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Stimuli-Responsive Gold Nanoparticles for Cancer Diagnosis and Therapy

Li Tian, Linfeng Lu, Yang Qiao, Saisree Ravi, Ferandre Salatan, Marites Melancon
2016 Journal of Functional Biomaterials  
An emerging concept is that cancers strongly depend on both internal and external signals for growth and invasion. In this review, we will discuss pathological and physical changes in the tumor microenvironment and how these changes can be exploited to design gold nanoparticles for cancer diagnosis and therapy. These intrinsic changes include extracellular and intracellular pH, extracellular matrix enzymes, and glutathione concentration. External stimuli include the application of laser,
more » ... on of laser, ultrasound and X-ray. The biology behind these changes and the chemistry behind the responding mechanisms to these changes are reviewed. Examples of recent in vitro and in vivo studies are also presented, and the clinical implications of these findings are discussed. implications for cancer diagnosis and treatment. A brief summary of the AuNPs that are responsive to intrinsic stimuli is presented in Tables 1-3. The majority of the work regarding intrinsic stimuli is still in the preclinical phase. Scheme 1. Review of gold nanoparticles (AuNPs) responsive to stimuli. On the left (blue region) are the reviewed external stimuli, including laser, ultrasound and X-ray, as well as photoacoustic imaging. On the right (pink region) are the reviewed intrinsic stimuli, including pH, matrix metalloproteinases (MMP), and redox condition (GSH). External stimuli include lasers and ultrasound, both of which are used clinically to treat cancer patients. AuNPs are also used in photoacoustic (PA) imaging. External stimuli activate certain physical properties of AuNPs, such as their surface plasmon resonance (SPR). The SPR can be finetuned by adjusting the shape and size of the AuNP, for example, the diameter of nanospheres, aspect ratio of nanorods, or thickness of nanoshells. Because the SPR is fine-tunable, AuNPs powerfully enhance hyperthermia when combined with lasers. Similarly, AuNPs can decrease the cavitation threshold of ultrasound. PA imaging, in which laser excitation is converted to ultrasound emission, is also discussed. Enhancement and sensitization of X-ray radiation by AuNP is also reviewed. Intrinsic Stimuli pH Tumors are slightly acidic because they are often hypoxic. Despite the release of angiogenesis factors that form neovasculature [4-9], tumor tissue often requires more oxygen and nutrition than can be supplied by the neovasculature. The oxygen concentrations in blood, healthy tissue, and typical hypoxic solid tumors are 10%-12.5%, 3%-6%, and 1%-2%, respectively [10, 11] . Hypoxia triggers many alterations in gene expression and metabolism in cells, including the upregulation of hypoxia-inducible factor 1 [11, 12] , which leads to the overexpression of glycolytic enzymes and glucose transporters (GLUT1 and GLUT3) [13] . Glucose molecules are more actively internalized and converted to pyruvate as a result. Interestingly, in tumor cells, the majority of the resulting pyruvate undergoes a truncated pathway and is converted to lactic acid directly, instead of entering the tricarboxylic acid cycle. This phenomenon is known as the Warburg effect and has been observed in tumor cells even in normoxia [14, 15] . Hypoxia also triggers the upregulation of Na+/H+ exchangers, which play an important role in maintaining intracellular pH [16, 17] , pumping large quantities of protons formed during glycolysis out of cells. These overproduced protons would normally be washed out by blood flow and lymphatic drainage, and the extracellular pH would remain normal [18] . However, because of the decreased blood flow [19] and impaired lymphatic drainage [20] in tumor tissues, the excess protons accumulate in the extracellular space [19] . Although the Scheme 1. Review of gold nanoparticles (AuNPs) responsive to stimuli. On the left (blue region) are the reviewed external stimuli, including laser, ultrasound and X-ray, as well as photoacoustic imaging. On the right (pink region) are the reviewed intrinsic stimuli, including pH, matrix metalloproteinases (MMP), and redox condition (GSH). External