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.
Covalently bonded
Eudragit S-100 (EU) and chitosan (CS) based colon-specific
nanoparticles (CSE NPs) were fabricated as drug carriers for treating
colorectal cancers through oral administration. Thiolation of EU and
CS prevents the usage of the cross-linking agent. This gives an advantage
over the shortcomings of existing EU- and CS-based delivery systems
that are associated with large sized nanoparticles with a broad range
of size distribution. Paclitaxel (PTX)-loaded CSE NPs presented an
efficacy of 8–10% after 48 h of treatment on the HCT 116 cell
line signifying uniform distribution of drug inside the cells. About
66% accumulation of cell population was observed in G2/M phase for
PTX-loaded CSE NPs, indicating arrest of cell division during the
mitotic phase. Biodistribution studies on male Balb/C mice demonstrated
retention of CSE NPs in the colon region up to 24 h post oral administration.
These findings confer a convenient and effective way for preparing
CS- and EU-based drug delivery systems with sustained release and
target specificity for colorectal cancers.
The imbalance in the bone remodeling process with more bone resorption by osteoclasts compared to bone formation by osteoblasts results in a metabolic bone disorder known as osteoporosis. This condition reduces the bone mineral density and increases the risk of fractures due to low bone mass and disrupted bone microarchitecture. Osteoclastogenesis increases when the receptor activator NFκB ligand (RANKL) on the osteoblast surface binds to the receptor activator NFκB (RANK) on the osteoclast surface and the function of the decoy receptor of RANKL, osteoprotegrin, is compromised due to external stimuli such as heparin and lipopolysaccharides. The RANK/RANKL axis promotes the nuclear factor kappa B (NFκB) expression, which in turn increases the histone methyltransferase activity of EzH2 and EzH1 for the epigenetic regulation of osteoclastogenesis-related genes. Genistein counteracts NFκB-induced osteoclastogenesis and downstream signaling through the direct regulation of histone methyltransferase, EzH2 and EzH1, transcription. However, genistein possesses limitations like low bioavailability, low water solubility, high estrogen activity, and thyroid side effects, which obstruct its therapeutic usage. Here, the nanoemulsified formulation of genistein with vitamin D was utilized to circumvent the limitations of genistein so that it can be utilized for therapeutic purposes in osteoporosis management. The nanoemulsification of genistein and vitamin D was performed through the spontaneous emulsification using Tween 80 and medium chain triglyceride oil as an organic phase. The physiologically stable and biocompatible combination of the genistein and vitamin D nanoemulsion (GVNE) exhibited the controlled release pattern of genistein with Korsmeyer−Peppas and Higuchi models under different pH conditions (7.4, 6.5, and 1.2). The GVNE potentially enhanced the therapeutic efficacy under in vitro osteoporosis models and helped restore disease parameters like alkaline phosphatase activity, tartrate-resistant acid phosphatase activity, and the formation of multinuclear giant cells. Molecularly, the GVNE overturned the LPS-induced osteoclastogenesis by downregulation of NFκB expression along with its binding on EzH2 and EzH1 promoters. GVNE effects on the osteoporosis model established it as an efficient antiosteoporotic therapy. This nanonutraceutical-based formulation provides an epigenetic regulation of osteoporosis management and opens new avenues for alternate epigenetic therapies for osteoporosis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.