Hypericin-Loaded Transferrin Nanoparticles Induce PP2A-Regulated BMI1 Degradation in Colorectal Cancer-Specific Chemo-Photodynamic Therapy

Abstract

Epigenetically regulated therapeutic intervention of cancer is an emerging era of research in the development of a promising therapy. Epigenetic changes are intrinsically reversible and providing the driving force to drug resistance in colorectal cancer (CRC). The regulation of polycomb group (PcG) proteins, BMI1 and EZH2, and the associated CRC progression hold promises for a novel treatment regime. The present study enlightens targeted photodynamic therapy (PDT) with potential photosensitizer hypericin nanocomposite in the development of epigenetic-based CRC therapy. We have synthesized hypericin-loaded transferrin nanoformulations (HTfNPs) overcoming the compromised hydrophobicity and poor bioavailability of the placebo drug. Targeted PDT with hypericin nanocomposite-induced BMI1 degradation assisted CRC retardation. In the present study, transferrin nanoparticles were reported to control the premature release of hypericin and improve its availability with better targeting at the disease site. Targeted intracellular internalization to colon cancer cells having a differential expression of transferrin receptors, in vivo biodistribution, stability, and pharmacokinetics provide promising applications in the nanodelivery system. Indeed, in vitro anticancer efficiency, cell cycle arrest at the G0/G1 phase, and elevated reactive oxygen species (ROS) generation confirm the anticancer effect of nanoformulation. In the exploration of mechanism, nanotherapeutic intervention by activation of PP2A, Caspase3 and inhibition of BMI1, EZH2, 3Pk, NFκB was evident. An exciting outcome of this study uncovered the camouflaged role of PP2A in the regulation of BMI1. PP2A mediates the ubiquitination/degradation of BMI1, which is revealed by changes in the physical interaction of PP2A and BMI1. Our study confirms the anticancer effect of HTfNP-assisted PDT by inducing PP2A-mediated BMI1 ubiquitination/degradation demonstrating an epigenetic-driven nanotherapeutic approach in CRC treatment.

Photodynamic diagnosis and photodynamic therapy of colorectal cancer in vitro and in vivo

“…92 Whereas, studies by Sardoiwala et al (2020) synthesized a hypericin-loaded transferrin nanoformulation (HTfNPs) composite, to overcome the PSs hydrophobicity and poor bioavailability, as well as serve as a PDT epigenetic-based CRC therapy. 93 This transferrin targeted PDT signicantly induced BMI1 degradation assisted CRC in vitro cell retardation, as well as improved hypericin's availability at diseased sites. 93 However, concerningly studies by Kaleta-Richter et al (2020) noted that hypericin-mediated PDT, stimulates release of interleukin-8 and -10 in CRC, which is responsible for the progression of cancer and metastasis.…”

“…93 This transferrin targeted PDT signicantly induced BMI1 degradation assisted CRC in vitro cell retardation, as well as improved hypericin's availability at diseased sites. 93 However, concerningly studies by Kaleta-Richter et al (2020) noted that hypericin-mediated PDT, stimulates release of interleukin-8 and -10 in CRC, which is responsible for the progression of cancer and metastasis. 74 Thus, PDT applications with third-generation hypericin PS, seems rather controversial and no studies noting its application in effective CRC PDD were found.…”

Nanoparticle-Mediated Delivery Systems in Photodynamic Therapy of Colorectal Cancer

“…Some of the widely investigated receptors and possible targets for CRC PDT include the epidermal growth factor receptor (EGFR), transferrin receptors, fibroblast growth factor receptors (FGFR), and the epithelial cell-adhesion molecule (EpCAM), among others [13]. For example, the transferrin receptor (CD71) is generally expressed to regulate iron homeostasis within normal human cells, however, malignant tumours are often found to express abnormal levels of expression of the transferrin receptor (CD71), which may be targeted by antibodies in targeted PDT [92]. In one study, Sardoiwala et al [92] synthesised hypericin-loaded transferrin nanoformulations (HTfNPs) for the treatment of colorectal cancer [92].…”

Current Landscape in Organic Nanosized Materials Advances for Improved Management of Colorectal Cancer Patients

“…Iron is vital for cell proliferation, and due to the increased need of tumors for nutrients, including iron, the overexpression of TFR1 is identified in cancer patients including CRC [ 94 , 95 ]. While the abundance of TFR1 impacts colorectal cancer cell proliferation rates [ 96 ], this is particularity appealing for engineering nanoparticles in CRC-targeted therapy by surface functionalization with TFR’s natural ligand transferrin [ 97 , 98 , 99 , 100 ].…”