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Theoretical simulation and experimental design of selenium and gold incorporated polymer-based microcarriers for ROS-mediated combined photothermal therapy
Abstract
Recently, multi-modal combined photothermal therapy (PTT) with the use of photo-active materials has attracted significant attention for cancer treatment. However, drug carriers enabling efficient heating at the tumor site are yet to be designed: this is a fundamental requirement for broad implementation of PTT in clinics. In this work, we design and develop hybrid carriers based on multilayer capsules integrated with selenium nanoparticles (Se NPs) and gold nanorods (Au NRs) to realize reactive oxygen species (ROS)-mediated combined PTT. We show theoretically and experimentally that cooperative interaction of Se NPs with Au NRs improves the heat release efficiency of the developed capsules. In addition, after uptake by tumor cells, intracellular ROS level amplified by Se NPs inhibits the tumor growth. As a consequence, the synergy between Se NPs and Au NRs exhibits the advantages of hybrid carriers such as (i) improved photothermal conversion efficiency and (ii) dual-therapeutic effect. The results of in vitro and in vivo experiments demonstrate that the combination of ROS-mediated therapy and PTT has a higher tumor inhibition efficiency compared to the single-agent treatment (using only Se-loaded or Au-loaded capsules). Furthermore, the developed hybrid carriers show negligible in vivo toxicity towards major organs such as the heart, lungs, liver, kidneys and spleen. This study not only provides a potential strategy for the design of multifunctional "all-in-one" carriers, but also contributes to the development of combined PTT in clinical practice.
... Photo-responsive materials are localized in the tumor area. [118,119] Targeting ligands such as antibodies, single-chain fragments of antibodies, carbohydrates, etc. can be furnished on AuNPs to combat low targeting ability [81] Low targeting ability due to the hindrance caused by the dense interstitial structure of the tumor and lack of vessels in the tumor [80] and defects of photosensitive materials [120] Produces high local temperatures with no or minimal influence on healthy cells and tissues [119] Possible thermal damage to normal tissue [120] PTT can be combined with other types of therapies with different mechanisms of action, which results in a synergetic treatment effect [5,88,121] Insufficient photothermal effect and limited penetration depth of light in biological tissues [88,120] Upgradable thermal capacity is achieved by manipulating the size of gold nanoparticles and modifying their surface properties for the targeted location of the tumor [78] Poor photothermal stability [78]. Can lose their photothermal conversion ability upon repetitive NIR radiation [79] Compensate for poor drug loading capacity with remarkable lightabsorbing and scattering abilities [67] AuNPs have a poor drug loading capacity, limiting the use of AuNPs as drug carriers [79] Vol.:(0123456789) Discover Nano (2023) 18:150 | https://doi.org/10.1186/s11671-023-03936-z ...
... The incorporation of gold nanoparticles (AuNPs) into polymer-based nanocarriers enhances the structural integrity of the core, enables precise control over dosage, and facilitates accumulation within tumor tissues [61]. Furthermore, SeNPs have demonstrated capability as ROS generators and photothermal ignitors [5]. ...
... Considering the fact that the utilization of gold nanoparticles (AuNPs) and selenium nanoparticles (SeNPs) in photothermal therapy (PTT) has the potential to elicit an immune response against tumors within the human body, it is reasonable to strategically combine this approach with antibody therapy. This can be achieved by administering immune-stimulating drugs, such as PD-1 immunological checkpoint inhibitors, in conjunction with the aforementioned nanoparticles [5]. ...
The acceptance of nanoparticle technology in the quest for cancer treatment is due to its many potentials and possibilities of filling in the gaps in the limitations of the current treatment modalities. Insights into the possibilities of getting even more from this technology, as well as the synergistic properties of photothermal therapy (PTT) and photodynamic therapy (PDT)—the use of reactive oxygen species (ROS)—can also be exploited in the ablation of prostate cancer tumors. Therefore, the combination of gold and selenium photoactive nanoparticles as platforms for drug delivery via PTT/PDT in prostate cancer therapy, with a specific emphasis on the 'micro-carrier' based approach, was discussed and explored in this review under relevant subtopics ranging from understanding the complex chemistry and biology of the pharmacologically active Se/Au-containing agents to giving a thorough knowledge of these therapeutic agents' potential as a targeted and successful treatment strategy for prostate cancer by investigating the complex mechanisms behind their delivery, activation, and synergistic effects. Furthermore, this article presents a comprehensive overview of the current research environment, problems encountered, and future perspectives in the continuous war against prostate cancer.
