Targetable Clinical Nanoparticles for Precision Cancer Therapy Based on Disease-Specific Molecular Inflection Points

Abstract

Novel translational approaches based on clinical modular nanoplatforms are needed, in order to treat solid cancers according to their discrete molecular features. In the present study, we show that the clinical nanopharmaceutical Ferumoxytol, which consists of a glucose-based coat surrounding an iron oxide core, could identify molecular characteristics of prostate cancer, corresponding to unique phases of the disease continuum. By affixing a targeting probe for the prostate-specific membrane antigen on its surface, the nanopharmaceutical was able to assess the functional state of the androgen receptor pathway via MRI, guiding therapy and delivering it with the same clinical nanoparticle. In order to simultaneously inhibit oncogenic signaling from key oncogenic pathways of more advanced forms of prostate cancer, a single-agent therapy for early-stage disease to inhibit DNA replication, as well as combination therapy with two drugs co-retained within the nanopharmaceutical’s polymeric coating, were tested, and resulted complete tumor ablation. Recalcitrant and terminal forms of the disease were effectively treated with a nanoparmaceutical delivering a combination that upregulates endoplasmic reticulum stress and inhibits metastasis, thereby showing that this multifunctional nanoplatfom can be used in the clinic for patient stratification, as well as precision treatment based on the individual’s unique disease features.

Biological Effects of Nanoparticles on Macrophage Polarization in the Tumor Microenvironment

“…Feraheme (also called ferumoxytol) is an FDA-approved carboxymethyl dextran-coated iron oxide nanoparticle that is used to treat iron deficient anemia. This nanoparticle has been used as a drug delivery system for anticancer drugs and for contrast agent delivery 35, 159, 160. Zanganeh et al investigated the effects of empty ferumoxytol on macrophage polarization in detail 161.…”

MRI-traceable theranostic nanoparticles for targeted cancer treatment

“…Nanoparticles can be utilized to maintain the synergistic drug concentrations and molar ratios to achieve optimal therapeutic performance 59 . In one study, Kaittanis et al used Ferumoxytol with a prostate-specific membrane antigen (PSMA)-targeting peptide and two drugs (enzalutamide and PI3K inhibitor BEZ235), co-retained within its polymeric coating, for targeted delivery to castration-resistant prostate cancer 60 . Intravenous administration of the dual-drug carrying nanoparticles resulted in complete tumor regression of PSMA-expressing, androgen receptor-positive tumor xenografts, in contrast to animals that received an intravenous combination of both drugs in their free form.…”

Molecular MR Imaging of Prostate Cancer

“…The nanopharmaceutical Ferumoxytol (Feraheme ® ) was modified by Kaittanis et al for use in PCa [ 108 ]. In the study, cell experiments (in vitro) were performed and then the nanopharmaceutical was examined in animal models (in vivo) for its therapeutic potential [ 108 ].…”