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Poly(ethylene glycol)-graft-hollow silica vesicles for drug delivery.

Vesicles formed by encapsulating a volume with a thin membrane are very important for formulation of drug delivery systems. For formulation of good drug delivery systems, vesicles should have a good stability for secure delivery of drug to target sites and a suitable fluidity for release of drugs at target sites; also vesicles should have suitable functional stealth layers, and it is well recognized that PEG stealth layers can prevent nonspecific adsorption of proteins and nonspecific uptake by the reticuloendothelial system (RES) and therefore render a long circulation time in bloodstream and passive targeting of cancer cells. However so far the dilemma between stability and fluidity of vesicles always exist, i.e., vesicles with good fluidity are instable and vice versa; and in some cases, it is not feasible to obtain vesicles with suitable stealth layers. Here we report that PEGgraft-hollow silica (PEG-g-hollow silica) vesicles have a good stability due to the silica layers, together with a good dispersity in aqueous solution due to PEG stealth layers; and water insoluble drug paclitaxel (PTX) loaded in PEG-g-hollow silica vesicles can be released faster than free PTX. Further it is shown that PEG-g-hollow silica vesicles have a low cytotoxicity and can enter cells; and PTX loaded PEG-g-hollow silica vesicles are potent to kill cancer cells. Self-assembly of amphiphilic lipids or copolymers is one of the most common approaches to vesicles, i.e., liposomes and polymer vesicles. Liposomes integrated by a weak interaction among the short hydrophobic lipid segments are dynamic but instable. Various efforts have been explored to increase the stability of the liposomes including forming polymer or silica cages. But the improvement in the stability is always compromised by loss of fluidity. In comparison, the structures and properties of polymer vesicles can be tuned in a wider range because of feasible changes in the molecular weight and chemistry of amphiphilic copolymers. High molecular weight hydrophobic polymer segments and additional interactions among polymer segments such as hydrogen bonding, -helix or ionic complexes lead to stable vesicles. Also silica containing polymer vesicles were obtained from self-assembly of block copolymers containing alkoxysilane species or deposition of alkoxysilane into polymer vesicles followed by sol-gel process. However, it is still difficult to obtain polymer vesicles with good stability and good fluidity simultaneously. Another interesting approach to vesicles is layer-by-layer adsorption of polyelectrolytes onto sacrificial templates. Vesicles with a membrane composed of multi-polyelectrolyte layers are obtained, and various species can be integrated to tune the properties. But it is difficult to prepare nanosized vesicles with membranes composed of non-ionic materials and suitable stealth layers via layer-by-layer approach. On the other hand, porous hollow silica spheres have been explored for drug delivery but have a poor dispersity in aqueous solution and an inert functionality. Polylelectrolyte multilayers coated hollow silica spheres showed salt-induce drug release, and PEG layers were applied to reduce the ultrasonication–triggered drug release rate from hollow silica spheres. However, hollow silica spheres with suitable polymer stealth layers are not reported. Nevertheless it is reasonable to expect that vesicles with excellent performances can be obtained by grafting dense polymer brushes to nanosized hollow silica spheres. Here PEG-g-hollow silica vesicles are obtained by grafting PEG brushes to nanosized porous hollow silica spheres. To prepare PEGg-hollow silica vesicles (as shown in Scheme S1), first nanosized hollow silica spheres were prepared by sol-gel reaction of TEOS in the presence of polystyrene templates followed by removing polystyrene templates under calcination at 550 C. From TEM images shown in Figure 1A, the average diameter and the average shell thickness of the hollow silica spheres are determined to be ca. 190 nm and ca. 14 nm respectively. The hollow silica spheres have pores with an average diameter of 1.19 nm, a surface area of 164 m/g and a total pore volume of 0.24 cm/g which were measured using BET and BJH methods (graphs shown in Figure S1 in supporting information). Then hollow silica spheres were modified with N-(3-trimethoxysilyl) propyl ethylene diamines (TMSPEA). As indicated by TGA results shown in Figure 1B, the degradation degree of TMSPEA attached hollow silica spheres increases by 6% (w/w) at 750 C as compared with the pristine hollow silica spheres. Finally PEG-g-hollow silica vesicles were obtained by grafting PEG brushes via urethane groups formed by the reaction among the amino groups on the surfaces of TMSPEA attached hollow silica spheres and monomethoxy PEG (Mn: 5 K) 4-nitrophenyl carbonate. The successful PEG grafting is verified by the characteristic peaks of urethane group at 1769, 1701 1526, 842 cm observed in FTIR spectrum of PEG-g-hollow silica vesicles (Figure S2); and the peaks at 3.61 ppm in H NMR spectrum (Figure S3) attributed to the protons of PEG. From TGA curve of PEG-g-hollow silica vesicles shown in Figure 1B (c), the content of PEG in PEG-g-hollow silica vesicles is determined to be ca. 46% (w/w). As compared to TEM images of pristine hollow silica shown in Figure 1A, PEG stealth layers of PEG-g-hollow silica vesicles can be observed obviously in TEM images of PEG-g-hollow silica vesicles shown in Figure 1C. The average diameter and shell thickness of PEG-g-hollow silica vesicles is ca. 210 nm and 37 nm respectively. The grafted PEG stealth layers render PEG-g-hollow silica vesicles good dispersion in aqueous solution. Dynamic laser light [] Dr. Y. Liu, C. L. Lay, Dr. D. C. Wu. Institute of Materials Research and Engineering A*STAR (Agency for Science, Technology and Research) 3 Research Link, Singapore 117602 Fax: (+65) 6872 7528 E-mail: ye-liu@imre.a-star.edu.sg