الفهرس 
Introduction and aim of the workOnly 14 pages are availabe for public view
Abstract
Drug delivery systems-based nanotechnology are considered as one of the most promising platforms for cancer chemotherapy due to their distinctive physicochemical and biological characteristics. In this study, we have designed three biocompatible stimuli- responsive nanocarriers to deliver doxorubicin (DOX) as a drug model for tumor chemotherapy. The first nanocarrier was chitosan grafted NIPAM copolymerized with acrylic acid as a dual pH and thermo-sensitive nanogel. The second nanocarrier was chitosan as a natural pH sensitive polymer. The third nanocarrier was ZIF-8 as synthetic coordination polymer. The characteristics of these nanocarriers were studied using FTIR, XRD, EDX, TEM, SEM and Zeta-potential analyses. In addition, the cytotoxic effects of DOX loaded these nanocarriers against MCF-7 and HepG2 cell lines were evaluated in vitro. In view of the efficient accumulation and penetration of nanocarriers into tumor tissues and the intracellular DOX release, targeted delivery of DOX@nanogel, DOX@nanoCS and DOX@ZIF-8 were performed to evaluate their in vivo anticancer effect against EAC bearing mice. These evaluations were based on assessment of body weight change, cell viability, liver, kidney and heart functions and antioxidants assays on both heart and liver tissues. The assessment also involves flow cytometric assays to study the mechanism of cell death and heart pathology to evaluate DOX cardiotoxicity and to study the possible protective effects of these nanocarriers against DOX carditoxicity.
The results showed that DOX loaded nanocarriers exhibited more anticancer activity than free DOX and enhanced the mean survival rate of EAC mice. Further, the nanocarriers retard oxidative stress elevation, suppress lipid peroxidation and NO formation induced by the free dose of DOX administration. The nanogel compensate for hepatic DNA deterioration, liver and cardiac enzymes elevations as well as renal complications. The results of the cell cycle and apoptosis revealed that, treatment of EAC inoculated mice with DOX loaded on each nanocarrier enhanced the accumulation of the EAC cells in sub G1 and G0/G1 phases comparing to that of the free DOX. This was followed by the reduction in the number of the cells at S and G2/M phases and ultimately activated apoptosis process more than free DOX. This was manifested by the elevation of p53 as a tumor suppressor gene and Caspas-3 activity with simultaneous reduction in Bcl-2 anti-apoptotic protein level in all treated groups when compared to those of the free DOX group. This study concluded that the use of responsive nanocarriers as drug delivery systems for chemotherapeutic agents not only improve the overall pharmacological properties of commonly used drugs in chemotherapy but also protect the major organs from cytotoxic effects of these chemotherapy.