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Protease‐activated peptide toxins for selective nanoparticle therapeutics (1054.4)
Author(s) -
Jallouk Andrew,
Palekar Rohun,
Schlesinger Paul,
Pan Hua,
Wickline Samuel
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1054.4
Subject(s) - melittin , prodrug , cytotoxicity , chemistry , peptide , protease , immunotoxin , pharmacology , ic50 , biochemistry , drug delivery , in vitro , enzyme , biology , organic chemistry
Objective: To enhance peptide toxin specificity by developing prodrugs which are locally activated by proteases and can be delivered by antigen‐targeted nanoparticles. Introduction: Melittin is a peptide toxin derived from bee venom which has been suggested as a cancer therapy due to its membranolytic activity. Yet, its therapeutic applications have been limited by its rapid clearance from the circulation and nonspecific cytotoxicity. We have previously developed an integrin‐targeted nanoparticle system which extends melittin circulation time and enhances delivery to tumors. Here, we present a platform for melittin prodrug design which allows activation by a protease of interest while still permitting delivery of the prodrug by nanoparticle carriers. Methods and Results: The prodrug consisted of melittin joined to a blocking sequence via a matrix metalloproteinase 2 (MMP‐2)‐cleavable linker. While native melittin was substantially hemolytic (HD50: 5.4 µM) and cytotoxic (IC50: 3.0 µM) to B16 melanoma cells, the prodrug demonstrated no hemolysis (HD50: > 100 µM) and only slight cytotoxicity (IC50: > 100µM) at concentrations up to 100 µM. MMP‐2 cleavage restored the hemolytic activity (HD50: 11.2 µM) and cytotoxicity (IC50: 4.8 µM) of the prodrug. Surface plasmon resonance spectroscopy confirmed the ability of the prodrug to insert into the lipid monolayer of perfluorocarbon nanoparticles. Conclusion: Protease‐activated melittin prodrugs minimize nonspecific cytotoxicity and show promise for development as selective nanoparticle‐based therapeutics. Grant Funding Source : Supported by a grant from the National Institutes of Health (R01 HL073646 to SAW)