Theranostic π Electron-Stabilized Polymeric Micelles for PET Imaging-Guided Drug Delivery to Tumors

Nanomedicines are increasingly employed in oncology. However, their efficacy is limited by heterogeneous nanoparticle accumulation in different tumors and patients. Nuclear imaging offers non-invasive, patient- and lesion-specific visualization and quantification of nanoparticle uptake, providing a biomarker to predict nanotherapy efficacy. We present a positron emission tomography (PET)-imageable [mPEG-b-p(HPMAm-Bz)]-based polymeric micelle platform for image-guided and tumor-targeted drug delivery, with potential for patient stratification and theranostics. Polymers with 1 or 3 deferoxamine (DFO) chelators were synthesized, and the corresponding micelles showed stable ⁸⁹Zr-radiolabeling and efficient drug (paclitaxel) encapsulation. PET imaging revealed long in vivo circulation times and high tumor accumulation, with more DFO per polymer accelerating drug release and increasing off-target accumulation. Hence, single-DFO-containing polymers were used to develop companion diagnostic and paclitaxel-loaded theranostic micelles. Both formulations displayed comparable biodistribution profiles and high levels of tumor uptake (>17% ID/g) and were able to capture inter- and intra-individual heterogeneity in tumor targeting. Importantly, cryo-preservation enables long-term storage while maintaining in vivo performance and tumor-targeting capabilities, bolstering translational potential. Taken together, DFO-functionalized π-electron-stabilized micelles allow direct quantification of nanoparticle accumulation in tumors while mediating effective drug delivery, showing promise for patient stratification and as a theranostic platform for image-guided and personalized cancer therapy.