Tumor control by hypoxia-specific chemotargeting of iron-oxide nanoparticle – Berberine complexes in a mouse model

摘要

Abstract Aim To evaluate the therapeutic efficacy of hypoxic cell-sensitizer Sanazole (SAN) –directed targeting of cytotoxic drug Berberine (BBN) and Iron-oxide nanoparticle (NP) complexes, to solid tumor in Swiss albino mice. Main methods NP-BBN-SAN complexes were characterized by FTIR, XRD, TEM and Nano-size analyzer. This complex was orally administered to mice-bearing solid tumor in hind limb. Tumor regression was analysed by measuring tumor volume. Cellular DNA damages were assessed by comet assay. Transcriptional expression of genes related to tumor hypoxia and apoptosis was evaluated by quantitative real-time PCR and morphological changes in tissues were analysed by histopathology. Also levels of antioxidants and tumor markers in tissues and serum biochemical parameters were analysed. Key findings Administration of NP-BBN-SAN complexes reduced tumor volume and studies were focussed on the underlying mechanisms. Extensive damage to cellular-DNA; down-regulated transcription of hif-1α, vegf, akt and bcl2 ; and up-regulated expression of bax and caspases, were observed in tumor. Results on tumor markers, antioxidant-status and serum parameters corroborated the molecular findings. Histopathology of tumor, liver and kidney revealed the therapeutic specificity of NP-BBN-SAN. Significance Thus SAN and NP can be used for specific targeting of drugs, to hypoxic solid tumor, to improve therapeutic efficacy. Graphical abstract The administration of NP-BBN-SAN complexes is found to down regulate the expression of genes responsible for hypoxia-induced tumor progression. Further the complexes initiates the up regulation of apoptotic genes' expression. It causes apoptosis in tumor, which is further evidenced from histopathology, and leads to tumor regression. SAN has the capability to accumulate in hypoxic area of tumor, hence it directs the cytotoxic drug BBN in the complexes to tumor to facilitate tumor regression. Histopathology of Liver and Kidney of these animals are appeared normal which is a major evidence for treatment specificity. NP- Iron-oxide nanoparticles, BBN- Berberine, SAN- Sanazole, hif-1alpha: hypoxia inducible factor-1 alpha, vegf: vascular endothelial growth factor, akt . protein kinase B, bcl2: B-cell lymphoma 2, bax: bcl2-associated X protein, GPx: glutathione peroxidase, GSH: glutathione, SOD- superoxidde dismutase, MDA- malodialdehyde. Display Omitted