Application of Mitochondrially Targeted Nanoconstructs to Neoadjuvant X-ray-Induced Photodynamic Therapy for Rectal Cancer

Abstract

In this work, we brought together two existing clinical techniques used in cancer treatmentX-ray radiation and photodynamic therapy (PDT), whose combination termed X-PDT uniquely allows PDT to be therapeutically effective in deep tissue. To this end, we developed mitochondrially targeted biodegradable polymer poly(lactic-co-glycolic acid) nanocarriers incorporating a photosensitizer verteporfin, ultrasmall (2−5 nm) gold nanoparticles as radiation enhancers, and triphenylphosphonium acting as the mitochondrial targeting moiety. The average size of the nanocarriers was about 160 nm. Upon X-ray radiation our nanocarriers generated cytotoxic amounts of singlet oxygen within the mitochondria, triggering the loss of membrane potential and mitochondria-related apoptosis of cancer cells. Our X-PDT strategy effectively controlled tumor growth with only a fraction of radiotherapy dose (4 Gy) and improved the survival rate of a mouse model bearing colorectal cancer cells. In vivo data indicate that our X-PDT treatment is cytoreductive, antiproliferative, and profibrotic. The nanocarriers induce radiosensitization effectively, which makes it possible to amplify the effects of radiation. A radiation dose of 4 Gy combined with our nanocarriers allows equivalent control of tumor growth as 12 Gy of radiation, but with greatly reduced radiation side effects (significant weight loss and resultant death).

Oxygen-Carrying Polymer Nanoconstructs for Radiodynamic Therapy of Deep Hypoxic Malignant Tumors

“…In addition to the cytotoxic action of ROS on blood vessels, PDT directly affects cancer cells by destabilization of cell membranes, enhancement of autophagy and apoptosis [ 27 ]. The efficiency of VP-aided PDT was demonstrated in various experimental models of mammary carcinoma [ 28 , 29 ], pancreatic [ 30 ] and colorectal [ 23 , 31 , 32 ] cancers, glioblastoma [ 33 ] and some other malignancies (see references in [ 34 ]). Clinical application of VP for PDT was reported for the eye, pancreatic and skin cancer [ 1 , 35 ].…”

“…The choice of VP was especially strongly motivated by our own recent results indicating a novel mechanism of light-independent triggering of PS activity of VP by clinically relevant dose of X-rays [ 19 , 23 , 31 , 32 ]. Shifting from the visible light to X-rays as initiators of ROS generation (such as PDT to RDT), allows to overcome the tissue penetration depth limit of conventional PDT [ 14 , 15 , 16 ].…”

Recent Advances in Photodynamic Therapy for Deep-Seated Tumors with the Aid of Nanomedicine

“…Deng et al proposed a platform using PLGA vesicles to carry PS verteporfin and gold NPs (2–5 nm) together for efficient energy transfer between the PS and Au NPs. The NPs showed excellent results in PDT with a low dose of radiation (4 Gy) [ 53 ]. PS-modified α-Zn 2 SiO 4 -doped silica NPs were also used to emit X-ray-excited optical luminescence (XEOL).…”

Pathological and Pharmacological Roles of Mitochondrial Reactive Oxygen Species in Malignant Neoplasms: Therapies Involving Chemical Compounds, Natural Products, and Photosensitizers

“…Similarly, other investigators have shown that verteporfin with 690 nm laser irradiation induced specific and severe damage to the mitochondrial membrane in astrocytes with elevated mROS generation [ 26 ]. PDT with verteporfin has been effective in various types of cancers such as gastric cancer, rectal cancer, and breast cancer [ 154 , 155 , 156 ]. Intracellular ROS production plays a crucial role in the anticancer effects of second-generation photosensitizers and its safety has been investigated in various types of malignant tumors [ 149 , 157 , 158 , 159 , 160 ].…”