Abstract
Ideal drug delivery systems deliver high doses of a therapeutic agent to diseased cells or bacteria without considerably interfering with healthy cells, inducing the desired pharmacokinetics and biodistribution, maximizing the higher therapeutic while minimizing side effects. Study I describes a novel time-controllable drug delivery system that exploits hollow microspheres (HMs) that repeatably release the drug at a concentration that is tightly managed within a therapeutic range. The HMs were fabricated from poly(D,L-lactic-co-glycolic acid) (PLGA) using a double-emulsion method; the polymer shell contained iron oxide nanoparticles (IONPs) and the aqueous core contained doxorubicin (DOX). Simtulation by a high-frequency magnetic field (HFMF), the encapsulated IONPs transformed magnetic energy into heat to increase rapidly the local temperature. As the temperature approached the Tg of PLGA, the polymeric chains became much more mobile, significantly increasing the number of local voids and thereby promoting the diffusion of DOX. Exploiting the repeated ON/OFF HFMF operation, the HMs served as a stimuli-responsive carrier with pulsatile drug release. Recent studies have suggested that chemopreventive agents can be used in cancer treatment to improve the antitumor activity of conventional chemotherapeutic drugs through synergistic actions. Study Ⅱ develops a co-delivery system that is based on the adsorption of cationic liposomes on an anionic hollow microsphere (Lipo-HM) by electrostatic interaction, allowing sequential drug release to be thermally driven in a time-controllable manner using an external magnetic stimulus. The sequential delivery of 1,25-dihydroxyvitamin D3 (VD3) and DOX remarkably promote the accumulation of reactive oxygen species (ROS) in tumor cells by reducing of antioxidant enzyme activity, which may contribute to VD3-potentiated DOX-induced cytotoxicity. Experimental results reveal that treatment with Lipo-HMs significantly worsened the damage that was caused to tumor cells by DOX, exhibiting a synergistic cytotoxic effect. The in vivo results demonstrate that Lipo-HMs exhibited stronger therapeutic action and significantly lower systemic toxicity than free-form drugs. Therefore, Lipo-HMs can be an effective delivery vehicle for chemopreventive agents and chemotherapy drugs, and therefore effective in the combined delivery of therapeutic agents. This sequential carrier system not only improves patient compliance by reducing the frequency of injections, but can also provide a synergistic therapeutic effect. Eradicating subcutaneous bacterial infections remains a significant challenge. Study Ⅲ describes an injectable system of HMs that can rapidly and locally generate heat when activated by near-infrared (NIR) light and control the release of an antibiotic using a “molecular switch” in their polymer shells. This functionality supports a combined strategy for treating subcutaneous abscesses. The HMs have a shell of PLGA and an aqueous core that is composed of vancomycin (Van) and polypyrrole nanoparticles (PPy NPs), which are photothermal agents. Experimental results indicate that the micro-HMs ensure the efficient spatial stabilization of their encapsulated Van and PPy NPs at injection sites in mice with subcutaneous abscesses. Without NIR irradiation, the HMs elute a negligible concentration of the drug, but release markedly more when exposed to NIR light, suggesting that this system is effective as a photothermally-responsive drug delivery system. The combination of photothermally-induced hyperthermia and antibiotic therapy with HMs increases cytotoxicity toward the bacteria in abscesses, to an extent that exceeds the sum of the cytotoxicities that are achieved by the two treatments alone, revealing a synergistic effect. This treatment platform may have other clinical applications, especially in localized hyperthermia-based cancer therapy.