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Peptide-based pharmacomodulation of a cancer-targeted optical imaging and photodynamic therapy agent
Klara Stefflova1, Hui Li, Juan Chen
1Departments of Chemistry and Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Abstract:
We designed and synthesized a folate receptor-targeted, water-soluble, and pharmacomodulated photodynamic therapy (PDT) agent that selectively detects and destroys the targeted cancer cells while sparing normal tissue. This was achieved by minimizing the normal organ uptake (e.g., liver and spleen) and by discriminating between tumors with different levels of folate receptor (FR) expression. This construct (Pyro-peptide-Folate, PPF) is composed of three components: (1) pyropheophorbide a (Pyro) as an imaging and therapeutic agent, (2) peptide sequence as a stable linker and modulator improving the delivery efficiency, and (3) Folate as a homing molecule targeting FR-expressing cancer cells. We observed an enhanced accumulation of PPF in KB cancer cells (FR+) compared to HT 1080 cancer cells (FR-), resulting in a more effective post-PDT killing of KB cells over HT 1080 or normal CHO cells. The accumulation of PPF in KB cells can be up to 70% inhibited by an excess of free folic acid. The effect of Folate on preferential accumulation of PPF in KB tumors (KB vs HT 1080 tumors 2.5:1) was also confirmed in vivo. In contrast to that, no significant difference between the KB and HT 1080 tumor was observed in case of the untargeted probe (Pyro-peptide, PP), eliminating the potential influence of Pyro's own nonspecific affinity to cancer cells. More importantly, we found that incorporating a short peptide sequence considerably improved the delivery efficiency of the probe--a process we attributed to a possible peptide-based pharmacomodulation--as was demonstrated by a 50-fold reduction in PPF accumulation in liver and spleen when compared to a peptide-lacking probe (Pyro-K-Folate, PKF). This approach could potentially be generalized to improve the delivery efficiency of other targeted molecular imaging and photodynamic therapy agents.
Insights
A novel folate receptor-targeted photodynamic therapy agent (PPF) selectively targets and destroys cancer cells. Its peptide linker enhances delivery and reduces off-target accumulation in organs like the liver and spleen.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Photodynamic therapy (PDT) faces challenges in targeted delivery and minimizing off-target effects.
- Folate receptor (FR) is overexpressed on various cancer cells, making it a viable target for selective cancer therapies.
- Developing agents that combine imaging, therapy, and targeted delivery is crucial for effective cancer treatment.
Purpose of the Study:
- To design and synthesize a novel folate receptor-targeted, water-soluble photodynamic therapy agent (Pyro-peptide-Folate, PPF).
- To evaluate the selective detection and destruction of FR-expressing cancer cells by PPF.
- To assess the role of a peptide linker in improving delivery efficiency and reducing non-specific organ uptake.
Main Methods:
- Synthesis of the PPF construct comprising pyropheophorbide a (Pyro), a peptide linker, and Folate.
- In vitro studies using FR+ (KB) and FR- (HT 1080) cancer cells to assess PPF accumulation and PDT efficacy.
- In vivo studies using tumor models to evaluate PPF tumor targeting, biodistribution, and therapeutic effect compared to controls.
Main Results:
- PPF demonstrated enhanced accumulation in FR+ KB cells compared to FR- HT 1080 cells, leading to more effective killing of KB cells post-PDT.
- Folic acid effectively inhibited PPF accumulation in KB cells, confirming FR-mediated targeting.
- In vivo studies showed preferential accumulation of PPF in KB tumors over HT 1080 tumors, with a 2.5:1 ratio.
- The peptide sequence in PPF significantly reduced accumulation in the liver and spleen by 50-fold compared to a peptide-lacking probe (PKF), indicating improved delivery efficiency.
- An untargeted probe (Pyro-peptide, PP) showed no significant difference in tumor accumulation, validating the FR-targeting specificity of PPF.
Conclusions:
- The developed PPF agent selectively targets and effectively destroys FR-expressing cancer cells via photodynamic therapy.
- The incorporated peptide linker plays a critical role in enhancing delivery efficiency and minimizing off-target organ accumulation.
- This pharmacomodulated, targeted PDT approach holds promise for improving cancer treatment and can be generalized for other targeted agents.
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