Development of MOF “Armor‐Plated” Phycocyanin and Synergistic Inhibition of Cellular Respiration for Hypoxic Photodynamic Therapy in Patient‐Derived Xenograft Models

Abstract

Significant progress has been made in the use of phycocyanin (PC) as a photosensitizer (PS) agent for photodynamic therapy (PDT). The clinical use of PC, however, has been limited by its poor stability, unfavorable pharmacokinetics, limited tumor cell uptake, and the hypoxic nature of the tumor microenvironment. In this study, a novel biomimetic mineralization approach is described for encapsulating PC using zeolitic imidazolate framework-8 (ZIF-8), after which MPEG 2000-COOH is further utilized as an anchor on the ZIF/PC complex in order to yield MPEG 2000-ZIF/PC composites (PMs). These PMs are then used as a stable reinforced PS for PDT, effectively improving the intracellular delivery of this protein PS. In contrast to prior studies that have sought to overcome intratumoral hypoxia via increasing oxygen delivery to the tumor site, the mitochondrial complex I inhibitor papaverine (PPV) is instead utilized to reduce intratumor oxygen consumption in an effort to augment the PDT efficacy of the PMs. It is found that this combination treatment strategy markedly improves the antitumor properties of these PMs both in vitro and in patient-derived xenograft (PDX) models without inducing significant side effects. It is therefore proposed that the "armor-plating" of protein PS agents with ZIF-8 in combination with PPV may be a promising approach to precision medicine-mediated tumor treatment.

Phycobiliproteins: Structural aspects, functional characteristics, and biotechnological perspectives

“…In this context, the electrospraying method showed high encapsulation efficiency of phycocyanin [159] , with especial emphasis on the food industry. In addition, other techniques have been applied in the last years for the microencapsulation of phycocyanin [160] , [161] , [162] , [163] , [164] in order to increase its stability. Nevertheless, a specific delivery of the PBPs should ensure its bioactivity in the target cells or tissues, especially for the treatment of tumor cells or other diseases in humans.…”

Recent Advances in Strategies for Addressing Hypoxia in Tumor Photodynamic Therapy

“…Although tumors acquire energy predominantly via the “Warburg effect” [ 59 ], seriously accelerated OXPHOS was still observed in considerable malignant cell lines during tumorigenesis, development, and metastasis [ 60 , 61 ]. Consequently, diverse mitochondria respiratory chain inhibitors, including α-tocopherol succinate [ 62 ], papaverine [ 63 ], atovaquone [ 64 , 65 , 66 , 67 , 68 ], tamoxifen [ 69 , 70 ], metformin [ 71 , 72 , 73 , 74 , 75 , 76 , 77 ], and nitric oxide (NO) [ 78 , 79 , 80 , 81 ], have been used for reducing oxygen consumption and increasing PDT efficiency. For example, a nanoplatform was prepared through incorporating L-Arginine and a photosensitizer chlorin e6 with poly-lactic-co-glycolic acid (PLGA) ( Figure 6 ) [ 79 ].…”

Metal-Organic Frameworks and Their Composites Towards Biomedical Applications

“…Other O 2 -evolving approaches such as MOF-nanozyme composites, including Au@ZIF-8 (Ma et al, 2019) and PCN-224-Pt (Zhang et al, 2018d) nanostructures, were also able to overcome the hypoxic conditions and improve the PDT efficiency. In contrast, to improve the O 2 supply, Chen et al introduced another ZIF/PC complex, in which mitochondrial complex I inhibitor papaverine (PPV) was encapsulated and delivered to the tumor to reduce the intratumor oxygen consumption (Chen et al, 2021). As highlevel GSH would also reduce the PDT effect, MOF-2 was designed with Cu(II) as an active center to absorb and lower GSH and then enhanced PDT (Zhang et al, 2018c).…”