stimuli include lasers and ultrasound, both of which are used clinically to treat cancer patients. AuNPs are also used in photoacoustic (PA) imaging. External stimuli activate certain physical properties of AuNPs, such as their surface plasmon resonance (SPR). The SPR can be fine-tuned by adjusting the shape and size of the AuNP, for example, the diameter of nanospheres, aspect ratio of nanorods, or thickness of nanoshells. Because the SPR is fine-tunable, AuNPs powerfully enhance hyperthermia when combined with lasers. Similarly, AuNPs can decrease the cavitation threshold of ultrasound. PA imaging, in which laser excitation is converted to ultrasound emission, is also discussed. Enhancement and sensitization of X-ray radiation by AuNP is also reviewed. Intrinsic Stimuli pH Tumors are slightly acidic because they are often hypoxic. Despite the release of angiogenesis factors that form neovasculature [4] [5] [6] [7] [8] [9] , tumor tissue often requires more oxygen and nutrition than can be supplied by the neovasculature. The oxygen concentrations in blood, healthy tissue, and typical hypoxic solid tumors are 10%-12.5%, 3%-6%, and 1%-2%, respectively [10, 11] . Hypoxia triggers many alterations in gene expression and metabolism in cells, including the upregulation of hypoxia-inducible factor 1 [11, 12] , which leads to the overexpression of glycolytic enzymes and glucose transporters (GLUT1 and GLUT3) [13] . Glucose molecules are more actively internalized and converted to pyruvate as a result. Interestingly, in tumor cells, the majority of the resulting pyruvate undergoes a truncated pathway and is converted to lactic acid directly, instead of entering the tricarboxylic acid cycle. This phenomenon is known as the Warburg effect and has been observed in tumor cells even in normoxia [14, 15] . Hypoxia also triggers the upregulation of Na+/H+ exchangers, which play an important role in maintaining intracellular pH [16, 17] , pumping large quantities of protons formed during glycolysis out of cells. These overproduced protons would normally be washed out by blood flow and lymphatic drainage, and the extracellular pH would remain normal [18] . However, because J. Funct. Biomater. 2016, 7, 19 3 of 31 of the decreased blood flow [19] and impaired lymphatic drainage [20] in tumor tissues, the excess protons accumulate in the extracellular space [19] . Although the intracellular pH remains close to normal, at around 7.2, studies have shown that the extracellular pH in several kinds of tumors is more acidic, with an average pH of around 6.8 [21, 22] . AuNPs are made sensitive to pH by using a polymer that has a different charge at different pH values, by adjusting the SPR, or by combining these two techniques (Table 1) . For example, shieldable tumor-targeting AuNPs that possessed a self-assembly/disassembly property triggered by extrinsic pH changes were prepared by surface modification of AuNPs with two other components, lipoyl tertiary amines (LA-NRn) and poly(ethylene glycol) (PEG) modified by a glycyrrhetinic acid (GA) derivative, forming PEG-GA-N(CH 3 ) 2 [23]. GA is a targeting ligand of hepatocytes. It also serves as the tuner of hydrophobicity in these AuNPs. The carboxylic acid group on GA was modified into a tertiary amine group, causing the modified GA moiety to transit from non-charged (hydrophobic) to positively charged (hydrophilic) as pH dropped, and LA-NRn underwent a similar transition (illustrated in Figure 1 ). This hydrophobic/hydrophilic transition resulted in the aggregation of the AuNPs and the hiding of the targeting ligand at pH 7.4, and disassembly and exposure of the targeting ligand at acidic pH (such as 6.8). The results of an in vitro study showed that the uptake of AuNPs@LA-NR4+PEG-GA-N(CH 3 ) 2 by HepG2 cells was about three times higher at pH 6.8 than at pH 7.4. Aside from the incorporation of a polymer/compound that has a different charge at different pH values, chemical bound that is prone to hydrolysis has also been used to introduce pH sensitivity. The hydrolysis of the citraconic amide moiety triggers the release of doxorubicin (Dox) to the tumor area and spurs the aggregation of AuNPs for photothermal therapy [24] .
doi:10.3390/jfb7020019 pmid:27455336 fatcat:5wwxmf4erjdhjde7mvnwqyopem