Antitumor Effect of Lonidamine-Polypeptide-Peptide Nanoparticles in Breast Cancer Models

Biomaterials folded into nanoparticles (NPs) can be utilized as targeted drug delivery systems for cancer therapy. NPs may provide a vehicle for the anticancer drug lonidamine (LND), which inhibits glycolysis but was suspended from use at the clinical trial stage because of its hepatotoxicity due to...

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Bibliographic Details
Published in:ACS applied materials & interfaces 2019-09, Vol.11 (36), p.32670-32678
Main Authors: Cohen-Erez, Ifat, Issacson, Carol, Lavi, Yael, Shaco-Levy, Ruthy, Milam, Jammi, Laster, Brenda, Gheber, Levi A, Rapaport, Hanna
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Breast Neoplasms - drug therapy
Breast Neoplasms - pathology
Cell Line, Tumor
Cell Survival - drug effects
Female
Humans
Indazoles - pharmacology
Indazoles - therapeutic use
Mice, Inbred BALB C
Mitochondria - drug effects
Mitochondria - metabolism
Nanoparticles - therapeutic use
Nanoparticles - ultrastructure
Peptides - pharmacology
Peptides - therapeutic use
Xenograft Model Antitumor Assays
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Summary:Biomaterials folded into nanoparticles (NPs) can be utilized as targeted drug delivery systems for cancer therapy. NPs may provide a vehicle for the anticancer drug lonidamine (LND), which inhibits glycolysis but was suspended from use at the clinical trial stage because of its hepatotoxicity due to poor solubility and pharmacokinetic properties. The NPs prepared by coassembly of the anionic polypeptide poly gamma glutamic acid (γ-PGA) and a designed amphiphilic and positively charged peptide (designated as mPoP-NPs) delivered LND to the mitochondria in cell cultures. In this study, we demonstrate that LND-mPoP-NP effective drug concentrations can be increased to reach therapeutically relevant concentrations. The self-assembled NP solution was subjected to snap-freezing and lyophilization and the resultant powder was redissolved in a tenth of the original volume. The NP size and their ability to target the proximity of the mitochondria of breast cancer cells were both maintained in this new formulation, C-LND-mPoP-NPs. Furthermore, these NPs exhibited 40% better cytotoxicity, relative to the nonlyophilized LND-mPoP-NPs and led to tumor growth inhibition with no adverse side effects upon intravenous administration in a xenograft breast cancer murine model.
ISSN:1944-8244
1944-8252
DOI:10.1021/acsami.9b09886