Baisong Chang

Thermo and pH dual responsive, polymer shell coated, magnetic mesoporous silica nanoparticles for controlled drug release

In this paper, a kind of core–shell composite microsphere was prepared based on poly(N-isopropylacrylamide-co-methacrylic acid) (P(NIPAM-co-MAA)) coated magnetic mesoporous silica nanoparticles (M-MSN) via precipitation polymerization. The composite microsphere presented a thermo/pH-coupling sensitivity and the volume phase transition could be precisely regulated by the molar ratio of MAA to NIPAM or the concentration of NaCl. At physiological conditions (37 °C, 0.15 M NaCl), the P(NIPAM-co-MAA) shell underwent a distinct transition from a swollen state in pH 7.4 to a collapsed state in pH 5.0, so that the polymer shell was active in moderating the diffusion of embedded drugs in-and-out of the pore channels of MSN. Doxorubicin hydrochloride (DOX) was applied as a model drug and the behaviors of drug storage/release were investigated. The drug loaded behavior was pH-dependent, and the composite microsphere had a drug embed efficiency of about 91.3% under alkaline conditions. The cumulative in vitro release of the DOX-loaded composite microsphere showed a low level of leakage below the volume phase transition temperature (VPTT) and was significantly enhanced above its VPTT, exhibiting an apparent thermo/pH-response controlled drug release. The cytotoxicity assay of a blank carrier to normal cells indicated that the composite microspheres were suitable as drug carriers, while the DOX-loaded composite microspheres had a similar cytotoxicity to HeLa cells compared with free DOX. Therefore, the thermo/pH-sensitive composite microsphere could, in principle, be used for in vivo cancer therapy with a low premature drug release during blood circulation whilst having a rapid release upon reaching tumor tissues.

Facile synthesis of pH sensitive polymer-coated mesoporous silica nanoparticles and their application in drug delivery

pH-responsive polymer shell chitosan/poly (methacrylic acid) (CS-PMAA) was coated on mesoporous silica nanoparticles (MSN) through the facile in situ polymerization method. The resultant composite microspheres showed a flexible control over shell thickness, surface charges and hydrodynamic size by adjusting the feeding amount of MSN and the molar ratio of [-NH(2)]/MAA. The MSN/CS-PMAA composite microspheres were stable in the pH range of 5-8 as well as in the physiological saline (0.15M NaCl). Doxorubicin hydrochloride (DOX) was applied as a model drug to investigate the drug storage and release behavior. The results demonstrated that DOX could be effectively loaded into the composite microspheres. The cumulative release of DOX-loaded composite microspheres was pH dependent and the release rate was much faster at low pH (5.5) than that of pH 7.4. The cytotoxicity test by MTT assay showed that the blank carrier MSN/CS-PMAA microspheres were suitable as drug carriers. The cellular uptake of composite microspheres was investigated by confocal laser scanning microscopy (CLSM), which indicated that MSN/CS-PMAA could deliver the drugs into HeLa cell. The above results imply that the composite microspheres are a promising drug delivery system for cancer therapy.

Poly(vinylcaprolactam)-based biodegradable multiresponsive microgels for drug delivery.

Poly(vinylcaprolactam) (PVCL)-based biodegradable microgels were prepared for the biomedical application as drug delivery system via precipitation polymerization, where N,N-bis(acryloyl) cystamine (BAC) served as cross-linker, methacrylic acid (MAA) and polyethylene glycol (PEG) methyl ether methacrylate acted as comonomers. The microgels with excellent stability had distinct temperature sensitivity as largely observed in the case of PVCL-based particles and their volume phase transition temperature (VPTT) shifted to higher temperature with increasing MAA content and ambient pH. In the presence of reducing agent glutathione (GSH) or dithiothreitol (DTT), the microgels could be degraded into individual linear polymer chains by the cleavage of the disulfide linkages coming from the cross-linker BAC. The microgels could effectively encapsulate Doxorubicin (DOX) inside and presented stimuli-triggered drug release in acidic or reducing environment. The results of the cytotoxicity assays further demonstrated that the blank microgels were nontoxic to normal cells while DOX-loaded microgels presented efficient antitumor activity to HeLa cells.

