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 89 Zr‐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.