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Abstract: Biocompatibility studies and cancer therapeutic applications of nanoparticulate β-emitting gold-198 (198Au; βmax = 0.96 MeV; half-life of 2.7 days) are described. Gum arabic glycoprotein (GA)–functionalized gold nanoparticles (AuNPs) possess optimum sizes (12–18 nm core diameter and 85 nm hydrodynamic diameter) to target individual tumor cells and penetrate through tumor vasculature and pores. We report the results of detailed in vivo therapeutic investigations demonstrating the high tumor affinity of GA-198AuNPs in severely compromised immunodeficient (SCID) mice bearing human prostate tumor xenografts. Intratumoral administration of a single dose of β-emitting GA-198AuNPs (70 Gy) resulted in clinically significant tumor regression and effective control in the growth of prostate tumors over 30 days. Three weeks after administration of GA-198AuNPs, tumor volumes for the treated animals were 82% smaller as compared with tumor volume of control group. The treatment group showed only transitory weight loss in sharp contrast to the tumor-bearing control group, which underwent substantial weight loss. Pharmacokinetic studies have provided unequivocal evidence for the optimum retention of therapeutic payload of GA-198AuNPs within the tumor site throughout the treatment regimen with minimal or no leakage of radioactivity to various nontarget organs. The measurements of white and red blood cells, platelets, and lymphocytes within the treatment group resembled those of the normal SCID mice, thus providing further evidence on the therapeutic efficacy and concomitant in vivo tolerance and nontoxic features of GA-198AuNPs. From the Clinical Editor: In this study, the biocompatibility and cancer therapeutic applications of glycoprotein (GA) functionalized gold nanoparticles containing b-emitting Au-198 are described in SCID mice bearing human prostate tumor xenografts. The findings of significant therapeutic efficacy, good in vivo tolerance and non-toxic features make these particles ideal candidates for future human applications. [Copyright &y& Elsevier]

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality with the 5-year survival rate at a dismal 16% for the past 40 years. Drug resistance is a major obstacle to achieving long-term patient survival. Identifying and validating molecular biomarkers responsible for resistance and thereby adopting multi-directional therapy is necessary to improve the survival rate. Previous studies indicated ~20% of tyrosine kinase inhibitor (TKI) resistant NSCLC patients overexpress AXL with increase in EMT and decrease in p53 expression. To overcome the resistance, we designed gelatin nanoparticles covalently conjugated with EGFR targeting antibody and siRNA (GAbsiAXL). GAbsiAXL efficiently silences AXL, decreases mTOR and EMT signaling with concomitant increase in p53 expression. Because of the molecular changes, the AXL silencing sensitizes the cells to TKI. Our results show AXL overexpression has an important role in driving TKI resistance through close association with energy-dependent mitochondrial pathways. Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality with the 5-year survival rate remains a dismal 16% for the past 40 years. Drug resistance is a major obstacle to achieving long-term patient survival. Identifying the various molecular determinants of resistance and thereby adopting multi-drug therapy is necessary to improve the survival rate. Previous studies indicated TKI resistant NSCLC, overexpress AXL with increase in EMT and decrease in p53 tumor suppressor protein. To overcome the resistance, we designed gelatin nanoparticle covalently conjugated with EGFR antibody and siRNA (GAbsiAXL). Our studies showed that GAbsiAXL efficiently silences AXL in cells. Treatment of drug-resistant cells with GAbsiAXL reduces mTOR and EMT signaling with concomitant increase in p53 expression. Because of the molecular changes, the AXL silencing sensitizes the cell to TKI by 2-fold. Our results show AXL overexpression has an important role in driving TKI resistance through close association with energy-dependent mitochondrial pathways. Unlabelled Image [ABSTRACT FROM AUTHOR]