Preparation of magnetite and tumor dual-targeting hollow polymer microspheres with pH-sensitivity for anticancer drug-carriers

The hollow poly(N,N′-methylenebisacrylamide-co-methacrylic acid) (P(MBAAm-co-MAA)) microspheres were prepared by the selective removal of poly(methacrylic acid) (PMAA) core from the corresponding PMAA/P(MBAAm-co-MAA) core-shell microspheres, which were synthesized via a two-stage distillation precipitation polymerization. The magnetic Fe₃O₄ nanoparticles onto the surface of hollow P(MBAAm-co-MAA) microspheres via partial oxidation of ferrous salt during the chemical deposition in the presence of potassium nitrate as oxidant with the aid of hexamethylene tetramine and the magnetic hollow microspheres were further functionalized with folic acid (FA) via the chemical linkage with amino groups of 3-aminopropyl triethoxysilane (APS)-modified P(MBAAm-co-MAA)@Fe₃O₄ microspheres to afford the magnetite and tumor dual-targeting hollow microspheres. The resultant dual-targeting hollow polymer microspheres with pH-sensitivity were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared-spectrometer (FT-IR), UV-vis absorption spectroscopy, and vibrating sample magnetometer (VSM). Finally, the drug loading capacities of the magnetite and tumor dual-targeting hollow P(MBAAm-co-MAA) microspheres and their releasing dependence on pH values were investigated with doxorubicin hydrochloride (DXR) as an anticancer drug model.     

Synthesis and characterization of poly(styrene-co-fluorescein O-methacrylate)/poly(N-isopropylacrylamide)-Fe3O4 core/shell composite particles

We demonstrate the synthesis and characteristics of multifunctional poly(styrene-co-fluorescein O-methacrylate)/poly(N-isopropylacrylamide)-Fe₃O₄ [P(St/FMA)/PNIPAAm-Fe₃O₄] core/shell composite particles, in which the core consists of fluorescent materials and the shell consists of magnetic and thermo-responsive components. First, core/shell particles consisting of a fluorescent P(St/FMA) core and thermo-responsive PNIPAAm-rich shell were prepared by two-stage shot-growth emulsion polymerization. Next, Fe₃O₄ nanoparticles were immobilized via electrostatic interactions and then covalently linked to the shell via surface coordinated Aphen by a coupling reaction in order to obtain magnetic properties. The morphology of P(St/FMA)/PNIPAAm-Fe₃O₄ composite particles, confirmed by transmission electron microscopy (TEM), reveals that Fe₃O₄ nanoparticles are located in the PNIPAAm shell. The thermo-sensitivity of composite particles to hydrodynamic diameter was confirmed by using dynamic light scattering (DLS). Photoluminescence (PL) spectra indicate that the fluorescence emission intensity of core/shell particles is highly sensitive to the pH of an aqueous medium. The core/shell composite particles exhibited a combination of fluorescent, magnetic, pH and thermo-responsive behavior.     

Development of a new azido-oxazoline monomer for the preparation of amphiphilic graft copolymers by combination of cationic ring-opening polymerization and click chemistry

A new monomer (2-(5-azidopentyl)-2-oxazoline) bearing an azido group was synthesized. The cationic ring-opening copolymerization of this monomer with 2-methyl-2-oxazoline resulted in a well-defined linear polymer backbone with pendant azido groups. Alkynyl-poly(d,l-lactide) was grafted onto the azido groups of poly(oxazoline) via a Huisgen 1,3-dipolar cycloaddition reaction to give a novel amphiphilic graft copolymer [poly(2-methyl-2-oxazoline-co-2-pentyl-2-oxazoline)-g-poly(d,l-lactide)] (P[(MeOx-co-PentOx)-g-LA]). Different graft copolymers were prepared with PLA of different lengths. Preliminary results of the self-association of this copolymer in water indicated the formation of nanoparticles, which suggests this copolymer may have applications as vehicles for drug delivery.     

Paclitaxel-loaded nanoparticles of star-shaped cholic acid-core PLA-TPGS copolymer for breast cancer treatment

A system of novel nanoparticles of star-shaped cholic acid-core polylactide-d-α-tocopheryl polyethylene glycol 1000 succinate (CA-PLA-TPGS) block copolymer was developed for paclitaxel delivery for breast cancer treatment, which demonstrated superior in vitro and in vivo performance in comparison with paclitaxel-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles and linear PLA-TPGS nanoparticles. The paclitaxel- or couramin 6-loaded nanoparticles were fabricated by a modified nanoprecipitation method and then characterized in terms of size, surface charge, surface morphology, drug encapsulation efficiency, and in vitro drug release. The CA-PLA-TPGS nanoparticles were found to be spherical in shape with an average size of around 120 nm. The nanoparticles were found to be stable, showing no change in the particle size and surface charge during 90-day storage of the aqueous solution. The release profiles of the paclitaxel-loaded nanoparticles exhibited typically biphasic release patterns. The results also showed that the CA-PLA-TPGS nanoparticles have higher antitumor efficacy than the PLA-TPGS nanoparticles and PLGA nanoparticles in vitro and in vivo. In conclusion, such nanoparticles of star-shaped cholic acid-core PLA-TPGS block copolymer could be considered as a potentially promising and effective strategy for breast cancer treatment.     

