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• W2477967577 abstract "Lung cancer is a major health problem in the United States. Despite the development of molecular-targeting agents such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and advances made in conventional chemoradiotherapy and surgical therapy, the overall five-year survival rate of lung cancer patients remains poor and is less than 15%. Recently, in an attempt to improve diagnosis and therapy, novel technologies such as nanotechnology have emerged for application in medicine. One major goal of nanomedicine is to develop multifunctional nanoparticles that can be applied for diagnosis and imaging of cancer as well as therapy for cancer. As a result, a number of nanoparticle agents of variousShinji Kuroda,a Tomohisa Yokoyama,a Justina O. Tam,b Ailing W. Scott,a Li Leo Ma,c Manish Shanker,a Jiankang Jin,a Corbin Goerlich,a David Willcutts,a Jack A. Roth,a Konstantin Sokolov,b,d Keith P. Johnston,c and Rajagopal Ramesha,e,f,*compositions, sizes, and shapes are being developed. A majority of the nanoparticles, however, are in preclinical studies, and only a few of them have advanced to early clinical testing. Efforts in several laboratories, including our own laboratory, are in developing tumor-targeted multifunctional metal-iron-oxide-based nanoparticles for imaging and therapy of lung cancer. In this article, we will discuss various nanomaterial-based nanoparticles, including our own tumor-targeted multifunctional nanoparticles that are being developed for lung cancer. Readers are encouraged to review additional literature to obtain more information on nanomaterials and their application in nanomedicine and cancer therapy. 2.1 IntroductionLung cancer is the most common cause of death across genders, races, and ethnicities [1, 2]. Approximately 85% of lung cancers are non-small-cell lung cancer (NSCLC), 75% of which are metastatic at diagnosis. This is because most symptoms do not appear until the disease is advanced. The treatment of NSCLC includes conventional cytotoxic chemotherapy and radiotherapy. Advances made in the treatment strategy, such as the emergence of molecular targeting agents, have demonstrated improvements in lung cancer patient survival. However, the overall five-year survival of patients diagnosed with NSCLC remains less than 15% [2]. One major challenge that remains with many therapeutic regimens is the inability to deliver cancer drugs specifically to tumors while achieving high intratu-moral drug concentrations. As a result, systemic administration of anticancer drugs results in poor drug accumulation within tumors, contributing to treatment failure [3]. Thus, it is important to develop novel therapies that are tumor targeted, effective in controlling tumor growth while maximizing tumor uptake. Advancements in the understanding of the molecular cause of lung cancer have resulted in the identification of the EGFR as an important player in lung cancer. EGFR is a member of the erythrob-lastic leukemia viral oncogene homolog (ErbB) family of receptor tyrosine kinases and approximately 50-80% of NSCLC demonstrate overexpression of the EGFR pathway [4-6]. This receptor has been shown to activate a variety of cellular signaling pathways and play an important role in cell proliferation, invasion, metastasis, and angiogenesis [7]. Thus, the elimination or reduction of EGFRexpression in lung cancer cells using EGFR-targeted drugs can lead to cancer cell death. Based on this concept, several EGFR-targeted biological (cetuximab) and synthetic small-molecule (erlotinib and gefitinib) inhibitors have been developed and are currently undergoing testing for lung cancer. Cetuximab (Erbitux; C225) is a humanized monoclonal antibody that targets the extracellular domain of EGFR while erlotinib (Tarceva) and gefitinib (Iressa) target the intracellular kinase domain of EGFR [8-11]. Studies have shown that lung cancer patients harboring mutations in EGFR responded to EGFR therapy, showed clinical response, and had improved survival. These results suggest that this subpopulation of lung cancer patients should receive EGFR-targeted therapy. However, recent studies have reported lung cancer patients without EGFR mutations also respond to treatment with EGFR inhibitors. These studies indicate that the expression or mutational status of EGFR alone is not a reliable marker for determining the outcome of EGFR inhibitor-based therapy; therefore, this therapy should be administrated to all patients with lung cancer, regardless of the patient’s EGFR mutational status. However, a potential drawback of EGFR-based therapy, as with other therapies, is the possibility that patients will develop resistance to treatment. For example, some patients who initially respond to gefitinib or erlotinib therapy develop resistance after prolonged treatment. This problem is further perpetuated since current treatment techniques do not allow for a rapid and noninvasive determination of whether patients receiving EGFR-based therapy are responding to treatment and when it is appropriate to discontinue therapy or change therapy. As a result, patients with lung cancer may receive an ineffective treatment for extended periods of time. Thus, it is of importance to develop tumortargeted therapies that not only maximize effectiveness and tumor uptake but also allow for noninvasive therapeutic evaluation. To overcome these limitations of cancer-targeted therapies, novel technologies such as nanotechnology are being developed and tested in the laboratory. Nanotechnology as defined by the National Cancer Institute (NCI; www.nci.gov) is the field of research that deals with the engineering and creation of materials that are less than 100 nm in size, especially single atoms or molecules. Nanotechnology for cancer is being developed to facilitate rapid monitoring of drug delivery and assess the therapeutic effect of the drug noninvasively. Synthesis of nanoparticles of various compositions, sizes, and shapesis an important subfield of nanotechnology. However, nanoparticles that are around 50 nm in size have been reported to be the most efficiently recognized and internalized by cells, resulting in an optimum therapeutic effect [15]. This, however, also raises concern for nonspecific toxicity, the phenomenon of noncancerous cells being able to internalize these nanoparticles. Therefore, to achieve tumor cell specificity and minimize normal cell toxicity, investigators are utilizing a plethora of scientific information (phenotype, genotype, biomarkers, and biochemical properties) available about cancer cells to engineer tumor-targeted nanoparticles. The most common approach is the coating of the outer surface of the nanoparticles with ligands (peptide, antibodies, DNA, etc.) that are uniquely expressed and recognized by tumor cells or ligands that are overexpressed by tumor cells compared to normal cells. The inner core of the nanoparticles can further be designed to carry drugs (chemotherapy, siRNA, microRNA [miRNA], and DNA) that are selectively released and activated only in tumor cells. The nanoparticles thus can be designed for delivering anticancer drugs specifically to cancer cells, thereby minimizing toxicity to normal cells, to carry molecules that will enable the detection of cancer cells by molecular imaging noninvasively without surgery, and to determine responses to treatment rapidly and noninvasively by imaging [12-14]. Thus, the application of nanotechnology in cancer medicine will prove to be beneficial in the clinic for patients diagnosed with cancer as these aforementioned properties of nanoparticles can address many common cancer therapy problems faced by clinicians. In this article we will discuss the utilization of biomarkers for developing targeted nanoparticles, describe various nanomaterial-based nanoparticles that are being developed for lung cancer, and finally explain the approach we have undertaken for the development of tumor-targeted multifunctional nanoparticles. 2.2 Biomarkers for Tumor TargetingTable 2.1 shows some of the biomarkers that have been reported to be overexpressed on tumor cell surfaces, blood vessel endothelium, and extracellular matrices (ECMs) of tumor tissues [16, 17]. These and other biomarkers, as discussed below, have been exploited for the development of tumor-targeted nanoparticles and achieving tumor specificity." @default.
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• W2477967577 title "Multifunctional Tumor-Targeted Nanoparticles for Lung Cancer" @default.
• W2477967577 doi "https://doi.org/10.1201/b12778-7" @default.
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