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Nanotechnology is an evolving field with enormous potential for biomedical applications. The growing interest to use inorganic nanoparticles in medicine is due to the unique size and shapedependent optoelectronic properties. Herein, we will focus on gold, silver and platinum nanoparticles, discussing recent developments for therapeutic applications with regard to cancer in terms of nanoparticles being used as a delivery vehicle as well as therapeutic agents. We will also discuss some of the key challenges to be addressed in future studies. IntroductionNanotechnology is a flourishing area with several interdisciplinary fields, such as medicine, electronics, and biomaterials (1). The long-term goal of nanomedicine is to revolutionize the health care system by fighting deadly diseases in more efficient ways (1). Gold nanoparticles are being investigated for biological applications due to their biocompatibility (1,2). In this review, we will focus on gold and a few other inorganic nanoparticles and discuss their potential applications in therapy and imaging. Gold nanoparticles have been used mostly as a probe for electron microscopy and as a delivery vehicle for biomolecules. However, the use of nanoparticles as a therapeutic agent is relatively new. Among all the nanomaterials, gold has attracted wide attention due to its relative non-toxic nature (2-5). Gold has been shown to have strong affinity to thiol and amine functionalities (2). Such affinity enables surface modifications to gold nanoparticles relatively easily through Au-S and Au-N bonding with targeting agents and/or chemotherapeutics that possess these functionalities (2). Thus, through intelligent design it is possible to develop multifunctional nanoparticles that could potentially increase the efficiency of detection, diagnosis and therapy (2,3). Application of Gold in Ancient MedicineGold compounds were used by Chinese and Indian cultures as early as 2500-2600 BC in the form of "Swarna Bhasma," a gold based medicine, for various purposes such as increasing vital power and curing male impotence (4-6). In the early 19 th and 20 th centuries gold compounds were utilized for the treatment of epilepsy, syphilis, rheumatic diseases, * Corresponding Author: Priyabrata Mukherjee, Ph.D, Department of Biochemistry and Molecular Biology, Department of Biomedical Engineering, Cancer Center, Mayo Clinic, Rochester, MN-55905, mukherjee.priyabrata@mayo.edu, Phone: 507-284-8563, Fax: 507-293-1058. NIH Public Access Synthesis of NanoparticlesPreparation of gold nanoparticles (AuNP) of different sizes and shapes are well documented (2,5,15,16 Physio-Chemical Properties of Metal NanoparticlesThe tunablility of optoelectronic properties through shape and size-dependent properties make inorganic nanomaterials unique for various biomedical applications (33)(34)(35)(36). Inorganic nanoparticles such as gold, silver and copper possess brilliant colors due to the presence of [39][40][41][42][43]. AuNPs show a strong SPR band that is dependent on particle size (...

Altered tumor microenvironment (TME) arising from a bidirectional crosstalk between the pancreatic cancer cells (PCCs) and the pancreatic stellate cells (PSCs) is implicated in the dismal prognosis in pancreatic ductal adenocarcinoma (PDAC), yet effective strategies to disrupt the crosstalk is lacking. Here, we demonstrate that gold nanoparticles (AuNPs) inhibit proliferation and migration of both PCCs and PSCs by disrupting the bidirectional communication via alteration of the cell secretome. Analyzing the key proteins identified from a functional network of AuNP-altered secretome in PCCs and PSCs, we demonstrate that AuNPs impair secretions of major hub node proteins in both cell types and transform activated PSCs toward a lipid-rich quiescent phenotype. By reducing activation of PSCs, AuNPs inhibit matrix deposition, enhance angiogenesis, and inhibit tumor growth in an orthotopic co-implantation model in vivo. Auto- and heteroregulations of secretory growth factors/cytokines are disrupted by AuNPs resulting in reprogramming of the TME. By utilizing a kinase dead mutant of IRE1-α, we demonstrate that AuNPs alter the cellular secretome through the ER-stress-regulated IRE1-dependent decay pathway (RIDD) and identify endostatin and matrix metalloproteinase 9 as putative RIDD targets. Thus, AuNPs could potentially be utilized as a tool to effectively interrogate bidirectional communications in the tumor microenvironment, reprogram it, and inhibit tumor growth by its therapeutic function.

Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership–AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.