Near-infrared laser photothermal therapy of cancer by using gold nanoparticles: Computer simulations and experiment

We describe applications of silica(core)/gold(shell) nanoparticles to photothermal therapy of spontaneous tumor of cats and dogs. The laser irradiation parameters was optimized by preliminary experiments with laboratory rats. The temperature distribution in tissue and solution samples was measured with a thermal imaging system. It is shown that the temperature in the volume region of nanoparticles localization can substantially exceed the surface temperature recorded by the thermal imaging system. We demonstrate effective optical destruction of cancer cells by local injection of plasmon-resonant gold nanoshells followed by continuous wave (CW) semiconductor laser irradiation at wavelength 808 nm.     

Photothermal-chemotherapy with doxorubicin-loaded hollow gold nanospheres: A platform for near-infrared light-trigged drug release

Photothermal ablation (PTA) is an emerging technique that uses near-infrared (NIR) laser light-generated heat to destroy tumor cells. However, complete eradication of tumor cells with PTA is difficult because of uneven heat distribution in the treatment volume. We hypothesized that combining PTA with chemotherapy using a single multifunctional nanoconstruct that mediates simultaneous photothermal cell killing and drug release (photothermal-chemotherapy) would result in enhanced antitumor activity and reduced toxicity compared to chemotherapy alone. Doxorubicin (DOX) was loaded to hollow gold nanospheres (HAuNS) coated with polyethylene glycol (PEG). The pharmacokinetics and biodistribution of both DOX and HAuNS in the resulting nanoconstruct, DOX@PEG-HAuNS having different DOX:PEG:HAuNS ratios, were evaluated using dual isotope labeling techniques. The antitumor activity of DOX@PEG-HAuNS with DOX:PEG:HAuNS weight ratio of 1:3:1 (NP3) in combination with NIR laser was studied in vitro and in vivo using human MDA-MB-231 breast cancer and A2780 ovarian cancer cells. In vitro, NP3 mediated PTA of both cancer cells and DOX release upon NIR laser treatment. In vivo, NP3 showed slower clearance in blood and greater accumulation in tumors than free DOX. NP3-plus-NIR laser demonstrated greater antitumor activity than free DOX, NP3, or liposomal DOX. Moreover, NP3 displayed significantly decreased systemic toxicity compared to free DOX or liposomal DOX. Enhanced antitumor effect with NP3-plus-laser can be attributed to both the cytotoxic effect of DOX released from NP3 and the photothermal effect mediated by HAuNS. Slow release of DOX from NP3 in normal tissues contributed to reduced systemic toxicity. Photothermal-chemotherapy exemplified by a single-agent nanoconstruct NP3 is a promising approach to anticancer therapy.     

In vitro and in vivo assessment of targeting lipid-based nanoparticles to the epidermal growth factor-receptor (EGFR) using a novel Heptameric ZEGFR domain

Lipid-based oil-filled nanoparticles (NPs) with a high concentration of surface-chelated nickel (Ni-NPs) were successfully prepared using a Brij 78-NTA-Ni conjugate synthesized with Brij 78 (Polyoxyethylene (20) stearyl ether) and nitrilotriacetic acid (NTA). The facile incorporation of the Brij 78-NTA-Ni conjugate into the NP formulation allowed up to 90% Ni incorporation, which was a significant improvement over the previously used standard agent DOGS-NTA-Ni which led to ~6% Ni incorporation. The Ni-NPs were targeted to the highly epidermal growth factor receptor (EGFR)-overexpressing epidermoid carcinoma cells A431. This was accomplished using a novel high affinity histidine×6-tagged EGFR-binding Z domain (heptameric Z(EGFR) domain). In vitro cell uptake studies showed enhanced internalization (up to 90%) of the targeted Ni-NPs in A431 cells with only ≤10% internalization of the untargeted Ni-NPs. ICP-MS analysis used to quantify the amount of Ni in the cells were in close agreement with flow cytometry studies, which showed a dose dependent increase in the amount of Ni with the targeted Ni-NPs. Cell uptake competition studies showed that internalization of the targeted Ni-NPs within the cells was competed off with free heptameric Z(EGFR) domain at concentrations of 8.75ng/mL or higher. In vivo studies were carried out in nude mice bearing A431 tumors to determine the biodistribution and intracellular delivery. Near Infrared (NIR) optical imaging studies using Alexa750-labeled heptameric Z(EGFR) domain showed localization of 19% of the total detected fluorescence intensity in the tumor tissue, 28% in the liver and 42% in the kidneys 16h post i.v. injection. ICP-MS analysis showed almost a two-fold increase in the amount of intracellular Ni with the targeted Ni-NPs. These new Ni-NPs could be a very useful tool for targeting and drug delivery to a wide range of EGFR positive cancers.     

