Porphyrin-Cross-Linked Unimolecular Polyglycerol Nanogels: Confinement-Controlled Metalation and Selective Cu2+ Detection

Abstract Unimolecular nanogels (NGs) based on (hyper)branched cyclic polyglycerols ((h)bcPGs) of two molecular weights (Mn = 8 and 60 kDa) were prepared through intramolecular cross-linking with the tetraboronic acid–functionalized porphyrin, 5,10,15,20-(tetra-4-dihydroxyborylphenyl) porphyrin (TPP-4B) under mildly basic aqueous conditions. In this design, the porphyrin simultaneously acted as a multifunctional cross-linking node and an optical reporter, integrating structural and sensing functionalities within a single macromolecular system. Small-angle X-ray scattering (SAXS) confirmed that cross-linking occurred predominantly intramolecularly, yielding stable unimolecular NGs while preserving the size and conformation of the precursor polymers. Nanogel formation significantly improved the aqueous compatibility of TPP-4B, enabling complete solubilization and stability over a broad pH range, including near-physiological conditions, without the need for organic cosolvents. Combined UV–Vis spectroscopy, density functional theory (DFT), time-dependent DFT (TD-DFT), and model compound studies demonstrated that the observed spectral changes arose primarily from confinement and microenvironmental effects rather than from boronate ester formation. Fluorescence spectroscopy revealed that confinement within the NG induced a slight red shift, emission band narrowing, and a marked increase in fluorescence intensity, particularly for NG60k, consistent with a more restricted local environment. Metalation studies with Cu2+ and Zn2+ revealed that polymer confinement markedly slowed metal incorporation and that this effect became more pronounced with increasing nanogel molecular weight. Importantly, the kinetic retardation was substantially greater for Zn2+ than for Cu2+, so that NG8k retained a measurable response toward Cu2+ while exhibiting only a minimal response toward Zn2+. This differential slowing of metalation enabled the selective determination of Cu2+ in mixed Cu2+/Zn2+ samples and identified nanogel molecular weight as a key parameter for balancing porphyrin accessibility, metal diffusion, and sensing selectivity under mildly basic aqueous conditions.