Controlled release of doxorubicin from amphiphilic depsipeptide–PDO–PEG-based copolymer nanosized microspheres

Novel biodegradable amphiphilic ABA triblock copolymers, i.e. poly(3(S)-methyl-morpholine-2,5-dione-co-p-dioxanone)-block-poly(ethylene glycol)-block-poly(3(S)-methyl-morpholine-2,5-dione-co-p-dioxanone) [P(MMD-co-PDO)-b-PEG-b-P(MMD-co-PDO)], were successfully prepared by ring-opening polymerization of 3(S)-methyl-morpholine-2,5-dione (MMD) and p-dioxanone (PDO) in the presence of poly(ethylene glycol) 6000 as an initiator. These triblock copolymers were characterized by ¹H NMR, ¹³C NMR, Fourier transform infrared, gel permeation chromatography and differential scanning calorimetry measurements. P(MMD-co-PDO)-b-PEG-b-P(MMD-co-PDO) could self-assemble into stable nanosized microspheres with critical micellar concentrations of 0.41–0.66 μg/mL. The microspheres showed high hydrolytic degradation. In addition, doxorubicin (DOX) was chosen as a model drug and successfully encapsulated into the microspheres by hydrogen-bond interaction and hydrophobic effect. The transmission electron microscopy and dynamic light scattering measurements revealed that these microspheres were ellipsoidal nanoparticles with diameters ranged from 50 to 100 nm. These copolymer microspheres exhibited high loading capacity (LC), encapsulation efficiency (EE) of DOX and sustained drug release behavior in phosphate buffered solution (PBS). Moreover, the release rate of DOX from those microspheres in pH 4.0 PBS was faster than that in pH 7.4 due to pH sensitivity of the polymer–drug systems and the degradation of the matrix polymers. These amphiphilic depsipeptide multiblock copolymers would be potential promising carriers for anti-tumour drug delivery.     

Flurbiprofen axetil loaded coaxial electrospun poly(vinyl pyrrolidone)–nanopoly(lactic‐co‐glycolic acid) core–shell composite nanofibers: Preparation,characterization, and anti‐adhesion activity

Flurbiprofen axetil (FA)‐loaded coaxial electrospun poly(vinyl pyrrolidone) (PVP)–nanopoly(lactic‐co‐glycolic acid) core–shell composite nanofibers were successfully fabricated by a facile coaxial electrospinning, and an electrospun drug‐loaded system was formed for anti‐adhesion applications. The FA, which is a kind of lipid microsphere nonsteroidal anti‐inflammatory drug, was shown to be successfully adsorbed in the PVP, and the formed poly(lactic‐co‐glycolic acid) (PLGA)/PVP/FA composite nanofibers exhibited a uniform and smooth morphology. The cell viability assay and cell morphology observation revealed that the formed PLGA/PVP/FA composite nanofibers were cytocompatible. Importantly, the loaded FA within the PLGA/PVP coaxial nanofibers showed a sustained‐release profile and anti‐adhesion activity to inhibit the growth of the IEC‐6 and NIH3T3 model cells. With the significantly reduced burst‐release profile, good cytocompatibility, and anti‐adhesion activity, the developed PLGA/PVP/FA composite nanofibers were proposed to be a promising material in the fields of tissue engineering and pharmaceutical science. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41982.     

P(NIPAM-co-AA)@BMMs with mesoporous silica core and controlled copolymer shell and its fractal characteristics for dual pH- and temperature-responsive performance of ibuprofen release

A kind of core–shell hybrid composite (P@BMMs) as a drug carrier was prepared through seed polymerization method, in which, biomodal mesoporous materials (BMMs) as core and copolymer poly(N-isopropylacryl-acrylamide)-co-poly(acrylicacid) [P(NIPAM-co-AA)] with pH- and temperature-responsive characteristics as shell. Its structural features and textural parameters were characterized using various techniques. The kinetic and thermodynamic evaluation demonstrated the existence of hydrogen bond interaction between IBU and P(NIPAM-co-AA)-coated surfaces. Meanwhile, the smart thermo/pH-responsive properties of ibuprofen (IBU) release could be regulated through adjusting coated amount of copolymer. Specially, the responsive properties of P@BMMs were traced by small-angle X-ray scattering technique, suggesting the surface roughness and structural irregularities.     

