Photodynamic therapy (PDT) is widely used to treat diverse diseases, but its dependence on oxygen to produce cytotoxic reactive oxygen species (ROS) diminishes the therapeutic effect in a hypoxic environment such as solid tumors. Here, we developed a ROS-producing hybrid nanoparticle-based photosensitizer capable of maintaining high levels of ROS under both normoxic and hypoxic conditions. Conjugation of an organometallic ruthenium complex (N3) to a TiO2 nanoparticle afforded TiO2-N3. Upon exposure of TiO2-N3 to light, the N3 injected electrons into TiO2 to produce three- and four-fold greater hydroxyl radicals and hydrogen peroxide, respectively, than TiO2 at 160 mmHg. TiO2-N3 maintained three-fold higher hydroxyl radicals than TiO2 under hypoxic conditions via N3-facilitated electron hole reduction of adsorbed water molecules. The incorporation of N3 transformed TiO2 from a dual type I and II PDT agent to a predominantly type I photosensitizer, irrespective of the oxygen content.

Reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a series of copolymers consisting of 2-hdroxyethyl methacrylate (HEMA) and poly(ethylene glycol) methyl ether methacrylate (FWavg ~ 950 Da) (O950) with variable comonomer compositions and molecular weights for use as polymeric scaffolds. Reactivity ratios for the monomer pair were determined to be 1.37 and 0.290 respectively. To these scaffolds trithiocarbonate-based RAFT chain transfer agents (CTAs) were grafted using carbodiimide chemistry. The resultant graft chain transfer agents (gCTA) were subsequently employed to polymerize dimethylaminoethyl methacrylate (DMAEMA) and (HPMA) between degrees of polymerization (DP) of 25 and 200. Kinetic analysis for the polymerization of DMAEMA targeting a DP of 100 from a 34 arm graft gCTA show linear Mn conversion and pseudo first order rate plots with narrow molecular weight distributions that move toward lower elution volumes with monomer conversion. Đ values for these polymerizations remain low at around 1.20 at monomer conversions as high as 70 %. pH-responsive endosomalytic brushes capable of spontaneously self-assembling into polymersomes were synthesized and a combination of dynamic light scattering (DLS), cryoTEM, and red blood cell hemolysis were employed to evaluate the aqueous solution properties of the polymeric brush as a function of pH. Successful encapsulation of ceftazidime and pH-dependent drug release properties were confirmed by HPLC. Intracellular antibiotic activity of the drug-loaded polymersomes was confirmed in a macrophage coculture model of infection with B. thailandensis and RAW 264.7 cells.