Targeted Delivery of Chlorin e6 via Redox Sensitive Diselenide-Containing Micelles for Improved Photodynamic Therapy in Cluster of Differentiation 44-Overexpressing Breast Cancer

Abstract

The off-target activation of photosensitizers is one of the most well-known obstacles to effective photodynamic therapy (PDT). The selected activation of photosensitizers in cancer cells is highly desired to overcome this problem. We developed a strategy that enabled diselenide bonds to link hyaluronic acid (HA) and photosensitizer chlorin e6 (Ce6) to assemble the micelles (HA-sese-Ce6 NPs) that can target cancer and achieve a redox responsive release of drugs to enhance the PDT efficiency in breast cancer. The HA was used to form a hydrophilic shell that can target cluster of differentiation 44 (CD44) on the cancer cells. The selenium-containing core is easily dissembled in a redox environment to release Ce6. The triggered release of Ce6 in a redox condition and the positive feedback release by activated Ce6 were observed in vitro . In cytotoxicity assays and in vitro cellular uptake assays, the increased PDT efficiency and targeted internalization of HA-sese-Ce6 NPs in the cells were verified, compared to a free Ce6 treated group. Similar results were showed in the therapeutic study and in vivo fluorescence imaging in an orthotopic mammary fat pad tumor model. In addition, a significant inhibition of metastasis was found after the HA-sese-Ce6 NPs treatment. In general, this study promises an ingenious and easy strategy for improved PDT efficiency.

Bio-Applications of Multifunctional Melanin Nanoparticles: From Nanomedicine to Nanocosmetics

“…Poinard et al suggested a two-step method, in which as PS, Chlorin e6 (Ce6) was loaded inside the polymeric matrix of PDA [ 218 ]. Chlorin e6 (Ce6) is a second-generation PS, which is widely used in PDT due to its high efficacy and low dark toxicity [ 219 ]. Since loading maintained the surface unaltered Ce6 containing MNP showed a potentially mucopenetrative enhanced performance, enabling more effective cancer phototherapy in organs, which require mucosal drug delivery.…”

Programmable Ce6 Delivery via Cyclopamine Based Tumor Microenvironment Modulating Nano-System for Enhanced Photodynamic Therapy in Breast Cancer

“…Among various emerging therapies, photodynamic therapy (PDT) is a promising non-invasive therapeutic method for superficial tumors, such as breast cancer (Agostinis et al, 2011; Wang D. et al, 2018). One of the most widely used photosensitizers is chlorin e6 (Ce6) (Du et al, 2016; Feng et al, 2019). However, the poor water solubility of photosensitizers hinders their clinical application.…”

“…As for the latter stage, these smaller “bomb” components would be better to modify tumor target ligands for effective tumor cells internalization and equip with sensitive linkages for tumor intracellular triggered drug release. Hyaluronic acid (HA), a natural anionic hydrophilic polysaccharide targeting differentiation 44 (CD44) on the cancer cell membrane, is a promising target ligand candidate due to its desirable biocompatibility, biodegradability, non-immunogenicity, and easy functionalization (Choi et al, 2011; Xia et al, 2018a; Feng et al, 2019). In addition, the diselenide bond has particular advantages owing to its high sensitivity to redox condition and singlet oxygen ( 1 O 2 ), which makes PDT positive drug release theoretically possible (Xia et al, 2016, 2018b; Sun et al, 2017).…”

“…Moreover, HA-SeSe-Ce6 as smaller “bomb” component will release and further infiltrate to deeper tumor tissue. In the redox condition of tumor intracellular or existence of 1 O 2 , diselenide bonds would cleave and lead to Ce6 release (Feng et al, 2019). The improved PDT anticancer effects via tumor microenvironment tailored multi-stage delivery was investigated in breast cancer cell line and breast cancer-bearing mice.…”

<p>Design and Fabrication of Dual Redox Responsive Nanoparticles with Diselenide Linkage Combined Photodynamically to Effectively Enhance Gene Expression</p>

“…9,29 Utilizing the redox reactivity of dienyl ether, the dienyl ether structure is introduced into the polymer chain to achieve drug encapsulation and controlled release. 28,[46][47][48] Based on this, the researchers are committed to designing and synthesizing diselenides crosslinked polymers as gene victors to improve transfection efficiency. 29,42,46,[49][50][51] Photodynamics is that the photosensitizer will produce single-line oxygen to directly kill tumor cells under the infrared light.…”