Polymeric Micellar Nanoparticles Enable Image-guided Drug Delivery in Solid Tumors

Uddin, M. J.; Oltman, C. G.; Lo, J. H.; Gupta, M. K.; Werfel, T. A.; mohyuddin, m. T.; nazmin, f.; Rahman, M. S.; Crews, B. C.; kingsley, p. J.; Marnett, L. J.; Duvall, C. L.; Cook, R. S.

doi:10.1101/2024.06.07.598019

bioRxiv · 10.1101/2024.06.07.598019

Polymeric Micellar Nanoparticles Enable Image-guided Drug Delivery in Solid Tumors

Uddin, M. J.·Oltman, C. G.·Lo, J. H.·Gupta, M. K.·Werfel, T. A.·mohyuddin, m. T.·nazmin, f.·Rahman, M. S.·Crews, B. C.·kingsley, p. J.·Marnett, L. J.·Duvall, C. L.·Cook, R. S.

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Abstract

We report the development of a nanotechnology to co-deliver chemocoxib A with a reactive oxygen species (ROS)-activatable and COX-2 targeted pro-fluorescent probe, fluorocoxib Q (FQ) enabling real time visualization of COX-2 and CA drug delivery into solid cancers, using a di-block PPS135-b-POEGA17 copolymer, selected for its intrinsic responsiveness to elevated reactive oxygen species (ROS), a key trait of the tumor microenvironment. FQ and CA were synthesized independently, then co-encapsulated within micellar PPS135-b-POEGA17 co-polymeric nanoparticles (FQ-CA-NPs), and were assessed for cargo concentration, hydrodynamic diameter, zeta potential, and ROS-dependent cargo release. The uptake of FQ-CA-NPs in mouse mammary cancer cells and cargo release was assessed by fluorescence microscopy. Intravenous delivery of FQ-CA-NPs to mice harboring orthotopic mammary tumors, followed by vital optimal imaging, was used to assess delivery to tumors in vivo. The CA-FQ-NPs exhibited a hydrodynamic diameter of 109.2 {+/-} 4.1 nm and a zeta potential ({zeta}) of -1.59 {+/-} 0.3 mV. Fluorescence microscopy showed ROS-dependent cargo release by FQ-CA-NPs in 4T1 cells, decreasing growth of 4T1 breast cancer cells, but not affecting growth of primary human mammary epithelial cells (HMECs). NP-derived fluorescence was detected in mammary tumors, but not in healthy organs. Tumor LC-MS/MS analysis identified both CA (2.38 nmol/g tumor tissue) and FQ (0.115 nmol/g tumor tissue), confirming the FQ-mediated image guidance of CA delivery in solid tumors. Thus, co-encapsulation of FQ and CA into micellar nanoparticles (FQ-CA-NPs) enabled ROS-sensitive drug release and COX-2-targeted visualization of solid tumors.

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Uddin, M. J., Oltman, C. G., Lo, J. H., Gupta, M. K., Werfel, T. A., mohyuddin, m. T., nazmin, f., Rahman, M. S., Crews, B. C., kingsley, p. J., Marnett, L. J., Duvall, C. L., Cook, R. S.. 2024-06-10. Polymeric Micellar Nanoparticles Enable Image-guided Drug Delivery in Solid Tumors. https://doi.org/10.1101/2024.06.07.598019

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