Tumor control by hypoxia-specific chemotargeting of iron-oxide nanoparticle – Berberine complexes in a mouse model
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.
Section snippets
Background
Success of chemotherapy is often limited by systemic toxicities and side effects. One of the means of overcoming these problems of antineopalstic agents is to deliver the drugs at the tumor site. Hypoxic region in tumor supports not only tumor growth but also resistance to major therapies such as chemotherapy and radiation. The major cellular adaptive response under the reduced oxygen state in tumor tissues is the expression of hypoxia-inducible factor-1 (HIF-1). HIF-1 is a DNA-binding protein
Chemicals
FeCl2, FeCl3, Chloroform and Isoamyl alcohol were bought from Merk, India. Berberine, chemicals for RNA isolation, β-D Glucuronidase, Brij and O-Dianisidine were purchased from Sigma Aldrich, India. Sanazole (AK2123) was obtained from Dr. V.T.Kagiya, Health Research Foundation, Kyoto, Japan. All other chemicals were obtained from reputed national manufactures (Otto Chemie Pvt. Ltd. and Himedia Pvt. Laboratories Ltd).
Animals
Female Swiss albino mice weighing 24-28 g were purchased from Small Animal
Characterization of NPs and NP-drug complexes
The characteristics of Fe3O4 nanoparticles (magnetite) prepared by co-precipitation method and its complexes with BBN and SAN were evaluated by FTIR, XRD, TEM and Size analysis. As shown in Fig. 1, FTIR measurements was recorded in the range of 500–4000 cm− 1. The strong peak at 3404.59 cm− 1 in NP was indicated the presence of –OH stretch in the nanoparticles. A peak observed around 2843 cm− 1in BBN could be allotted to CH stretching vibrations of methoxy group in BBN. The peak located around 1504 cm−
Discussion
The uncontrolled rapid proliferation of tumor cells confers special microenvironment in the tissues of tumors due to inadequate vasculature, hypoxia, lower nutrient status as well as drainage of cellular metabolic toxins. This would manifest in altered gene expression and metabolism in tumor tissues, drug resistance and therapeutic availability of administered chemotherapeutics leading to dose escalation and the resultant systemic toxicity. Tumor targeted delivery of therapeutics is the best
Conclusion
NP-BBN-SAN complexes were found to be more effective in reducing tumor volume compared to the other treatments. The mechanism behind the tumor regression can be ascribed to i) the down regulation in the transcription of hif-1α and its associated genes- vegf and akt, thereby resulting in tumor regression and ii) tnf-α induced extrinsic pathway of apoptosis through caspase 8, although other apoptotic pathways also may be involved. The present study convincingly demonstrates clinical relevance and
Acknowledgements
The authors thank University Grants Commission (UGC), Government of India for senior research fellowship to SS. The authors thank Dr. M.O. Annamma, Head, Department of Pathology, Pushpagiri Institute of Medical Sciences and Research Centre, Thiruvalla for histopathology analysis, Sreekanth K Mahadeva and K V Rao, Department of Materials Science and Engineering, Royal Institute of Technology Stockholm, Sweden; Dr. Jacob Varkey, Rubber Research Institute, Kottayam and Dr. Nandakumar, School of
Funding source
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors except senior research fellowship from University Grants Commission, Government of India to one of the authors (SS).
Conflict of interest
None.
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