Synthesis of discrete and dispersible hollow mesoporous silica nanoparticles with tailored shell thickness for controlled drug release

By employing poly (tert-butylacrylate) (PTBA) nanospheres as the dissolvable core templates, we develop a new method to synthesize hollow mesoporous silica nanoparticles (HMSN). Both the PTBA core and the structure-directing surfactant, cetyltrimethylammonium bromide (CTAB), can be easily and synchronously removed through solvent extraction in ethanol, which ensures the complete structure and ideal dispersibility of the products compared with the previous template synthesis that often needs calcination to remove the templates. Given that hollow core diameter and shell thickness are the key properties of HMSN, the hollow core diameter and shell thickness can be tailored precisely. In addition, as novel inorganic nanomaterials with a tuned structure, HMSN show notable biocompatibility and efficient doxorubicin (DOX) loading. In in vitro tests, the release rate of DOX-loaded HMSN exhibit a surprising shell-thickness-dependent and a pH responsive drug release character, suggesting that HMSN are a very promising drug delivery system for shell-thickness-controlled drug release. The results of intracellular tracking and cytotoxicity assays further demonstrate the potential and efficiency of HMSN as a drug delivery system.

pH-responsive composite microspheres based on magnetic mesoporous silica nanoparticle for drug delivery

pH-responsive composite microspheres, consisting of a core of Fe₃O₄ nanoparticle, a sandwiched layer of mesoporous silica and a shell of crosslinked poly (methacrylic acid) (PMAA), were successfully synthesized via distillation precipitation polymerization. The pKa of the composite microsphere increased with the increase in the crosslinking density. Doxorubicin hydrochloride (DOX) was applied as a model drug, and the behavior of drug storage/release was investigated. The cumulative release of DOX-loaded composite microsphere in vitro showed that the drug release rate was much faster below its pKa than that of above its pKa. Because pH of most tumor tissues was lower than that of normal tissues, the pH-responsive composite microspheres are promising drug delivery system especially for cancer therapy.

Gold nanorods@mSiO2 with a smart polymer shell responsive to heat/near-infrared light for chemo-photothermal therapy

Novel composite nanoparticles based on poly(N-isopropylacrylamide-co-N-hydroxymethyl acrylamide) (P(NIPAM-co-NHMA)) layer coated gold nanorod@mesoporous silica (GNR@mSiO2) has been successfully synthesized by precipitation polymerization. The composite nanoparticles exhibited a thermo/near-infrared (NIR) light sensitivity. The volume phase transition temperature (VPTT) could be precisely regulated by the content of NHMA in monomers and an excellent photothermal conversion effect was expressed due to the surface plasmon resonance of gold nanorods in the composite nanoparticles. Doxorubicin hydrochloride (DOX) was applied as a model drug and the drug storage/release behavior was investigated. The results demonstrated that DOX could be effectively loaded into the composite nanoparticles with 21% loading capacity. The cumulative release of DOX-loaded composite nanoparticles was temperature dependent and the release rate was significantly enhanced above the VPTT. Therefore, the composite nanoparticles applied as a drug delivery system could reduce the side effect of DOX to normal tissues as only a small fraction of DOX was released from the composite nanoparticles at 37 °C. In addition, the DOX-loaded composite nanoparticles demonstrated a synergistic effect, the therapeutic efficacy was improved significantly by the combination of photothermal therapy and traditional chemotherapy with low composite nanoparticle concentration and short laser irradiation time in an in vitro study.

In vivo distribution and antitumor activity of doxorubicin-loaded N-isopropylacrylamide-co-methacrylic acid coated mesoporous silica nanoparticles and safety evaluation.

The objective of this study was to develop and evaluate the antitumor activity and the safety of a delivery system containing mesoporous silica nanoparticles (MSN) coated with pH-responsive poly (N-isopropylacrylamide-co-methacrylic acid; P NIPAM-co-MAA) for doxorubicin (DOX) delivery (P-MSN-DOX) in vitro and in vivo. We reported that P-MSN-DOX nanoparticles (190 ± 30 nm) offered a DOX-loading coefficient of more than 20%. DOX release from the P-MSN-DOX formulation was pH-dependent with enhanced antitumor effects in vitro compared with traditional MSN-DOX, which was weakly cytotoxic due to negligible drug release at tested pHs. P-MSN-DOX circulated longer, with less cardiac and renal accumulation as shown by pharmacokinetics and biodistribution studies in vivo. Also, the P-MSN-DOX delivery system had greater antitumor activity in mice bearing a murine sarcoma S-180 cell line. This finding was correlated with both in vitro and in vivo. Subacute toxicity tests revealed a low P-MSN-DOX toxicity in vivo, as well. Thus, P-MSN-DOX appears to be an efficacious and safe cancer treatment strategy.

