Photo-responsive drug delivery system based on photodynamic and photothermal effect

Abstract

Numerous types of chemotherapeutics have been developed in order to conquer the various diseases. In particular, chemotherapy is one of the most commonly implemented therapy for the conventional treatment of cancer. Nevertheless, a hydrophobic nature of the most of the anticancer drugs impedes an efficiency of chemotherapy. Moreover, severe side effect are manifested owing to the nonspecifically delivered drugs after systemic administration. For the reduction the side effect and enhancement of the efficacy, therefore, construction of an intelligent drug delivery system have been on the rise for biomedical application of chemotherapy. A brief overview of the emerging needs for the drug delivery system begins Chapter I, followed by grafting stimuli-responsive properties into drug delivery system. Among the various stimuli, an importance and the application of light, in particular, near infrared (NIR) window in a biomedical application is featured. Finally, the end of the chapter is focused on the recent progress of photodynamically and photothermally assisted drug delivery system. In Chapter II, a model study of long wavelength light responsive drug releasing platform based on the combination of the singlet oxygen sensitive linker (SOSL) and the photosensitizer (PS) is demonstrated. A long wavelength light responsive MSN (Pc@AP-E) was successfully rendered through the incorporation of PS into the pores of mesoporous silica nanoparticle (MSN) and the decoration of model drug on the surface of via SOSL. Upon an irradiation of the long wavelength light, singlet oxygen (1O2) was actively generated and it readily broke the SOSL to facilitate the release of the model drug from the surface of the carrier. Considering an excellent sensitivity of the Pc@AP-E against external stimulus and the active generation of 1O2, a potential as a photodynamically assisted drug releasing system had to be further investigated in advance. In the quest for the realization of the previous study for the biomedical application, an improved platform was developed and the detail is described in Chapter III. To provide better biocompatibility and stability in biological application, the real anticancer drug doxorubicin (DOX) was loaded in the PEGylated MSN which PEG was conjugated via SOSL. The release of the loaded drug was promoted by external irradiation of red light as expected. Surprisingly, the nano-carrier also exhibited an accelerated drug release at acidic pH condition, which is further favorable for the effective intracellular drug delivery. Moreover, the nano-carrier showed an enhanced cytotoxicity, especially, against chemo-resistant hepatocellular carcinoma (Hep3B) and colorectal cancer (HCT-8) cell line, as a result of the combination between photodynamic process and chemotherapy. In accordance to the high biocompatibility and photodynamically assisted drug release, our precisely designed platform has an immense potential to provide a combination of photodynamic and chemotherapy for the effective treatment of cancer. Beside photodynamic therapy, another technique commonly tried for the treatment of cancer with regard to the irradiation of NIR is photothermal therapy. Chapter IV and V present the development of photothermally assisted drug delivery platform mediated by the combination of photothermal agent and the thermo-sensitive phase change material (PCM). In particular, Chapter IV is mainly focused on the first introduction of PCM into the photo-responsive drug delivery system and its biomedical application. Among the various photothermal agents, gold nanorods (AuNRs) have attracted much attention by means of strong photothermal conversion and great biocompatibility. In order to combine the AuNRs and PCM, AuNR was covered by mesoporous silica shell (AuNR@mSiO2) to provide the stability and the reservoir for the drug. Through the facile fabrication method, several AuNR@mSiO2 formed a nano-assembly (DOX/PCM-AuNR@mSiO2) mediated by DOX loaded PCM. Photothermal conversion of AuNR core under the irradiation of NIR induced the phase transition of PCM, followed by the rapid release of the loaded drug. The nano-assembly exhibited an enhanced cytotoxicity against various cancer cells and the intracellular release of the DOX was easily monitored. Overall results reveal the broad applicability of PCM-based photothermally controllable drug delivery platform for an effective hydrophobic drug carrier in biomedical application. While the previous chapter is mainly focused on the comprehensive study of PCM-based photothermally assisted drug releasing platform, more fundamental studies for the investigation of the basic mechanism of PCM-based drug delivery platform is described in Chapter V. A PCM-based photothermally assisted drug releasing platform was formulated in a different manner. Single-layered graphene oxide (GO) was covered by mesoporous silica channel to form a honeycomb-like structure (GO@MS). Blend of DOX and PCM was loaded in the porous structure, thus the chocolate waffle-like nano-composite (DOX/PCM-GO@MS) was obtained. The nano-composite exhibited a similar photothermo-responsive releasing property in a same manner with previous nano-assembly and the even more than 50 times higher photo-induced cytotoxicity was observed. Moreover, intracellular uptake of GO material was successfully demonstrated by single cell Raman spectroscopy of trafficking GO. Additionally, the uptake inhibitor study implied that the main route of the endocytosis of PCM-coated material relies on the lipid-raft mechanism. Along with a series of studies for PCM-based photothermo-repsonsive system, photothermally assisted drug releasing platform possesses a feasibility for the spatiotemporally controllable drug delivery system.