No abstract

No abstract

No abstract

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.

Acute myeloid leukemia (AML) is a malignant disorder of hematopoietic progenitor cells with a poor prognosis of 26% of patients surviving 5 years after diagnosis. Poor bioavailability and solubility are significant factors limiting the efficacy of chemopreventive agents. In AML, the epigenetic regulator polycomb group of protein member EZH2 is highly expressed and is essential for the survival of leukemic cells. An EZH2-specific inhibitor, EPZ011989, encapsulated in human serum albumin nanoparticles (HSANPs) was synthesized for the first time via the desolvation method. The noncovalent interactions between EPZ011989 and HSANPs in nanocomposites facilitating the efficient loading and sustainable release of the drug showed enhanced cellular uptake and nuclear localization of EPZ011989-loaded HSANPs in human AML cell lines. The reduction of cell viability, colony formation inhibition, cell cycle arrest at the G2/M phase, and cell proliferation assay promoting apoptosis through the loss of mitochondrial homeostasis exerting antileukemic activity were evident. The real-time polymerase chain reaction (PCR) and western blot-based studies showed that the present nanoformulation reduces the level of PcG proteins, including EZH2, BMI-1, etc. This downregulation is associated with reduced H3K27me3 and H2AK119ub modifications conferring chromatin compaction. The immunoprecipitation study showed the physical interaction of EZH2 and c-Myb can be linked to the regulation of leukemogenesis. Further investigation revealed the mechanism of EZH2 and c-Myb downregulation via ubiquitination and proteasomal degradation pathway, confirmed by using proteasome inhibitor, suggesting the key role of proteasomal degradation machinery. Moreover, c-Myb interacted with the EZH2 promoter, which is evident by the chromatin immunoprecipitation assay and siRNA silencing. Furthermore, the formulation of EPZ011989 in HSANPs improved its biodistribution in vivo and showed excellent aqueous dispersibility and biocompatibility. In vivo studies further showed that EPZ011989-loaded HSANPs reduce the expression of CD11b + and CD45 + markers in immunophenotyping from peripheral blood and bone marrow in engrafted nude mice. Targeted depletion of EZH2 alleviated the disease progression in nude mice and prolonged their survival. The findings provide valuable experimental evidence for the targeted epigenetic therapy of AML. The present results demonstrate an epigenetic regulation-based superior antileukemic therapy.