Journal of Innovative Optical Health Sciences

Gold nanoparticles (AuNPs) exhibit superior optical and physical properties for more effective treatment of cancer through incorporating both diagnostic and therapeutic functions into one single platform. The ability to passively accumulate on tumor cells provides AuNPs the opportunity to become an attractive contrast agent for X-ray based computed tomography (CT) imaging in vivo. Because of facile surface modification, various size and shape of AuNPs have been extensively functionalized and applied as active nanoprobes and drug carriers for cancer targeted theranostics. Moreover, their capabilities on producing photoacoustic (PA) signals and photothermal effects have been used to image and treat tumor progression, respectively. Herein, we review the developments of AuNPs as cancer diagnostics and chemotherapeutic drug vector, summarizing strategies for tumor targeting and their applications in vitro and in vivo.

Among the several types of inorganic nanoparticles available, silica nanoparticles (SNP) have earned their relevance in biological applications namely, as bioimaging agents. In fact, fluorescent SNP (FSNP) have been explored in this field as protective nanocarriers, overcoming some limitations presented by conventional organic dyes such as high photobleaching rates. A crucial aspect on the use of fluorescent SNP relates to their surface properties, since it determines the extent of interaction between nanoparticles and biological systems, namely in terms of colloidal stability in water, cellular recognition and internalization, tracking, biodistribution and specificity, among others. Therefore, it is imperative to understand the mechanisms underlying the interaction between biosystems and the SNP surfaces, making surface functionalization a relevant step in order to take full advantage of particle properties. The versatility of the surface chemistry on silica platforms, together with the intrinsic hydrophilicity and biocompatibility, make these systems suitable for bioimaging applications, such as those mentioned in this review.

Upconversion nanoparticles (UCNPs) as a promising material are widely studied due to their unique optical properties. The material can be excited by long wavelength light and emit visible wavelength light through multiphoton absorption. This property makes the particles highly attractive candidates for bioimaging and therapy application. This review aims at summarizing the synthesis and modification of UCNPs, especially the applications of UCNPs as a theranostic agent for tumor imaging and therapy. The biocompatibility and toxicity of UCNPs are also further discussed. Finally, we discuss the challenges and opportunities in the development of UCNP-based nanoplatforms for tumor imaging and therapy.

Photoacoustic therapy, using the photoacoustic effect of agents for selectively killing tumor cells, has shown promising for treating tumor. Utilization of high optical absorption probes can help to effectively improve the photoacoustic therapy efficiency. Herein, we report a novel high-absorption photoacoustic probe that is composed of indocyanine green (ICG) and graphene oxide (GO), entitled GO-ICG, for photoacoustic therapy. The attached ICG with narrow absorption spectral profile has strong optical absorption in the infrared region. The absorption spectrum of the GO-ICG solution reveals that the GO-ICG particles exhibited a 10-fold higher absorbance at 780nm (its peak absorbance) as compared with GO. Importantly, ICG’s fluorescence is quenched by GO via fluorescence resonance energy transfer. As a result, GO-ICG can high-efficiently convert the absorbed light energy to acoustic wave under pulsed laser irradiation. We further demonstrate that GO-ICG can produce stronger photoacoustic wave than the GO and ICG alone. Moreover, we conjugate this contrast agent with integrin ${\alpha }_v{\beta }_3$ mono-clonal antibody to molecularly target the U87-MG human glioblastoma cells for selective tumor cell killing. Finally, our results testify that the photoacoustic therapy efficiency of GO-ICG is higher than the existing photoacoustic therapy agent. Our work demonstrates that GO-ICG is a high-efficiency photoacoustic therapy agent. This novel photoacoustic probe is likely to be an available candidate for tumor therapy.

