Development of functional thermo-responsive nanosponge for biomedical application

Abstract

Despite the advantages of small molecule drugs such as good stability for storage, simple fabrication procedure, and cost-effectiveness, their application as 'free molecules' in systemic circulation can lead to unexpected pharmacokinetic properties, restricted therapeutic efficacy, insufficient targeting to desired sites, and potential toxicity to normal organs. To address these challenges, drug delivery systems (DDS) have been developed. Through DDS, drugs can be reached, targeted, confined, and extended at the desired site while minimizing impact on non-targeted tissues. For improved therapeutic efficacy through the DDS, the controlled release is a major factor, since the controlled release profile can induce long-lasting release, compliance and acceptance of patients, pharmacological activity, and decreased toxicity of the drug. Current DDS aims to improve therapeutic efficacy through characteristics such as sustained delivery, smaller particle size, specific site targeting, increased permeability, efficacy, raised solubility, non-toxicity, and stability compared to conventional administration. However, these developed DDS still face challenges including toxicity, safety, side effects when administration, complications of targeting delivery, instability, and so on. Thus, we propose a novel DDS platform utilizing FDA-approved polymers. Poly(lactic acid) (PLA), known for its biodegradability and biocompatibility, has been widely used in biomedical applications such as implants, sutures, and DDS. Pluronic, another polymer used in DDS, exhibits unique thermo-responsive properties. Based on these polymers, we have developed thermo-responsive nanosponges (TNPs) which have found applications in various biomedical fields including chemotherapy, anti-aging treatments, and vaccination. In Chapter 2, we employed the TNP for chemotherapy, especially targeting MDR-related chemotherapy. According to our previous study, we prepared two anticancer drugs (doxorubicin; DOX, and paclitaxel; PTX) and one P-gp inhibitor (tetrandrine; TET) loaded TNP. We conducted comprehensive assessments of stability, safety, and efficacy through both in vitro and in vivo experiments. Expanding on the previous experiment, we further examined the efficacy of DOX/PTX/TET@TNP in MDR-related cancer cell bearing xenograft mice. Remarkably, the DOX/PTX/TET@TNP showed highly enhanced tumor suppression compared to other formulations, while demonstrating minimal acute toxicity. In Chapter 3, we applied the TNP for anti-aging, especially focusing on its anti-wrinkle effect. The anti-wrinkle peptides (Regentide®-AWP013; RG) were successfully synthesized by modification of C-terminal and N-terminal amino acids through amidation and acetylation. The RG enhanced the cell proliferation and wound healing activity without significant toxicity. Subsequently, the RG was encapsulated into the TNP and optimized without considerable change in its characterization. The optimized RG@TNP showed good colloidal stability. In addition, through pig skin, we confirmed that TNP could increase skin permeability. Finally, following clinical trials, the RG@TNP effectively alleviated the aging symptoms; decreased eye wrinkles, improved elasticity, reduced skin sagging, and mitigated pigmentation. In Chapter 4, we employed the TNP both as a carrier for efficiently delivering antigens and as nano-adjuvants. We optimized the ratio of core to shell in TNP for enhanced immune responses. With prepared TNP with optimized ratio, maximal amounts of the model antigens (ovalbumin; OVA) were encapsulated without severe change in physicochemical properties. Besides, enhanced immune responses in DC cells were observed after treatment with OVA@TNP, compared to free OVA. Furthermore, the improved preventative vaccination effect through OVA@TNP was exhibited in mice model. In conclusion, this thesis highlights the potential of thermo-responsive nanosponge (TNP) as a DDS platform in various biomedical applications. The TNP was successfully used as a DDS platform for chemotherapy, anti-aging, and vaccination.