic shell, DEA as pH sensitive content and disulfide as redox responsive linkage. The micelle diameters were all less than 200 nm and the micelle diameter distributions were narrow. These micelles could be triggered by pH and redox condition. The drug release from the drug-loaded micelles displayed fastest under simultaneously acidic and reductive conditions. Results of in vitro cell toxicity evaluation showed that introduction of sulfobetaines could greatly decrease the toxicity of poly(ɛ-caprolactone)-SS-poly(N,N-diethylaminoethyl methacrylate) (PCL-SS-PDEA) micelles. DOX-loaded PCL-SS-PDEASB micelles showed higher efficiency to kill HeLa cells than DOX-loaded PCL-PDEASB micelles. Half inhibitory concentration (IC50) of DOX-loaded PCL-SS-PDEASB micelles decreased with the content of sulfobetaines increasing and was even closer to that of DOX·HCl. Thus, the pH and redox dually responsive biodegradable micelles generated by PCL-SS-PDEASB may be potential smart drug carriers for tumor targeted delivery.

Characteristic of core materials in polymeric micelles effect on their micellar properties studied by experimental and dpd simulation methods

Polymeric micelles are one important class of nanoparticles for anticancer drug delivery, but the impact of hydrophobic segments on drug encapsulation and release is unclear, which deters the rationalization of drug encapsulation into polymeric micelles. This paper focused on studying the correlation between the characteristics of hydrophobic segments and encapsulation of structurally different drugs (DOX and β-carotene). Poly(ϵ-caprolactone) (PCL) or poly(l-lactide) (PLLA) were used as hydrophobic segments to synthesize micelle-forming amphiphilic block copolymers with the hydrophilic methoxy-poly(ethylene glycol) (mPEG). Both blank and drug loaded micelles were spherical in shape with sizes lower than 50 nm. PCL-based micelles exhibited higher drug loading capacity than their PLLA-based counterparts. Higher encapsulation efficiency of β-carotene was achieved compared with DOX. In addition, both doxorubicin and β-carotene were released much faster from PCL-based polymeric micelles. Dissipative particle dynamics (DPD) simulation revealed that the two drugs tended to aggregate in the core of the PCL-based micelles but disperse in the core of PLLA based micelles. In vitro cytotoxicity investigation of DOX loaded micelles demonstrated that a faster drug release warranted a more efficient cancer-killing effect. This research could serve as a guideline for the rational design of polymeric micelles for drug delivery.

Uptake enhancement of curcumin encapsulated into phosphatidylcholine-shielding micelles by cancer cells

Internalization of drugs by cancer cells is a crucial factor to impact cancer treatment effect. Curcumin, having inhibitory effect on a variety of cancers, was encapsulated into micelles of six-arm star-shape poly(ε-caprolactone)-b-poly(2-methacryloyloxyethylphosphorylcholine) (6sPCL-PMPC) in order to enhance its concentration in blood and cellular uptake. Micelles and curcumin-loaded micelles were prepared by the solvent-evaporation method. Drug-loading content and drug-loading efficiency could be achieved as high as 18.9 and 98%. MTT results showed that these curcumin-loaded micelles displayed significant cell cytotoxicity, while these blank micelles were noncytotoxic. The curcumin-loaded 6sPCL-PMPC micelles showed higher efficiency to kill HeLa cells than that of curcumin-loaded PCL-PEG micelles. The cellular uptake study indicated that the curcumin encapsulated into 6sPCL-PMPC micelles was ingested more by HeLa cells than the curcumin encapsulated into PCL-PEG micelles. In conclusion, the micelles with phosphatidylcholine (PC) groups as their exterior can greatly enhance the uptake by HeLa cells and the cytotoxicity of curcumin due to excellent internalization by cancer cells.

Preparation and characterization of chitosan composite membranes crosslinked by carboxyl-capped poly(ethylene glycol)

In this study a series of chemically crosslinked chitosan/poly(ethylene glycol) (CS/PEG) composite membranes were prepared with PEG as a crosslinking reagent other than an additional blend. First, carboxyl-capped poly(ethylene glycol) (HOOC-PEG-COOH) was synthesized. Dense CS/PEG composite membranes were then prepared by casting/evaporation of CS and HOOC-PEG-COOH mixture in acetic acid solution. Chitosan was chemically crosslinked due to the amidation between the carboxyl in HOOC-PEG-COOH and the amino in chitosan under heating, as confirmed by FTIR analysis. The hydrophilicity, water-resistance and mechanical properties of pure and crosslinked chitosan membranes were characterized, respectively. The results of water contact angle and water absorption showed that the hydrophilicity of chitosan membranes could be significantly improved, while no significant difference of weight loss between pure chitosan membranes and crosslinked ones was detected, indicating that composite membranes with amidation crosslinking possess excellent water resistanance ability. Moreover, the tensile strength of chitosan membranes could be significantly enhanced with the addition of certain amount of HOOC-PEG-COOH crosslinker, while the elongation at break didn’t degrade at the same time. Additionally, the results of swelling behaviors in water at different pH suggested that the composite membranes were pH sensitive.

