Activable Photodynamic DNA Probe with an "AND" Logic Gate for Precision Skin Cancer Therapy
Jiaojiao Zhu1, Lanyuan Peng2, Shah Jehan1,3
1Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.
Abstract:
Photodynamic therapy (PDT) has emerged as a promising approach for squamous cell carcinoma treatment but hindered by tumor hypoxia, acquired resistance, phototoxicity, and so on. To address these issues, we developed a smart strategy utilizing activable photosensitizers delivered by an aptamer-functionalized DNA probe (ADP). The ADP incorporated an AS1411 aptamer for tumor targeting and a linear antisense oligonucleotide (ASO) for recognition of Survivin mRNA. In the absence of the target, PDT remained quenched, thereby avoiding phototoxicity during circulation and nonselective distribution. With the aid of the aptamer, ADP achieved selective targeting of tumors. Upon internalization, ADP targeted recognized Survivin mRNA, triggering PDT activation, and releasing ASO to down-regulate Survivin expression and reverse tumor resistance. Consequently, the activable photosensitizers exhibited an "AND" logic gate, combining tumor-targeting delivery and tumor-related gene activation, thus enhancing its specificity. Additionally, the incorporation of hemin into the ADP provided catalase activity, converting tumor-abundant H2O2 into O2, thereby ameliorating tumor hypoxia. The resulting functionalized G-quadruplex/hemin-DNA probe complex demonstrated targeted delivery and activation, minimized side effects, and enhanced PDT efficacy in both xenograft tumor-bearing mice and patient-derived xenograft models. This study offers a unique and promising platform for efficient and safe PDT, thus holding great potential for future clinical translation and improved cancer therapy.
Insights
This study presents an activable photosensitizer for photodynamic therapy (PDT) that targets tumors and combats resistance by down-regulating Survivin mRNA and alleviating hypoxia, improving cancer treatment safety and efficacy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Photodynamic therapy (PDT) shows promise for squamous cell carcinoma but faces challenges like tumor hypoxia and drug resistance.
- Existing PDT approaches can suffer from off-target toxicity and limited efficacy due to these hindering factors.
Purpose of the Study:
- To develop an activable photosensitizer system for enhanced and safer photodynamic therapy (PDT) of squamous cell carcinoma.
- To overcome limitations of PDT including tumor hypoxia, acquired resistance, and phototoxicity through a smart DNA-based delivery platform.
Main Methods:
- Developed an aptamer-functionalized DNA probe (ADP) incorporating an AS1411 aptamer for tumor targeting and an antisense oligonucleotide (ASO) for Survivin mRNA recognition.
- Incorporated hemin into the ADP to provide catalase activity, converting hydrogen peroxide (H2O2) into oxygen (O2) to address tumor hypoxia.
- Utilized an "AND" logic gate system for targeted activation of PDT upon tumor recognition and Survivin mRNA interaction.
Main Results:
- The ADP system demonstrated selective tumor targeting and quenched PDT activity in circulation, minimizing phototoxicity.
- Upon internalization, the ADP activated PDT and released ASO to down-regulate Survivin, reversing tumor resistance.
- The hemin incorporation effectively ameliorated tumor hypoxia by generating oxygen.
- The functionalized G-quadruplex/hemin-DNA probe complex showed enhanced PDT efficacy and minimized side effects in preclinical models.
Conclusions:
- This novel activable photosensitizer platform offers a targeted and stimuli-responsive approach for improved photodynamic therapy.
- The system effectively addresses key challenges in PDT, including tumor hypoxia and acquired resistance, paving the way for enhanced cancer treatment.
- The developed platform holds significant potential for clinical translation and advancing cancer therapy.