超声靶向微泡破碎和生物可降解纳米粒

目的 探讨超声靶向微泡破碎(UTMD)的物理靶向和纳米粒的生物靶向联合的双靶向方法细胞内递送siRNAs的效果.方法 制备RGD和非RGD生物可降解纳米粒;L16(45)正交设计筛选超声、微泡、纳米粒的优化参数;实验分成优化参数组、RGD纳米粒组、非RGD纳米粒组和空白对照组;倒置荧光显微镜和流式细胞仪观察并检测分子探针Cy3标记的siRNAs在细胞内的摄取.结果 RGD纳米粒组的细胞摄取率和荧光强度分别为(93.49±1.37)%和34.28±2.06,优化参数组的细胞摄取率和荧光强度分别为(88.33±1.24)%和30.59±3.93,两组比较差异均无统计学意义(P＞0.05).非RGD纳米粒组的细胞摄取率和荧光强度分别为(71.24±2.80)%和18.39±0.90,优化参数组的细胞摄取率和荧光强度分别为(84.78±2.13)%和27.18±0.91,两组比较差异均有统计学意义(P＜0.05).结论 UTMD物理靶向和纳米粒生物靶向联合的双靶向方法不能提高siRNAs的细胞内递送.

Abstract：

Objective To investigate the intracellular delivery of siRNAs through the applications of ultrasound targeted microbubbles destruction(UTMD)and biodegradable nanoparticles carriers.Methods Preparation of nanoparticles with and without RGD sequences,parameters optimization via L16(45)orthogonal design,control experiments in groups of optimization,RGD targeted nanoparticles,non-RGD nanoparticles and blank control, and determinations by inverted fluorescence microscope and flow cytometry were performed.Results The uptake and fluorescence intensity of PC-3 cells in group of RGD targeted nanoparticle was (93.49±1.37)% and 34.28±2.06 respectively,and that in group of optimization was (88.33±1.24)% and 30.59±3.93 respectively(P＞0.05).Whereas the uptake and fluorescence intensity of PC-3 cells in group of non-RGD nanoparticles was(71.24±2.80)% and 18.39±0.90 respectively,and that in group of optimization was (84.78±2.13)% and 27.18±0.91 respectively(P＜0.05).ConclusionsThe applications of UTMD with RGD targted nanoparticles cannot increase the intracellular delivery of siRNAs.     

Magnetically targeted nanoparticles for imaging-guided photothermal therapy of cancer

Over the past several decades, nanocarriers have constituted a vital research area for accurate tumor therapy. Herein, magnetically targeted nanoparticles (IRFes) for photothermal therapy were generated by integrating IR780, a molecule with strong emission and absorption in the NIR spectrum and the ability to produce heat after laser irradiation, with Fe₃O₄ nanoparticles (NPs). These IRFes were guided to the tumor site by the application of an external magnetic field. In particular, the strong NIR absorption of IR780 was used for NIRF imaging, and we also demonstrated effective magnetic targeting for the photothermal ablation of tumors. In vitro cell viability and in vivo antitumor experiments showed that these IRFes can ablate 4T1 cells or transplanted 4T1 cell tumors when exposed to 808 nm laser irradiation and a magnetic field. In vivo experiments showed that IRFes only act on tumors, do not damage other organs and can be used to image tumors. These results demonstrate the enormous potential of local photothermal therapy for cancer under the guidance of external magnetic fields and reveal the prospect for the use of multifunctional nanoparticles in tumor therapy.

Magnetically targeted nanoparticles (IRFes) for photothermal therapy were generated by integrating IR780, a molecule with strong emission and absorption in the NIR spectrum and the ability to produce heat after laser irradiation, with Fe₃O₄ nanoparticles.     

