Abstract
Purpose
The development of diagnostic and therapeutic agents utilizing small peptides (e.g., bombesin (BBN)) to target the overexpression of the gastrin-releasing peptide receptor (GRPR) in cancers has been widely investigated. Herein, we examine the capabilities of BBN-modified HPMA copolymers to target the GRPR.
Methods
Four positive, four negative, and two zwitterionic BBN HPMA copolymer conjugates of varying peptide content and charge were synthesized. In vitro and in vivo studies were conducted in a GRPR-overexpressing prostate cancer cell line (PC-3) and a normal CF-1 mouse model, respectively.
Results
Cellular uptake of the conjugates were found to be charge and BBN density dependent. The positively-charged conjugates illustrated a direct relationship between the extent of cellular internalization, ranging from 0.7 to 20%, and BBN-incorporation density. The negative and zwitterionic conjugates showed low PC-3 uptake values. Blocking studies confirmed the GRPR-targeting effect of the positively-charged constructs. In vivo studies of the positively-charged copolymers resulted in rapid blood clearance by the mononuclear phagocyte system (MPS)-associated tissues (e.g., liver and spleen).
Conclusion
Positively-charged BBN-HPMA copolymer conjugates demonstrated good GRPR-targeting and internalization in vitro. However, the impact of peptide density and charge on in vivo MPS recognition are parameters that must be optimized in future agent development.
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Abbreviations
- BBN:
-
Bombesin
- BBN-EE:
-
Bombesin peptide modified with two negatively charged amino acids
- BBN-RR:
-
Bombesin peptide modified with two positively charged amino acids
- GRPR:
-
Gastrin releasing peptide receptor
- P-D-RR:
-
HPMA copolymer modified with D-BBN-RR
- P-EE:
-
HPMA copolymer modified with BBN-EE
- P-RR:
-
HPMA copolymer modified with BBN-RR
- P-RREE:
-
HPMA copolymer modified with BBN-RR and BBN-EE
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Alshehri, S., Fan, W., Zhang, W. et al. In Vitro Evaluation and Biodistribution Studies of HPMA Copolymers Targeting the Gastrin Releasing Peptide Receptor in Prostate Cancer. Pharm Res 37, 229 (2020). https://doi.org/10.1007/s11095-020-02952-3
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DOI: https://doi.org/10.1007/s11095-020-02952-3