Synthesis and biological activity assay of novel camptothecin-peptidic conjugates based on PEPT1
Qiang Zhang1, Ping Zou1, Meixuan Zhu2
1Key Laboratory of Saline-alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, Harbin, China.
Abstract:
Camptothecin (CPT) and its derivatives are potent candidates for cancer treatment. However, the clinical applications are largely restricted by non-selectivity and severe toxicities. The peptide transporter 1 (PEPT1), which is highly expressed in human intestines, has been found to be overexpressed in several cancer cells. This discovery suggests that PEPT1 has the potential to serve as a therapeutic target for both improving bioavailability and cancer-targeting treatment. Therefore, a prodrug approach for CPT targeting at PEPT1 highly expressed cancer cells was adopted in the present study. Eighteen CPT prodrugs, its peptidic conjugates, were synthesized and the structures were confirmed by NMR and HRMS. The protein expression profiles of PEPT1 in different cell lines were performed using immunofluorescence assay and western blotting analysis. The cytotoxicity of CPT prodrugs and their uptake via competition with Gly-Sar, a typical substrate of PEPT1, were evaluated in both PEPT1-overexpressed and under expressed cells. The results demonstrated that most CPT prodrugs significantly impaired Gly-Sar uptake, suggesting a higher affinity of CPT-peptidic conjugates for PEPT1 and PEPT1 overexpression cells. In addition, these prodrugs demonstrated a higher capability for inhibiting cell growth in PEPT1 highly-expressed cancer cells compared to PEPT1 under expressed cells. These results indicated that this peptidic prodrug strategy might offer great potential for improved tumor selectivity and chemotherapeutic efficacy of CPT.
Insights
This study developed novel camptothecin (CPT) prodrugs targeting peptide transporter 1 (PEPT1) overexpressed in cancer cells. These CPT-peptidic conjugates show promise for improved tumor selectivity and enhanced cancer treatment efficacy.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Camptothecin (CPT) derivatives are promising cancer therapeutics but suffer from poor selectivity and toxicity.
- Peptide transporter 1 (PEPT1), highly expressed in the intestine, is also overexpressed in various cancer cells, presenting a potential therapeutic target.
- Targeting PEPT1 could improve drug bioavailability and enable cancer-specific delivery.
Purpose of the Study:
- To design and synthesize novel camptothecin (CPT) prodrugs conjugated with peptides for targeted delivery to PEPT1-overexpressing cancer cells.
- To evaluate the affinity, cellular uptake, and cytotoxicity of these CPT prodrugs in cancer cells with varying levels of PEPT1 expression.
Main Methods:
- Synthesis and structural confirmation of eighteen CPT-peptidic conjugates using NMR and HRMS.
- Assessment of PEPT1 protein expression in different cell lines via immunofluorescence and Western blotting.
- Evaluation of prodrug cytotoxicity and PEPT1-mediated uptake through competition assays with Gly-Sar.
Main Results:
- The synthesized CPT-peptidic conjugates demonstrated significant inhibition of Gly-Sar uptake, indicating high affinity for PEPT1.
- Prodrugs exhibited enhanced cellular uptake in PEPT1-overexpressing cells compared to PEPT1-underexpressing cells.
- Most CPT prodrugs showed superior inhibition of cancer cell growth in PEPT1-high expressing cells.
Conclusions:
- Peptidic prodrugs targeting PEPT1 offer a viable strategy for enhancing the tumor selectivity of camptothecin (CPT).
- This approach holds significant potential for improving the chemotherapeutic efficacy of CPT in cancer treatment.
- PEPT1 represents a promising target for developing targeted cancer therapies with reduced systemic toxicity.
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