Ultra-small bimetallic iron–palladium (FePd) nanoparticle loaded macrophages for targeted tumor photothermal therapy in NIR-II biowindows and magnetic resonance imaging

Nanoparticles working in the NIR-II biowindows possess larger maximum permissible exposure (MPE) and desirable penetration depth to the laser. However, most NIR-II responsive nanomaterials lack tumor targeting and Magnetic Resonance Imaging (MRI) ability. This greatly limits their applications. This study reported ultra-small bimetallic iron–palladium (FePd) nanoparticle loaded macrophages for targeted tumor photothermal therapy in NIR-II biowindows and magnetic resonance imaging. The crystal phase, morphology, absorption spectrum and photothermal performance of the synthesized samples were systematically characterized. The effects of photothermal therapy and nuclear magnetic imaging (MRI) were studied both in vitro and in vivo. Since FePd nanoparticles have both iron and palladium elements, it had a good MRI imaging capability and high photothermal conversion efficiency (36.7%). After binding to macrophages, FePd nanoparticles@macrophages (FePd@M) showed a good tumor targeting ability and were used for targeting NIR-II photothermal therapy and MRI imaging of tumors. The results of photothermal treatment showed that the tumor volume decreased by 90% compared to the control group, and no significant organ toxicity was observed. The results of MRI imaging showed that the FePd@M has the best imaging effect. The nanoparticles with the excellent NIR-II PTT ability and MRI effect have overcome the problem of tumor targeting and avoid the rapid removal of ultra-small nanoparticles. The FePd@M delivery system provides new ideas for material construction in the NIR-II region and has great clinical application potential.

Nanoparticles working in the NIR-II biowindows possess larger maximum permissible exposure (MPE) and desirable penetration depth to the laser.     

Folate receptor-targeting mesoporous silica-coated gold nanorod nanoparticles for the synergistic photothermal therapy and chemotherapy of rheumatoid arthritis

The synergy of photothermal therapy (PTT) and chemotherapy is widely regarded as an effective treatment for complex diseases, such as cancer and inflammation. In this paper, we report the synthesis of a nanoscaled drug delivery system, which was composed of a gold nanorod (GNR) as the photothermal agent and a mesoporous silica shell as the methotrexate (MTX) reservoir, named FAGMs. Due to folate modification on the surface, FAGMs targeted specifically activated macrophages in rheumatoid arthritis (RA). Under 808 nm laser irradiation, FAGMs could kill macrophages by reaching sufficient local hyperthermia with excellent efficiency in the photothermal conversion of GNRs. Meanwhile, internal heating caused hydrogen bond fracture; thus, MTX released rapidly from FAGMs for localized synergistic PTT and chemotherapy. The FAGMs had a mean particle size of about 180 nm and a zeta potential of 14.36 mV. The release rate of MTX from FAGMs in vitro increased markedly under 808 nm laser irradiation. In a cellular uptake study, stronger fluorescence signals were observed in activated macrophages when treated with FAGMs, suggesting that folic acid molecules enabled the enhancement of endocytosis into activated macrophages. In rats with adjuvant-induced arthritis, synergistic treatment excellently inhibited the progression of RA. These results demonstrated that FAGMs could be promising for the treatment of RA.

The use of targeted nanoparticles MTX-FAGMs in combined NIR-induced PTT and traditional chemotherapy has potential as a desirable nanopharmaceuticals platform for the treatment of RA.     

Tumor Uptake of Hollow Gold Nanospheres After Intravenous and Intra-arterial Injection: PET/CT Study in a Rabbit VX2 Liver Cancer Model

Purpose

This study was designed to investigate the intratumoral uptake of hollow gold nanospheres (HAuNS) after hepatic intra-arterial (IA) and intravenous (IV) injection in a liver tumor model.