General one-pot strategy to prepare multifunctional nanocomposites with hydrophilic colloidal nanoparticles core/mesoporous silica shell structure.

A general and facile strategy was developed to coat hydrophilic inorganic nanoparticles directly with mesoporous silica nanoparticles (MSNs). The cationic surfactant of cetyltrimethylammonium bromide (CTAB) was adsorbed to various negatively charged CdTe quantum dots, Fe(3)O(4) nanocrystals or Au nanoparticles, introducing the bilayer of CTAB overcoating with positive charge. The subsequent sol-gel reaction of TEOS with the basic catalyst resulted in uniform nanocomposites. The concentration of CTAB and NH(4)OH in the recipe strongly influenced the number of inorganic nanoparticles in the nanocomposites and the homogeneity of MSNs shell. One dimensional Au nanorods and larger size of solid SiO(2) nanoparticles were also able to coat with MSNs using a similar synthetic procedure. The proposed method was greatly simplified without the help of any mediators or silane coupling agents and excellent mesostructural performance was readily achieved. Compared to the methods known from the literatures for the coating of hydrophobic nanoparticles, this efficient way is especially useful for trapping different hydrophilic nanoparticles with arbitrary sizes and shapes into MSNs. These highly versatile multifunctional nanocomposites, together with the pH-responsible drug release behaviors, non-toxicity to normal cells and ease of uptake into cancer cells, are expected to be utilized as drug delivery system for simultaneous imaging and therapeutic applications.

Silica composite nanoparticles containing fluorescent solid core and mesoporous shell with different thickness as drug carrier.

Nonporous silica transitional approach was employed to create core-shell architectural nanocomposites, which performed particularly well in morphology and controllable synthesis. The silica nanocomposites containing fluorescent solid SiO2 core and mesoporous silica shell (F-nSiO2/mSiO2) presented distinct structures of narrow size distribution, stable and shell thickness independent fluorescence, and high specific surface area. Furthermore, the thickness of mesoporous shell could be precisely tailored by the amount of TEOS and solid SiO2 seeds. Drug delivery study of F-nSiO2/mSiO2 with different mesoporous thicknesses were carried out, and Peppas equation was adopted to demonstrate the controlled releasing mechanism of doxorubicin (DOX). The diffusion rate of DOX from F-nSiO2/mSiO2 nanocomposites depended on the thickness of mesoporous shell and electrostatic interaction between drug and silanol group, which facilitated an enhanced drug releasing activity at pH 5.5 than 7.4. Whats more, particles loaded DOX showed similar cytotoxicity compared with pure DOX, while no obvious cytotoxicity of carrier was observed in MTT tests for blank particles. These characteristics mentioned above implied that core/shell structured F-nSiO2/mSiO2 had a great potential for controlled drug delivery system.

Blue-emitting PEGylated hyperbranched PAMAM: transformation of cross-linked micelles to hollow spheres controlled by the PEG grafting density

Here we reported the synthesis of polyethylene glycol 2000 monomethyl ether (PEG)ylated hyperbranched poly (amido amine) (h-PAMAM-g-PEG) and the study of an elaborate control over the structure transition by solvents. The double hydrophilic hyperbranched copolymers could form micelles with h-PAMAM core and solvophilic PEG shell in tetrahydrofuran (THF). It was found that the micellization stage was prolonged if more PEG chains were anchored onto h-PAMAM cores. After cross-linking the h-PAMAM cores, well-dispersed hollow spheres were obtained when the micelles were transferred into water from THF. More grafted PEG chains on h-PAMAM may prohibit the creation of a hollow cage upon the swelling of the hydrophilic h-PAMAM cores. Such engineered hollow spheres also retained the pH-sensitive fluorescence characteristic, identical with the luminescent behavior of the free h-PAMAM molecules. H-PAMAM-g-PEG hollow spheres with pH-sensitive fluorescence have a potential application as a drug delivery vehicle for chemotherapy.