Peripherally Cross-Linking the Shell of Core-Shell Polymer Micelles Decreases Premature Release of Physically Loaded Combretastatin A4 in Whole Blood and Increases its Mean Residence Time and Subsequent Potency Against Primary Murine Breast Tumors After IV Administration
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Determine the feasibility and potential benefit of peripherally cross-linking the shell of core-shell polymer micelles on the premature release of physically loaded hydrophobic drug in whole blood and subsequent potency against solid tumors.
Individual Pluronic F127 polymer micelles (F127 PM) peripherally cross-linked with ethylenediamine at 76% of total PEO blocks (X-F127 PM) were physically loaded with combretastatin A4 (CA4) by the solid dispersion method and compared to CA4 physically loaded in uncross-linked F127 PM, CA4 in DMSO in vitro, or water-soluble CA4 phosphate (CA4P) in vivo.
X-F127 PM had similar CA4 loading and aqueous solubility as F127 PM up to 10 mg CA4 / mL at 22.9 wt% and did not aggregate in PBS or 90% (v/v) human serum at 37°C for at least 24 h. In contrast, X-F127 PM decreased the unbound fraction of CA4 in whole blood (fu) and increased the mean plasma residence time and subsequent potency of CA4 against the vascular function and growth of primary murine 4T1 breast tumors over CA4 in F127 PM and water-soluble CA4P after IV administration.
Given that decreasing the fu is an indication of decreased drug release, peripherally cross-linking the shell of core-shell polymer micelles may be a simple approach to decrease premature release of physically loaded hydrophobic drug in the blood and increase subsequent potency in solid tumors.
KEY WORDSdrug delivery peripheral shell cross-linking pluronic F127 poloxamer 407 polymer nanocarriers premature drug release vascular disrupting agents
- 4 T1
Breast tumor epithelial cells from BALB/c mice
- 4 T1-Luc
4 T1 cells that stably express luciferase
Atomic force microscopy
Combretastatin A4 Phosphate / Fosbretabulin disodium
Dynamic light scattering
Electric cell-substrate impedance sensing
Pluronic F127 (Poloxamer 407)
- F127 PM
Pluronic F127 polymer micelles
Unbound fraction of drug in whole blood
Human umbilical vein endothelial cells
In vivo imaging system
DSC-activated Pluronic F127
- NHS-F127 PM
DSC-activated Pluronic F127 polymer micelles
- X-F127 PM
Pluronic F127 polymer micelle shell cross-linked with ED at 76%
ACKNOWLEDGEMENTS AND DISCLOSURES
This work was supported by NIH COBRE grant 2P20GM103480-06 (Nebraska Center for Nanomedicine) (RRW, RKS, JAV), NIH 1U54CA163120-01 grant (RKS), and UNMC Predoctoral Fellowships (SPRB, ST, VVA). The Nanoimaging Core Facility was supported by the NIH (SIG program), the UNMC Program of Excellence (POE), and the Nebraska Research Initiative (NRI). The Authors would also like to acknowledge Todd A. Wyatt, PhD and the VA Nebraska-Western Iowa Health Care System Research Service for providing access to and assistance with the Electric Cell Impedance Sensing apparatus.
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