Materials and methods

Fifteen VX2 tumor-bearing rabbits were randomized into five groups (n?=?3 in each group) that received either IV ⁶⁴Cu-labeled PEG-HAuNS (IV-PEG-HAuNS), IA ⁶⁴Cu-labeled PEG-HAuNS (IA-PEG-HAuNS), IV cyclic peptide (RGD)-conjugated ⁶⁴Cu-labeled PEG-HAuNS (IV-RGD-PEG-HAuNS), IA RGD-conjugated ⁶⁴Cu-labeled PEG-HAuNS (IA-RGD-PEG-HAuNS), or IA ⁶⁴Cu-labeled PEG-HAuNS with lipiodol (IA-PEG-HAuNS-lipiodol). The animals underwent PET/CT 1 h after injection, and uptake expressed as percentage of injected dose per gram of tissue (%ID/g) was measured in tumor and major organs. The animals were euthanized 24 h after injection, and tissues were evaluated for radioactivity.

Results

At 1 h after injection, animals in the IA-PEG-HAuNS-lipiodol group showed significantly higher tumor uptake (P?<?0.001) and higher ratios of tumor-to-normal liver uptake (P?<?0.001) than those in all other groups. The biodistribution of radioactivity 24 h after injection showed that IA delivery of PEG-HAuNS with lipiodol resulted in the highest tumor uptake (0.33 %ID/g; P?<?0.001) and tumor-to-normal liver ratio (P?<?0.001) among all delivery methods. At 24 h, the IA-RGD-PEG-HAuNS group showed higher tumor uptake than the IA-PEG-HAuNS group (0.20 vs. 0.099 %ID/g; P?<?0.001).

Conclusion

Adding iodized oil to IA-PEG-HAuNS maximizes nanoparticle delivery to hepatic tumors and therefore may be useful in targeted chemotherapy and photoablative therapy. PET/CT can be used to noninvasively monitor the biodistribution of radiolabeled HAuNS after IV or IA injection.     

Antibody‐functionalized nanoparticles for imaging cancer: influence of conjugation to gold nanoparticles on the biodistribution of 89Zr‐labeled cetuximab in mice

Antibody‐labeled gold nanoparticles represent a promising novel tool regarding cancer imaging and therapy. Nevertheless, the characterization of biodistribution of such immunonanocarriers has been poorly documented. In this study, the biodistribution of ⁸⁹Zr‐labeled cetuximab before and after the coupling reaction to gold nanoparticles (AuNPs) was compared and the quantitative imaging performance of ⁸⁹Zr immuno‐PET was evaluated. Cetuximab was functionalized with the desferal moiety and labeled with ⁸⁹Zr (⁸⁹Zr–Df–Bz–NCS–cetuximab). AuNPs with a mean diameter of 5 nm were synthesized according a new method developed in the laboratory, and conjugated to ⁸⁹Zr–Df–Bz–NCS–cetuximab using carbodiimide chemistry (AuNPs–PPAA–cetuximab–⁸⁹Zr). The two tracers were injected in A431 xenograft‐bearing mice. Tumor and liver uptakes were assessed at different times after injection using quantitative PET imaging. The in vivo specificity of the binding was investigated using a saturating dose of unlabeled cetuximab. Radiolabeled cetuximab was conjugated to AuNPs with a coupling reaction yield >75%. All conjugates were stable in vitro and to a lesser extent in plasma. In vivo distribution studies revealed no significant difference in tumor uptake for cetuximab conjugated to nanoparticles up to 72 h after injection, compared with unconjugated cetuximab. Immuno‐PET studies showed that AuNPs–PPAA–cetuximab–⁸⁹Zr provided high tumor‐to‐background ratio. The liver uptake of AuNPs–PPAA–cetuximab–⁸⁹Zr was higher, compared with ⁸⁹Zr–Df–Bz–NCS–cetuximab. In vivo blocking experiments demonstrated selective tumor targeting after coupling reaction. This study showed that the conjugation of AuNPs to cetuximab did not affect its tumor accumulation and that the efficacy of EGFR‐targeted nanoparticles was unaltered. The ⁸⁹Zr‐labeled cetuximab‐targeted gold nanoparticles could be a valuable tool for theranostic purposes. Copyright © 2013 John Wiley & Sons, Ltd.     