Integrins, over-expressed in a broad range of cancer diseases, are widely utilized as a tumor biomarker. Metabolism investigation also plays important roles in tumor theranostics. Developing simple integrin-targetting probe and monitoring tumor metabolism will give opportunities to find ways for cancer treatment, however, the investigation of tumor metabolism with integrin receptor based probes has been rarely reported so far. Here, we developed an octavalent fluorescent probe Octa-RGD by convenient genetic method, based on one tetrameric far-red fluorescent protein (fRFP) linked with RGD peptides. We validated its intergin targeting by confocal imaging in vitro. Then we screened a variety of tumor cells, and differentiated their binding affinity based on the fluorescence of the probe via flow cytometry. Among these cells, CNE-2 cells had the highest uptake of the probe, while B16 cells had the lowest, corresponding with their intergin expression levels. Next, the fluorescent and metabolic imaging was performed in HT1080 (intergin postive) tumor, where nicotinamide adenine dinucleotide hydrogen (NADH), flavoprotein (Fp) and fRFP fluorescent signals were collected. The tumor from mice intravenously injected with Octa-RGD probe displayed obviously higher NADH redox ratio NADH/(Fp+NADH) and fRFP signal, than those with fRFP protein. It suggested that integrin targeting may have influence on the target cell metabolism, and further demonstrated Octa-RGD probe facilitated its uptake in the targeted tumor in vivo. This paper developed a useful probe, which can bind integrins specifically and efficiently in tumor cells, and together with tumor metabolic information, it may provide new insight for RGD targeting-based cancer therapeutics.

Gold nanoparticles (AuNPs) could serve as potential radiotherapy sensitizers because of their exceptional biocompatibility and high-Z material nature; however, since in vitro and in vivo behaviors of AuNPs are determined not only by their particle size but also by their surface chemistries, whether surface ligands can affect their radiosensitization has seldom been investigated in the radiosensitization of AuNPs. By conducting head-to-head comparison on radiosensitization of two kinds of ultrasmall ($\sim 2$nm) near-infrared (NIR) emitting AuNPs that are coated with zwitterionic glutathione and neutral polyethylene glycol (PEG) ligands, respectively, we found that zwitterionic glutathione coated AuNPs (GS-AuNPs) can reduce survival rates of MCF-7 cells under irradiation of clinically used megavoltage photon beam at low dosage of $\sim 2.25$Gy. On the other hand, PEG-AuNPs can serve as a radiation-protecting agent and enabled MCF-7 cells more resistant to the irradiation, clearly indicating the key role of surface chemistry in radiosensitization of AuNPs. More detailed studies suggested that such difference was independent of cellular uptake and its efficiency, but might be related to the ligand-induced difference in photoelectron generation and/or interactions between AuNPs and X-ray triggered reactive oxygen species (ROS).

Recently gold nanoparticles (GNPs) have been actively studied as photothermal converters, drug carriers, and imaging agents in a wide range of applications in cancer diagnosis and therapy. The prolonged peroral administration of GNPs in a range of sizes was performed to investigate the morphological changes and their reversibility in the internal organs of laboratory animals. In this study, GNPs with average diameters of 2nm, 15nm and 50nm were administered during 30 days, and the reversibility of morphological changes was investigated 14 days after administration. After the prolonged administration of GNPs, the severity of morphological changes in the liver, kidney, spleen and lymph nodes depended on the nanoparticle size. Specifically, 50nm nanoparticles caused the most pronounced dystrophic and necrobiotic effects, whereas the smallest 2nm nanoparticles caused proliferative changes. Most importantly, the development of pathological processes was reversible, as evidenced by the gradual restoration of the organ structure at 14 days after the end of GNPs administration.

Surface enhanced resonance Raman scattering (SERRS) is a physical phenomenon that occurs when the energy of incident light is close to that of electronic excitation of reporter molecules (RMs) attached on substrates. SERRS has showed great promise in healthcare applications such as tumor diagnosis, image-guided tumor surgery and real-time evaluation of therapeutic response due to its ultra-sensitivity, manipulating convenience and easy accessibility. As the most widely used organic near-infrared (NIR) fluorophore, heptamethine cyanines possess the electronic excitation energy that is close to the plasmon absorption energy of the gold nano-scaffolds, which results in the extraordinary enhancement of the SERRS signal. However, the effect of heptamethine cyanine structure and the gold nanoparticle morphology to the SERRS intensity are barely investigated. This work developed a series of SERRS nanoprobes in which two heptamethine cyanine derivatives (IR783 and IR780) were used as the RM and three gold nanoparticles (nanorod, nanosphere and nanostar) were used as the substrates. Interestingly, even though IR780 and IR783 possess very similar chemical structure, SERRS signal produced by IR780 was determined as 14 times higher than that of IR783 when the RM concentration was 6.5 × 10⁻⁶M. In contrast, less than 4.0 fold SERRS signal intensity increase was measured by changing the substrate morphologies. Above experimental results indicate that finely tuning the chemical structure of the heptamethine cyanine could be a feasible way to develop robust SERRS probes to visualize tumor or guide tumor resection with high sensitivity and target to background ratio.