Synthesis and characteristics of poly(methyl methacrylate-methacrylic acid-3,3-(trimethoxysilyl) propyl methacrylate) hollow latex particles and their application to drug carriers

In this study, the hollow latex particle was synthesized by three processes. The first process was to synthesize the poly(methyl methacrylate-co-methacrylic acid) (poly(MMA-MAA)) copolymer latex particles by the method of soapless emulsion polymerization. Following the first process, the second process was to polymerize MMA, MAA, 3,3-(trimethoxysilyl) propyl methacrylate (MPS), and ethylene glycol dimethacrylate in the presence of poly(MMA-MAA) latex particles to form the linear poly(MMA-MAA)/crosslinking poly(MMA-MAA-MPS) core–shell latex particles. In the third process, the core–shell latex particles were heated in the presence of ammonia to form the poly(MMA-MAA-MPS) hollow latex particles. A sufficient heating time and high-heating temperature were necessary for the ammonia to dissolve the linear poly(MMA-MAA) core to form a perfect hollow structure. The crosslinking poly(MMA-MAA-MPS) shell was a barrier for the ammonia to diffuse into the latex particles so that the latex particle with the high-crosslinking shell showed an imperfect hollow structure. Besides, the hollow poly(MMA-MAA-MPS) latex particles reacted with ZnO nanoparticles, which were synthesized by a traditional sol-gel method, to form the polymer/inorganic poly(MMA-MAA-MPS)/ZnO composite hollow latex particles. With the increase of crosslinking degree would increase the amount of ZnO bonding. Moreover, the poly(MMA-MAA-MPS) hollow latex particles were used as carriers to load with the model drug, caffeine. The release of caffeine from poly(MMA-MAA-MPS) hollow latex particles was investigated.     

pH-responsive nanosized-micelles based on poly(monomethylitaconate)-co-poly(dimethylaminoethyl methacrylate) and cholesterol side chains effect on pH change-induced release of piroxicam

Novel double hydrophilic poly(monomethylitaconate)-co-poly(N,N-dimethylaminoethyl methacrylate) (PMMI-co-PDMAEMA) synthesized via free radical polymerization of corresponding monomers with defined molar ratios in the presence of K₂S₂O₈ as an initiator in an aqueous solution. The resulting copolymer was subsequently converted to a cholesterol conjugate (PMMICholC₆-co-PDMAEMA) by esterification reaction with 6-cholesteryl-1-hexanol (CholC₆). Two copolymers self-assembled into micelles by simply adjusting the solution pH at room temperature. The non-conjugated polymer had a sharp transition at pH 5. TEM and DLS studies showed that both micelles were spherical in shape with a mean diameter around 85 and 26 nm, respectively. Piroxicam (PX) as a hydrophobic model drug was encapsulated into micelles. The results indicated that PMMICholC₆-co-PDMAEMA micelles were able to load more amounts of drug than PMMI-co-PDMAEMA micelles which could be attributed to the strong hydrophobic interactions of cholesterol molecules in the core. In vitro release studies demonstrated that PX release from PMMI-co-PDMAEMA micelles was significantly fast at physiological pH compared with mildly acidic pH 4.5. However, at pH 4.5, PMMICholC₆-co-PDMAEMA micelles, with core-shell-corona structure, released loaded drug molecules faster than pH 7.4 which contained a relatively steady drug release profile. In summary, cholesterol-modified micelles could be introduced as stable and effective pH responsive nanocarriers to make a promising system for enhancing the efficacy of hydrophobic drugs in cancer cells for improved cancer therapy.     

Synthesis of silver/polymer colloidal composites from surface-functional porous polymer microspheres

This study presents a different colloidal silver (Ag)/polymer system where Ag nanoparticles are deposited uniformly onto surface-functional porous poly(ethylene glycol dimethacrylate-co-acrylonitrile) (poly(EGDMA-co-AN)) microspheres. The formation and morphology of the composite microspheres were characterized from electron microscopy and X-ray diffraction analyses. The significance of the present report is that owing to the high affinity between Ag and nitrile group (CN) on the large surface of the microspheres, the Ag nanoparticles having a face-centered cubic phase were incorporated evenly into the deep pores of the microspheres with fine size and size distribution. In the preservation test, the Ag/poly(EGDMA-co-AN) composite microspheres obtained showed an excellent anti-bacterial performance, elucidating a high applicability for a new preservative.