Ultrasound Improves the Delivery and Therapeutic Effect of Nanoparticle-Stabilized Microbubbles in Breast Cancer Xenografts

Compared with conventional chemotherapy, encapsulation of drugs in nanoparticles can improve efficacy and reduce toxicity. However, delivery of nanoparticles is often insufficient and heterogeneous because of various biological barriers and uneven tumor perfusion. We investigated a unique multifunctional drug delivery system consisting of microbubbles stabilized by polymeric nanoparticles (NPMBs), enabling ultrasound-mediated drug delivery. The aim was to examine mechanisms of ultrasound-mediated delivery and to determine if increased tumor uptake had a therapeutic benefit. Cellular uptake and toxicity, circulation and biodistribution were characterized. After intravenous injection of NPMBs into mice, tumors were treated with ultrasound of various pressures and pulse lengths, and distribution of nanoparticles was imaged on tumor sections. No effects of low pressures were observed, whereas complete bubble destruction at higher pressures improved tumor uptake 2.3 times, without tissue damage. An enhanced therapeutic effect was illustrated in a promising proof-of-concept study, in which all tumors exhibited regression into complete remission.     

Cooperative nanoparticle self-assembly and photothermal heating in a flexible plasmonic metamaterial

We theoretically investigate equilibrium behaviors and photothermal effects of a flexible plasmonic metamaterial composed of aramid nanofibers and gold nanoparticles. The fiber matrix is considered as an external field to reconfigure a nanoparticle assembly. We find that the heating process tunes particle–particle and fiber–particle interactions, which alter adsorption of nanoparticles on fiber surfaces or clustering in pore spaces. Thus, it is possible to control the nanoparticle self-assembly by laser illumination. Gold nanoparticles strongly absorb radiations and efficiently dissipate absorbed energy into heat. By solving the heat transfer equation associated with an effective medium approximation, we calculate the spatial temperature rise. Remarkably, our theoretical results quantitatively agree with prior experiments. This indicates that we can ignore plasmonic coupling effects induced by particle clustering. Effects of the laser spot size and intensity on the photothermal heating are also discussed.

We theoretically investigate equilibrium behaviors and photothermal effects of a flexible plasmonic metamaterial composed of aramid nanofibers and gold nanoparticles.     

Enhancement of tumor thermal therapy using gold nanoparticle-assisted tumor necrosis factor-alpha delivery

Tumor necrosis factor-alpha (TNF-alpha) is a potent cytokine with anticancer efficacy that can significantly enhance hyperthermic injury. However, TNF-alpha is systemically toxic, thereby creating a need for its selective tumor delivery. We used a newly developed nanoparticle delivery system consisting of 33-nm polyethylene glycol-coated colloidal gold nanoparticles (PT-cAu-TNF-alpha) with incorporated TNF-alpha payload (several hundred TNF-alpha molecules per nanoparticle) to maximize tumor damage and minimize systemic exposure to TNF-alpha. SCK mammary carcinomas grown in A/J mice were treated with 125 or 250 microg/kg PT-cAu-TNF-alpha alone or followed by local heating at 42.5 degrees C using a water bath for 60 minutes, 4 hours after nanoparticle injection. Increases in tumor growth delay were observed for both PT-cAu-TNF-alpha alone and heat alone, although the most dramatic effect was found in the combination treatment. Tumor blood flow was significantly suppressed 4 hours after an i.v. injection of free TNF-alpha or PT-cAu-TNF-alpha. Tumor perfusion, imaged by contrast enhanced ultrasonography, on days 1 and 5 after treatment revealed perfusion defects after the injection of PT-cAu-TNF-alpha alone and, in many regions, complete flow inhibition in tumors treated with combination treatment. The combination treatment of SCK tumors in vivo reduced the in vivo/in vitro tumor cell survival to 0.05% immediately following heating and to 0.005% at 18 hours after heating, suggesting vascular damage-mediated tumor cell killing. Thermally induced tumor growth delay was enhanced by pretreatment with TNF-alpha-coated gold nanoparticles when given i.v. at the proper dosage and timing.     

A feasible strategy for self-assembly of gold nanoparticles via dithiol-PEG for photothermal therapy of cancers

We designed and explored self-assembled gold nanoparticles (SAGNPs) by introducing dithiol modified polyethylene glycol (PEG) for internanoparticle cross-linking. SAGNPs could enhance uptake into cancer cells and be disintegrated by glutathione (GSH) to achieve tumor microenvironment-activated biodegradation. This assembled structure improved the photothermal effect compared to single gold nanospheres.