Effects of copolymer component on the properties of phosphorylcholine micelles

Zwitterionic polymers have unique features, such as good compatibility, and show promise in the application of drug delivery. In this study, the zwitterionic copolymers, poly(ε-caprolactone)-b-poly(2-methacryloyloxyethyl phosphorylcholine) with disulfide (PCL-ss-PMPC) or poly(ε-caprolactone)-b-poly(2-methacryloyloxyethyl phosphorylcholine) or without disulfide (PCL-PMPC) and with different block lengths in PCL-ss-PMPC, were designed. The designed copolymers were obtained by a combination of ring-opening polymerization and atom transferring radical polymerization. The crystallization properties of these polymers were investigated. The micelles were prepared based on the obtained copolymers with zwitterionic phosphorylcholine as the hydrophilic shell and PCL as the hydrophobic core. The size distributions of the blank micelles and the doxorubicin (DOX)-loaded micelles were uniform, and the micelle diameters were <100 nm. In vitro drug release and intracellular drug release results showed that DOX-loaded PCL-ss-PMPC micelles could release drugs faster responding to the reduction condition and the intracellular microenvironment in contrast to PCL-PMPC micelles. Moreover, in vitro cytotoxicity evaluation revealed that the designed copolymers possessed low cell toxicity, and the inhibiting effect of DOX-loaded phosphorylcholine micelles to tumor cells was related to the components of these copolymers. These results reveal that the reduction-responsive phosphorylcholine micelles with a suitable ratio of hydrophilic/hydrophobic units can serve as promising drug carriers.

The effect of architecture/composition on the pH sensitive micelle properties and in vivo study of curcuminin-loaded micelles containing sulfobetaines

The polymeric architecture greatly influences the properties of polymer drug carriers. In this study, copolymers of poly(e-caprolactone)-b-poly(N,N-diethylaminoethyl methacrylate)-r-poly(N-(3-sulfopropyl)-N-methacryloxyethy-N,N-diethylammoniumbetaine) with linear (L-PCL-PDEASB) and four-armed star-shape (4s-PCL-PDEASB) were designed and prepared to explore the relationship between the architecture/composition and the micelle properties. The structures of these copolymers were characterized by nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR), elemental analysis, gel permeation chromatograph (GPC), differential scanning calorimetry (DSC), and water contact angle (WCA) measurements. The results showed that the copolymer composition/structure affects the thermal properties, hydrophilicity, micelle properties, pH sensitivity and drug releasing performance. In cytotoxicity experiment the micelles of star-shaped copolymer displayed lower cell toxicity than those of the linear copolymer with the same composition. The drug release rate of the curcumin-loaded micelles was related to the sulfobetaine units and was very different for different copolymer micelles. The curcumin-loaded micelles of star-shaped copolymer prolonged the retention time of curcumin in blood circulation in pharmacokinetic experiments and accumulated more in tumor sites than the free curcumin in breast carcinoma bearing mice in drug distribution experiments. The tissue section images illustrated that the curcumin-loaded micelles could reduce curcumin damage to the liver and lungs. Therefore, the pH sensitive micelles of star-shaped copolymer containing sulfobetaines with suitable composition are promising carriers.

Framework effect of amphiphilic polyesters on their molecular movement and protein adsorption-resistance properties.

Surface chemical characteristics of biomedical polymers, which are determined by the migration and rearrangement of polymeric chains, play an important role in the protein adsorption. In this work, the relationship between the architectures of amphiphilic polyesters and their protein adsorption resistance was investigated. Three poly (ɛ-caprolactone)s containing sulfobetaines (PCL-b-PDEAS) segments with linear, four arms and six arms star-shaped architectures were synthesized with the combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The structures of the amphiphiles were confirmed by (1)H NMR and FTIR. Water contact angles (WCA) and X-ray photoelectron spectroscopy (XPS) were used to study the surface properties of the amphiphilic copolymer films. The water contact angles were decreased due to the surface migration of hydrophilic segments. Transmission electron microscopy (TEM) displayed the occurrence of microphase separation phenomena for PCL-b-PDEAS above glass transition temperature (Tg). The results showed that the hydrophilic segments in the copolymers would migrate to the surface of the films, which resulted in the surface more hydrophilic to resist protein adsorption. The adsorption of both fibrinogen (Fg) and bovine serum albumin (BSA) were studied. The results showed that protein adsorption was depended on not only the hydrophilic chain migration but also the shape of proteins.