Combining Radiotherapy (RT) and Photodynamic Therapy (PDT): Clinical Studies on Conventional RT-PDT Approaches and Novel Nanoparticle-Based RT-PDT Approaches under Preclinical Evaluation

Abstract

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.

Radiation-induced photodynamic therapy using calcium tungstate nanoparticles and 5-aminolevulinic acid prodrug

“…Biomaterials Science ability to overcome radio-resistance can be attributed to the ability of RT-PDT to induce cell death through necrosis or P53independent apoptosis. 7 ALA metabolization to PPIX occurs in the mitochondria, resulting in subcellular localization of PPIX in the mitochondria or cytoplasm. 10 Consequently, 1 O 2 that is produced during PDT can oxidize the mitochondrial or cell membrane, respectively.…”

“…Photodynamic therapy (PDT) has emerged as an optimal candidate due to its highly localized effects and ability to kill cancer cells primarily through membrane damage rather than DNA damage. 7 5-Aminolevulinic acid (ALA) and protoporphyrin IX (PPIX) are endogenous compounds formed along the heme synthesis pathway. The conversion of the penultimate intermediate, PPIX, to heme is catalyzed by the enzyme ferrochelatase.…”

“…17 However, the application of this technique to treat subcutaneous tumors has been limited due to the inadequate penetration depth of visible light photons in tissue. 7 An emerging treatment strategy involves the use of radiotherapy, particularly X-rays, to activate photodynamic therapy using nanoparticles as in situ energy transducers. 7 This combination approach addresses the limitations of both treatment modalities; X-rays from external beam radiation can penetrate tissue more effectively than visible light, and the resulting photodynamic effect can effectively eliminate radio-resistant cancer cells.…”

“…7 An emerging treatment strategy involves the use of radiotherapy, particularly X-rays, to activate photodynamic therapy using nanoparticles as in situ energy transducers. 7 This combination approach addresses the limitations of both treatment modalities; X-rays from external beam radiation can penetrate tissue more effectively than visible light, and the resulting photodynamic effect can effectively eliminate radio-resistant cancer cells. We herein report the development of poly(ethylene glycol-b-lactic acid) (PEG-PLA)-coated calcium tungstate (CaWO 4 , CWO for short) nanoparticles (PEG-PLA/CWO NPs) as energy transducers for X-ray-activated PDT (RT-PDT) using ALA as illustrated in Fig.…”

“…Photodynamic therapy (PDT) has emerged as an optimal candidate due to its highly localized effects and ability to kill cancer cells primarily through membrane damage rather than DNA damage. 7…”