We designed and explored self-assembled gold nanoparticles (SAGNPs) by introducing dithiol modified polyethylene glycol (PEG) for internanoparticle cross-linking.     

Photothermal conversion of SiO2@Au nanoparticles mediated by surface morphology of gold cluster layer

Photothermal effects in SiO₂@Au core–shell nanoparticles have demonstrated great potential in various applications for drug delivery, thermo-photovoltaics and photothermal cancer therapy, etc. However, the photothermal conversion of SiO₂@Au nanoparticles partially covered by disconnected gold clusters has rarely been investigated systematically. Here, we control the surface morphology of gold clusters on the photothermal conversion performance of SiO₂@Au core–shell nanoparticles by means of chemically adjusting the synthesis parameters, including amounts of gold salts, pH value and reducing agent. The macroscopic variations of the photothermal heating of different nanoparticle dispersions are significantly influenced by the nanoscale differences of gold cluster morphologies on the silica core. The temperature rise can be enhanced by the strong near-field coupling and collective heating among gold clusters with a relatively uniform distribution on the silica core. A numerical model of the simplified photothermal system is formulated to interpret the physical mechanism of the experimental observation, and shows a similar trend of temperature rise implying a reasonably good agreement with experimental data. Our work opens new possibilities for manipulating the light-to-heat conversion performance of SiO₂@Au core–shell nanoparticles and potential applications of heat delivery with spatial resolution on the nanoscale.

We manipulate the surface morphology of gold clusters on SiO₂@Au nanoparticle and found that macroscopic photothermal conversions of different nanoparticle dispersions are significantly affected by nanoscale differences of gold cluster morphologies.     

Gold nanorod-based multifunctional nanocarrier for synergistic chemo-photothermal therapy in tumors

Synergistic photothermal therapy (PTT) and chemotherapy is an efficient strategy for tumor therapy. However, it is still a challenge to design a smart delivery system able to release a drug at the appropriate time and site of action. Here, we have synthesized photosensitive molecule 7-(double dodecylamine)-4-hydroxymethylcoumarin which was introduced in a nanocarrier GNR@SiO₂-DOX@CouC₁₂-HA (GSDCH) to achieve manually controlled drug release. The specific nanocarrier was fabricated using a GNR core for photothermal therapy, a mesoporous silica shell for drug loading, and the coumarin moiety as a blocking agent and intelligent controlled switch. In addition, cellular uptake of GSDCH by HeLa cells can be achieved effectively with the help of hyaluronic acid (HA). Owing to the controlled and targeted drug release properties, the GSDCH with photothermal- and chemo-therapy showed significantly enhanced therapeutic efficiency for HeLa tumor-bearing mice compared to the results of single therapy alone. It indicated that the GSDCH had great potential in tumor therapy with negligible systematic toxicity.

Synergistic photothermal therapy (PTT) and chemotherapy is an efficient strategy for tumor therapy.     

Quercetin loaded folate targeted plasmonic silver nanoparticles for light activated chemo-photothermal therapy of DMBA induced breast cancer in Sprague Dawley rats

