Implications of Molecular Signaling in Therapeutic Efficacy of Nanodrug Delivery Systems in Cancer Model

Abstract

Acute Myeloid Leukemia (AML) presents significant clinical challenges due to its heterogeneous molecular profile and the limitations of traditional chemotherapy, which often result in inadequate efficacy and high toxicity. This research has been conducted to address these issues by exploring the potential of nanomedicines, combined with doxorubicin, to enhance therapeutic outcomes and reduce adverse effects in AML treatment. . This multidisciplinary study explores the combined efficacy of three different test compounds — caffeine-coated nanoparticles (CcNPs), copper diethyldithiocarbamate (CuET) nanoparticles, and nickel diethyldithiocarbamate (NiET) nanoparticles — as adjuncts to doxorubicin in the treatment of AML. Our research unfolds the anti-leukemic properties of these nanoparticles using a variety of investigative methodologies, including in silico, in vitro, and in vivo assays.. In silico docking studies act as a foundational scaffold, revealing the molecular complexities of nanoparticle interactions with critical cellular targets. Complementing these computational efforts are in vitro antioxidant assays, which provide insight into the nanoparticles' potential for modulating oxidative stress—an important aspect in AML pathogenesis. In vivo experimentation with AML rat models demonstrates the profound impact of nanoparticles, particularly when combined with doxorubicin. Our findings suggest that CcNP, CuET and NiET nanoparticles, when combined with doxorubicin, could be viable transformative therapeutic approaches in AML. These nanomedicines especially CcNPs act as potent inducers of the TRAIL-DR5 complex while also inhibiting the NF-kB p52/RelB/DNA complex. This dual action suggests their potential for reshaping the AML treatment landscape by targeting specific molecular pathways involved in leukemia progression. Moreover, their ability to modulate specific molecular pathways, improve treatment efficacy, and potential mitigation of the risks associated with conventional chemotherapies is a hallmark of their potential. Notably, the combination therapies have a significant impact on key leukemic genetic markers, specifically the downregulation of STMN1 and S1009A expressions, as well as xii Abstract the restoration of aberrant Wnt and HIF-1 alpha pathway gene expressions. The potent efficacy of these combination therapies is further supported by Annexin V/PI based apoptosis detection and CD4 viability tests, which highlight their significant potential against leukemic cells owing to enhanced intermolecular interaction of test compounds with CD33+ myeloid cells. This study heralds a new era in AML therapeutics, urging further clinical investigation to confirm their efficacy and safety profiles. The tantalizing prospect of these nanomedicines redefining AML treatment paradigms signals a promising path towards more effective, targeted, and less toxic therapies, highlighting a transformative phase in the fight against this aggressive hematological malignancy. xiii Abstract The work presented here has resulted in the following manuscripts:  Siddique MH, Bukhari S, Khan IU, Essa A, Ali Z, Sabir U, Ayoub O, Saadia H, Yaseen M, Sultan A, Murtaza I, Kerr PG, Bhat MA, Anees M. In silico, in vitro, and in vivo evaluation of caffeine-coated nanoparticles as a promising therapeutic avenue for AML through NF-Kappa B and TRAIL pathways modulation. Pharmaceuticals (2023) 16 (12), 1742 (Published).  Siddique MH, Bukhari S, Sabir U, Khan I, Waheed W, Yaseen M, Sultan A, Murtaza I, Kerr P, Rehman ZU, Anees M. In silico, in vitro, and in vivo analysis of copper-diethyldithiocarbamate nanoparticles and doxorubicin: a novel combination strategy against AML (under review).  Siddique MH, Bukhari S, Sabir U, Khan I, Waheed W, Yaseen M, Sultan A, Murtaza I, Kerr P, Rehman ZU, Anees M. Exploring the Synergistic Therapeutic Potential of Ni-Diethyldithiocarbamate Nanoparticles with Doxorubicin in Acute Myeloid Leukemia (in preparation).