Abstract:
:TGX-221 is a highly potent phosphoinositide 3-kinase β (PI3Kβ) inhibitor that holds great promise as a novel chemotherapeutic agent to treat prostate cancer. However, poor solubility and lack of targetability limit its therapeutic applications. The objective of this present study is to develop a peptide-drug conjugate to specifically deliver TGX-221 to HER2 overexpressing prostate cancer cells. Four TGX-221 derivatives with added hydroxyl groups were synthesized for peptide conjugation. Among them, TGX-D1 exhibited a similar bioactivity to TGX-221, and it was selected for conjugation with a peptide promoiety containing a HER2-targeting ligand and a prostate specific antigen (PSA) substrate linkage. From this selection, the peptide-drug conjugate was proven to be gradually cleaved by PSA to release TGX-D1. Cellular uptake of the peptide-drug conjugate was significantly higher in prostate cancer cells compared to the parent drug. Moreover, both the peptide-drug conjugate and its cleaved products demonstrated comparable activities as the parent drug TGX-D1. Our results suggest that this peptide-drug conjugate may provide a promising chemotherapy for prostate cancer patients.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Tai W,Shukla RS,Qin B,Li B,Cheng Kdoi
10.1021/mp200007bsubject
Has Abstractpub_date
2011-06-06 00:00:00pages
901-12issue
3eissn
1543-8384issn
1543-8392journal_volume
8pub_type
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