Development of photo-controlled nano delivery systems with DEACM for cancer therapy

Abstract

Nano-drug delivery system is an emerging approach to precisely deliver therapeutics for improved cancer therapies. Currently, dozens of nano-drugs are in market and saving thousands of patients. Among all categories, photoresponsive nano-drug delivery systems have been extensively explored owing to their advantages in targeted delivery and controlled drug release, as the light irradiation could provide a powerful, noninvasive, and precise spatiotemporal control. However, many current photoresponsive nano-drug delivery systems achieved promising therapeutic effects by increasing the complexity of design, which hinders their clinical translation. Taken together, simple yet efficient nano-drug delivery systems with photo-controlled targeting or drug release behaviors should be highlighted for cancer treatments. The overall aim of this thesis was to develop compact photo-controlled nano-drug delivery systems with enhanced delivery efficiency and biocompatibility for cancer therapy. Three photo-controlled delivery strategies were exploited in this thesis, including nucleus-targeted drug delivery systems, self-carried drug delivery systems, and biomacromolecule delivery systems. A commonly used photocleavable molecule, DEACM, was used as the core material for all systems. The first strategy was to develop a photoresponsive drug delivery system with high nucleus-targeting efficiency. Nucleus delivery is critical for anticancer drugs that interact with DNA to kill cancer cells. However, it is particularly challenging due to the tight membrane structure and high osmotic pressure in nucleus. By exposing a nucleus-localizing sequence with a photocleavable polymer, nucleus-targeted drug delivery was achieved after light irradiation with high efficiency. The synthesis and characterization of the drug delivery system were systemically performed. The promising nucleus-targeting and anticancer effect were demonstrated in vitro. In the second strategy, a dendrimer-based photoresponsive system loaded with autophagy inhibitors was developed. The cationic dendrimer, PAMAM, was utilized as both carrier and the therapeutics. By conjugating with DEACM, the cytotoxicity of PAMAM was shielded during blood circulation. Upon light irradiation, the photo-triggered release of PAMAM and autophagy inhibitors could kill cancer cells synergistically. The multifunctional nanoparticles were systemically characterized and demonstrated to have photoenhanced autophagy-mediated anticancer effect both in vitro and in vivo. Based on the protein adsorption property of DEACM-conjugated PAMAM, the system was further exploited in delivering proteins. Proteins are biomacromolecules involved in multiple biological processes. However, their vulnerable structures and large molecular weights pose challenges in their delivery in human body. In the third study, the mechanisms of protein-conjugate interactions were explored and a photoresponsive system was tailored for protein delivery. This delivery system was developed with simple synthesis and high biocompatibility, applicable for a variety of functional proteins with high stability, photo-controllability, and delivery efficiency on in vitro models. Such versatile delivery system with simple design showed great potential in accelerating clinical translation of protein delivery. In summary, three nano-drug delivery strategies presented in this thesis demonstrated the possibility of using simple designs to achieve desirable delivery of small molecules and biomacromolecules for cancer therapy. Moreover, these strategies proved the superiority of photoresponsive systems in precisely controlled targeted delivery or drug release, addressing the limitations of low accumulation in diseased sites and undesirable off-targeting side effects.