Currently, the paucity of free drugs in conventional chemotherapy for breast-cancer curbs the desired therapeutic efficiency, often aggravating systemic toxicity. Quercetin (QRC) is a potential chemotherapeutic bio-flavonoid that is associated with poor hydrophilicity. In contrast to spherical silver nanoparticles (AgNPs), anisotropic AgNPs exhibit prominent plasmonic tunability in the near infrared (NIR) region allowing deep tissue penetration and endowing them with the ability to act as photothermal transducers as well. In this study, we optimized a simple and novel method for synthesizing folate-receptor-targeted-plasmonic silver-nanoparticles (QRC-FA-AgNPs) to serve as an efficient nanoscopic carrier system for breast cancer-cell targeted delivery of QRC and to induce photothermal therapy. A one-pot chemical synthesis method was followed for synthesizing the QRC-FA-AgNPs by finely tailoring the hydrogen bond between the reductant and stabilizer. Detailed characterization through UV-visible, near infrared (UV-vis-NIR) spectroscopy, Fourier transform infrared (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), selected area electron diffraction (SAED), and energy-dispersive X-ray spectroscopy (EDX), along with particle-size, zeta-potential analysis, drug-loading and release capacity and stability studies were also performed. In vitro targeted cellular uptake, viability studies, chemo-photothermal efficacy, induction of apoptosis and the reactive oxygen species (ROS) generating potential were studied in the MDA-MB-231 cell-line and in vivo evaluation of the chemo-photothermal efficacy of QRC-FA-AgNPs was performed using a 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast-carcinogenesis model in Sprague Dawley rats. Unlike conventional AgNPs, these novel pentagonal QRC-FA-AgNPs (<50 nm) manifested a robust plasmon tunability in the NIR (>800 nm) region. Detailed in vitro and in vivo studies revealed their active role in improving breast-cancer conditions by allowing controlled and targeted discharge of QRC at the tumor site, along with evoking hyperthermia under NIR laser irradiation that induced selective ablation of cancer cells. Following successful cellular internalization, the photothermal efficacy of QRC-FA-AgNPs supplemented their chemotherapeutic potency, allowing apoptosis and restraining the tumor growth. This current study highlighted the augmented efficacy of plasmonic QRC-FA-AgNPs in comparison to free quercetin, thus the development of a potential nanocarrier based on the pleiotropic function of plasmonic AgNPs may provide an efficient combined chemo-photothermal based strategy for the assassination of breast-cancer cells.

Novel plasmonic (>800 nm) pentagonal QRC-FA-AgNPs synthesized through simple chemical technique induces light activated combined chemo-photothermal efficacy against breast cancer.     

Photothermal therapy of tumors in lymph nodes using gold nanorods and near-infrared laser light

Lymph node dissection for regional nodal metastasis is a primary option, but is invasive and associated with adverse effects. The development of non-invasive therapeutic methods in preclinical experiments using mice has been restricted by the small lymph node size and the limited techniques available for non-invasive monitoring of lymph node metastasis. Here, we show that photothermal therapy (PTT) using gold nanorods (GNRs) and near-infrared (NIR) laser light shows potential as a non-invasive treatment for tumors in the proper axillary lymph nodes (proper-ALNs) of MXH10/Mo–lpr/lpr mice, which develop systemic swelling of lymph nodes (up to 13 mm in diameter, similar in size to human lymph nodes). Tumor cells were inoculated into the proper-ALNs to develop a model of metastatic lesions, and any anti-tumor effects of therapy were assessed. We found that GNRs accumulated in the tumor in the proper-ALNs 24 h after tail vein injection, and that irradiation with NIR laser light elevated tumor temperature. Furthermore, combining local or systemic delivery of GNRs with NIR irradiation suppressed tumor growth more than irradiation alone. We propose that PTT with GNRs and NIR laser light can serve as a new therapeutic method for lymph node metastasis, as an alternative to lymph node dissection.     

Near-infrared light modulated photothermal effect increases vascular perfusion and enhances polymeric drug delivery

Hyperthermia, which is heating of tumors above 43 °C for about 30 min, has been known to modulate vascular permeability for enhanced chemotherapy. However, it is not clear whether a similar effect exists when temperature at tumor sites is elevated above 43 °C, such as temperature achieved in laser-induced photothermal ablation (PTA) therapy. Also, the effect of timing of chemotherapeutic drug administration following heating in the efficiency of drug delivery is not established. In this study, we investigated the impact of near infrared (NIR) laser irradiated anti-EGFR monoclonal antibody C225-conjugated hollow gold nanospheres (C225-HAuNS) on vascular permeability and subsequent tumor uptake of a water-soluble polymer using combined MRI, ultrasound and optical imaging approaches. Magnetic temperature imaging showed a maximum temperature of 65.2 ± 0.10 °C in A431 tumor xenograft of mice treated with C225-HAuNS plus laser and 47.0 ± 0.33 °C in tumors of mice treated with saline plus laser at 4 W/cm² for 3 min (control) at 2 mm from the light incident surface. Dynamic contrast enhanced (DCE) MRI demonstrated greater than 2-fold increase of DTPA-Gd in the initial area under the curve (IAUC₉₀) in mice injected with C225-HAuNS and exposed to NIR laser compared with control mice at 3 min after laser treatment. Similarly, Power Doppler (PD) ultrasound revealed a 4- to 6-fold increase in percentage vascularization in mice treated with C225-HAuNS plus NIR laser compared to control mice and confirmed increased vascular perfusion immediately after laser treatment. Twenty-four hours later, the blood perfusion was shut down. On optical imaging, tumor uptake of PG-Gd-NIR813, which is the model polymeric drug used, was significantly higher (p-value < 0.05) in mice injected with PG-Gd-NIR813 at 5 min after laser treatment than in mice injected with PG-Gd-NIR813 at 24 h after laser treatment and the saline-treated mice. In conclusion, laser irradiation of tumors after intravenous injection of C255-HAuNS induces a thermally mediated modulation of the vascular perfusion, which enhances the delivery of polymeric drugs to the tumors at the time phototherapy is initiated.     

