Design, Synthesis, and Bioevaluation of Novel Enzyme-Triggerable Cell Penetrating Peptide-Based Dendrimers for Targeted Delivery of Camptothecin and Cancer Therapy.

Abstract

Novel enzyme-triggerable cell penetrating peptide (ETCPP) dendrimers with a camptothecin (CPT) warhead were designed and synthesized based on an amphiphilic penetrating peptide (FKKFFRKLL, discovered by us before). Among the newly synthesized ETCPP dendrimer conjugates, BL_Oc-SS-CPT (a high-generation dendrimer) exhibited the highest activity with IC50s in the nanomolar range (31-747 nM) against a panel of cancer cells, which is 3-10 times better than that of CPT. BL_Oc-SS-CPT remained intact during transit to target cells and in normal tissues with a plasma half-life of 4.2 h, 2.3-fold longer than that of the monomer (1.8 h). Once reaching the tumor site, BL_Oc-SS-CPT gradually released CPT in the presence of excessive matrix metalloproteinase-2/9 and GSH in cancer cells. Importantly, BL_Oc-SS-CPT exhibited excellent in vivo tumor targeting capability and antitumor efficacy with benign toxicity profiles. Thus, the novel ETCPP dendrimer-based drug delivery system (e.g., BL_Oc-SS-CPT) represents a safe and effective strategy for targeted cancer therapy.

• Authors: Ruiyao Mai, Bulian Deng, Huiting Zhao, Ling Li, Yuyu Fang, Siming Li, Xin Deng, Jianjun Chen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 7 Pg. 5850-5865 (04 14 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35380045 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cell-Penetrating Peptides
• Dendrimers
• Matrix Metalloproteinase 2
• Camptothecin

Topics

• Antineoplastic Agents (administration & dosage)
• Camptothecin (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell-Penetrating Peptides (pharmacology)
• Dendrimers
• Drug Delivery Systems
• Drug Design
• Humans
• Matrix Metalloproteinase 2
• Neoplasms (drug therapy)