Radiotherapy (RT) is the primary standard of care for many locally advanced cancers. Often times, however, the efficacy of RT is limited due to radio-resistance that cancer cells develop. Photodynamic therapy (PDT) has gained importance as an alternative local therapy. Because its mechanism involves minimal acquired resistance, PDT is a useful adjunct to RT. This review discusses recent advances in combining RT with PDT for cancer treatment. In the first part of this review, we will discuss clinical trials on RT + PDT combination therapies. All these approaches suffer from the same inherent limitations as any current PDT methods; (i) visible light has a short penetration depth in human tissue (<∼10 mm), and (ii) it is difficult to illuminate the entire tumor homogeneously by external/interstitial laser irradiation. To address these limitations, scintillating nanoparticle-mediated RT-PDT approaches have been explored in which nanoparticles convert X-rays (RT) into visible light (PDT); high-energy X-rays can reach deep into the body to irradiate cancers uniformly and precisely. The second part of this review will discuss recent efforts in developing and applying nanoparticles for RT-PDT applications.

Photodynamic therapy (PDT) has shown potential as a cancer treatment modality, but its clinical application is limited due to its visible-light activation since visible wavelengths of light cannot penetrate tissues well. Additionally, combination therapies utilizing PDT and radiotherapy have shown clinical promise in several cancers but are limited again by light penetration and the need for selective photosensitization of the treatment area. Herein, we report the development of bilirubin-photodynamic nanoparticles (PEGylated bilirubin-encapsulated CaWO4 nanoparticles or “PEG-BR/CWO NPs”). PEG-BR/CWO NPs are a formulation of PEGylated bilirubin micelles encapsulating CaWO4 nanoparticles. These particles are capable of activating PDT via X-ray irradiation within deep tissues due to the radioluminescence properties of their CaWO4 nanoparticle cores. PEG-BR/CWO NPs facilitate a combination of photodynamic and radiation therapy and represent a previously unexplored application of PEG-bilirubin conjugates as photosensitizing agents. When irradiated by X-rays, PEG-BR/CWO NPs emit UV-A and visible light from their CaWO4 cores, which excites bilirubin and leads to the production of singlet oxygen. PEG-BR/CWO NPs exhibit improvements over X-ray therapy alone in vitro and in murine xenograft models of head and neck cancer. The data presented in this study indicate that PEG-BR/CWO NPs are promising agents for facilitating combined radio-photodynamic therapy in deep tissue tumors.

Extensive studies have been conducted to elucidate the effects of such parameters as molecular weight, polydispersity, and composition on the controlled release properties of poly(D,Llactic-co-glycolic acid) (PLGA). However, studies dealing with the effect of monomer sequence distribution have been sparse mainly because of the difficulty of precisely controlling the monomer sequence in PLGA. Herein, we present a semibatch copolymerization strategy that enables the production of statistically sequencecontrolled "uniform PLGA" polymers through control of the rate of comonomer addition. Using this method, a series of PEG− PLGA samples having a comparable molecular weight and composition but different sequence distributions (uniform vs gradient) were prepared. The properties of these materials (PEG crystallization/melting, hygroscopicity, aqueous sol−gel transition, drug release kinetics) were found to significantly vary, demonstrating that sequence control only at the statistical level still significantly influences the properties of PLGA. Most notably, uniform PLGA exhibited the more sustained drug release behavior compared to gradient PLGA.

Previous studies have shown that calcium tungstate (CaWO 4 ) nanoparticles (NPs) can be used as a radiosensitizing/Xray contrast agent for cancer treatment. However, due to the propensity of calcium tungstate to agglomerate in physiological solutions, there is a need to encapsulate these NPs within poly(ethylene glycol)-poly(D,L-lactic acid) (PEG−PLA) polymeric micelles through a solvent exchange process. Several parameters including solvent type, polymer to NP ratio, mixing method, and lyophilization were studied to optimize the encapsulation and storage procedures for future scale-up. Herein, we report that the cosolvent that was previously used in this procedure (dimethylformamide) can be replaced with a less toxic cosolvent (acetone), the polymer to NP ratio can be reduced from 600:1 to 50:1 without increasing the particle size by 20%, and mixing methods that create a more uniform flow field produce a more homogenous and less polydisperse particle distribution. In addition, our results indicate that sucrose as a lyophilization excipient produces less agglomeration during freeze-drying compared to mannitol. The smaller molecular weight 2 kDa and 2 kDa ("2 k−2 k") PEG−PLA was less prone to agglomeration during freeze-drying compared to 5 k−5 k PEG−PLA.