Glioma-homing peptide with a cell-penetrating effect for targeting delivery with enhanced glioma localization,penetration and suppression of glioma growth

Tumor-targeted delivery systems are useful in enhancing drug delivery and increasing anti-tumor effects. Cell-penetrating peptides have been widely used for this purpose but have been hampered by the poor selectivity between neoplastic and non-neoplastic cells. As a peptide derived from interleukin-13, interleukin-13 peptide (IL-13p) is specifically targeted to IL13Rα2, a tumor-restricted receptor. More interestingly, IL-13p possesses cell-penetrating properties that can specifically enhance the uptake by tumor cells compared with endothelial cells. Thus, we anchored IL-13p onto nanoparticles (ILNPs) for glioma-targeting delivery. The uptake of ILNPs by U87 cells was higher than that of unmodified nanoparticles (NPs). However, there was no significant difference in the uptake by human umbilical vein endothelial cells. In addition, free IL-13p could also enhance the uptake of both NPs and ILNPs by U87 cells. Anchoring with IL-13p could enhance the penetration of particles into the core of spheroids. In vivo, the fluorescence intensity of ILNPs in tumors was 2.96-fold higher than that of NPs. The modification with IL-13p also significantly improved the speed and rate of penetration from vessels to tumor cells. The enhanced tumor localization of ILNPs was mostly attributable to the elevated tumor cell internalization of ILNPs, whereas most NPs were colocalized with microvessels or macrophages. Correspondingly, docetaxel-loaded NPs effectively suppressed the growth of subcutaneous U87 tumors. The average tumor volume of the ILNP group was only 31.4% that of the control, which was significantly smaller than that of the docetaxel and NP groups. In conclusion, the modification of IL-13p selectively enhanced tumor cell uptake, improved the penetration effect of NPs and improved the glioma localization ability, which led to a better tumor-suppression effect.     

High and low molecular weight hyaluronic acid-coated gold nanobipyramids for photothermal therapy

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. It is known that hyaluronic acid (HA) binds CD44 receptors, which are overexpressed on the surface of TNBC cells. To optimize the targeting ability of HA, in this study we coated gold nanobipyramids (GBPs) with high and low molecular weight HA (380 kDa and 102 kDa), named GBPs@h-HA and GBPs@l-HA, respectively. GBPs@l-HA and GBPs@h-HA had excellent stability when dispersed in water and PBS (pH 7.4) for seven days. The HA density was calculated by the ratio of HA to GBPs@l-HA and GBPs@h-HA, which was 13.22 and 4.77, respectively. The two nanoparticles displayed good photostability, which was evaluated by their photothermal performance and similar biocompatibility. Inductively coupled plasma atomic emission spectrometry (ICP-AES) revealed superior cellular uptake of GBPs@h-HA over GBPs@l-HA. Upon 808 nm laser irradiation, the GBPs@h-HA also showed higher therapeutic efficacy than GBPs@l-HA both in vitro and in vivo. Overall, our study demonstrates that the molecular weight of HA plays an important role in the targeting ability and thus photothermal therapeutic efficacy of HA-coated gold nanobipyramids.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Hyaluronic acid (HA) could bind CD44 receptors, which are overexpressed on the surface of TNBC cells. Upon 808 nm laser irradiation, the GBPs@HA showed high therapeutic efficacy in vivo.