Well-defined gold nanoparticles (AuNPs) are accessible via simple synthetic methods, and their surface chemistry stands as a key factor in determining applications in the biomedical field. While macromolecules featuring amino groups are already known to successfully mediate the formation of stable gold colloids in one-pot, two-reactant, no workup reactions in aqueous media, we herein report the discovery that, under mild reaction temperatures, polymers of outstanding biomedical interest not only can play the simultaneous role of reducing and capping agent but also lead to particulate systems with unique features. From a library of samples that included branched polyethylenimine (BPEI), poly­(l-lysine) (PLL), bovine serum albumin (BSA), poly­(2-methyl-2-oxazoline) (PMeOx), poly­(N-(2-hydroxypropyl) methacrylamide) (PHPMA), and amine-functionalized poly­(N-(2-hydroxypropyl)­methacrylamide-co-N-(3-aminopropyl)­methacrylamide) P­(HPMA-co-APMA), we found that PHPMA end-functionalized with nitrile motifs generate spherical and stable AuNPs@PHPMA of very small size (diameter of ∼2.4 nm), as underlined by imaging experiments. Cell viability experiments indicated exceptionally good biocompatibility up to very high numerical particle concentrations as compared to the other systems. The reduced size imparted to the AuNPs@PHPMA outstanding catalytic properties (no induction time and high reaction rate constant for the hydrogenation of p-nitrophenol) and antimicrobial activity (total antibacterial activity against Escherichia coli and dose-dependent antibacterial activity against Staphylococcus aureus). The introduction of primary amine groups (13.4 mol %) of higher nucleophilicity known to work better for AuNP synthesis makes these unique features disappear, as evidenced for P­(HPMA-co-APMA). The other systems yielded 6–28 nm particles whose properties reflected both the size of the metallic core and chemical nature and conformation of the capping agent. These findings point to novel applications of PHPMA polymers worthy of further development, especially in light of their excellent water solubility and biocompatibility.

To effectively combat advanced cancers, next-generation nanomedicines should combine both therapeutic and diagnostic functions. In this study, we developed stimulus-responsive theranostics systems based on micellar nanostructures that deliver derivatives of tetraphenylporphyrins (TPP) bound via tumor microenvironment-sensitive hydrazone bonds. These nanomedicines are engineered using a micelle-forming polymer-TPP conjugate, enabling the pH-sensitive activation of both photodynamic therapy (PDT) and fluorescence. Two pH-sensitive and one stable polymer-TPP conjugates were synthesized and characterized by size exclusion chromatography and TPP release rates. Micelle stability was evaluated using UV/vis spectroscopy, while fluorescence and singlet oxygen production were measured to determine their theranostics potential. Femtosecond transient absorption and time-correlated single photon counting techniques were employed for the photophysical evaluation of micellar systems. Compared to polymer conjugates where TPP is linked through nondegradable amide bonds, the pH-sensitive systems exhibit superior physicochemical properties. These micellar conjugates are highly stable, allowing prolonged circulation in the body while remaining in an “off” state, where fluorescence and singlet oxygen production are minimized. Overall, the hydrazone-linked conjugates display favorable properties that make them strong candidates for future anticancer theranostic applications.

Background/Objectives: Photodynamic therapy (PDT) relies on light activation of photosensitizers to generate reactive oxygen species for tumor ablation; however, limited tumor selectivity and systemic toxicity of free photosensitizers remain challenges. This study aimed to develop polymer-based nanotheranostics carrying tetraphenylporphyrin (TPPc) derivatives and to evaluate how linker structure impacts their performance. Methods: TPPc derivatives were covalently conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymers via either pH-sensitive hydrazone linkages (using aliphatic 5-hydroxy-2-pentanone or aromatic 1-(4-hydroxymethyl)phenyl)ethanone spacer) or stable amide bonds, forming amphiphilic polymer conjugates. The conjugates were characterized based on their physicochemical and in vitro and in vivo biological behavior. Results: Polymer conjugation reduced dark toxicity while preserving photodynamic activity. Linker structure influenced intracellular behavior and singlet oxygen production, with hydrazone systems showing faster activation-related responses under acidic conditions in vitro. All conjugates accumulated in tumors and induced significant tumor growth inhibition after irradiation at low doses (2.5 mg kg⁻¹ TPPc equivalent), while the amide-linked conjugate showed the strongest overall in vivo therapeutic effect, likely due to more favorable biodistribution and sustained delivery. Conclusions: The developed HPMA-based polymer–TPPc conjugates improve the therapeutic profile of photosensitizers by reducing toxicity and enabling effective PDT. These findings highlight the importance of linker design in balancing photosensitizer activation, circulation stability, and biodistribution, which together determine the overall therapeutic outcome.