Free radical therapy, based on the sulfate radical derived from peroxymonosulfate, has recently been explored as a potential cancer treatment. However, while it is promising, its successful application is restricted by several limitations including the uncontrollable generation of free radicals and the instability in aqueous medium. Herein, we prepared LCP nanoparticles by using PMS as a core, the Co-coordination polymer (Co-CP) as a coating layer, and lactobionic acid as a targeting ligand for hepatoma carcinoma cells. LCP could be activated by cobalt ions released from Co-CP, and successfully induced apoptosis and ferroptosis via the inhibition of glutathione peroxidase 4 and caused the accumulation of lipid peroxidation to enhance the efficacy of free radical therapy.
Frequent oil spill accidents and the discharge of oily wastewaters cause significant threats to the marine ecological systems and human health. Herein, a CuS microspheres-based superhydrophobic paper (CuS SP) has been prepared with the photothermal property for efficient oil/water separation and emulsions. To increase the durability, polydopamine is introduced to cellulosic fibers of the filter paper via the self-assembly of dopamine. The CuS SP exhibits a water contact angle of 150.5° and an oil contact angle of ~ 0°, displaying excellent superhydrophobicity and superoleophilicity. Also, the CuS SP possesses excellent chemical resistance, thermal stability, mechanical durability, and self-cleaning property. More importantly, the maximum surface temperature of the CuS SP can reach about 54.6 °C after 100 s under one sunlight irradiation (1.0 kW m⁻²), and it remains at about 54 ℃ even after 10 cyclic tests with light on and off. The separation flux of CCl4 can be increased by about 14.3% under one sunlight irradiation by using the CuS SP when compared with that without sunlight irradiation. Although the photothermal effect has no obvious influence on the separation efficiency, the CuS SP still shows a high separation efficiency (> 99%) for CCl4/water mixture under 15 cyclic separation tests with/without sunlight irradiation. Besides, in situ experimental observations for the separation of oil-in-water emulsions have been investigated with the CuS SP by using an optical microscopy, and the possible mechanisms for the separation of oil-in-water emulsions are discussed. Thus, the as-prepared CuS SP shows great potentials in the fields of self-cleaning, and the separation of oil/water mixtures and emulsions.
Graphical abstract
Photothermal therapy (PTT) ablates tumors by thermal effects of photothermal agents (PTAs), and attracts wide attention due to the non‐invasive characteristic. The ideal PTAs are expected to have high photothermal conversion effect under NIR irradiation, as well as targeting abilities and good biocompatibility satisfying the need of application in vivo. Nanoparticles (NPs) are commonly used as anti‐tumor materials, and plenty of researches on therapeutical NPs for PTT treatment have been developed. Among various building blocks for photothermal NPs, polymer materials for biomedical applications have great advantages due to their negligible toxicity, flexibility for functional modification, and ability to integrate multiple therapeutic strategies. This review focuses on the polymer materials utilized in photothermal NP designing, including their application as excellent carriers and powerful PTAs with great PTT effects. Furthermore, the synergy therapy based on polymeric nanoplatform for enhancing PTT therapeutic efficiency will be introduced.
Photothermal therapy (PTT) has attracted increasing interest as a complementary method to be used alongside conventional therapies. Despite a great number of studies in this field, only a few have explored how temperatures affect the outcome of the PTT at nanoscale. In this work, we study the necrosis/apoptosis process of cancerous cells that occurs during PTT, using a combination of local laser heating and nanoscale fluorescence thermometry techniques. The temperature distribution within a whole cell was evaluated using fluorescence lifetime imaging microscopy during laser-induced hyperthermia. For this, gold nanorods were utilized as nanoheaters. The local near-infrared laser illumination produces a temperature gradient across the cells, which is precisely measured by nanoscale thermometry. This allows one to optimize the PTT conditions by varying concentration of gold nanorods associated with cells and laser power density. During the PTT procedure, such an approach enables an accurate determination of the percentages of apoptotic and necrotic cells using 2D and 3D models. According to the performed cell experiments, the influence of temperature increase during the PTT on cell death mechanisms has been verified and determined. Our investigations can improve the understanding of the PTT mechanisms and increase its therapeutic efficiency while avoiding any side effects.
Heptamethine cyanine dye (Cy7) has been widely applied in cell imaging and tumor phototherapy by virtue of its excellent photophysical properties and biocompatibility. However, in the presence of oxygen, large conjugated skeletons are easily destroyed by photooxidation reaction under light irradiation, which greatly limits its inoxidizability and photothermal therapy (PTT) effect. Accordingly, in this study, a new strategy (Cy‐GOx) is developed by the catalytic reaction of glucose oxidase (GOx) that consumes oxygen to highly improve the antioxidant capacity of Cy7, achieving the combination of enhanced PTT and starvation therapy. During this catalytic reaction, glucose as an important nutrient for cancer cell growth is consumed, achieving GOx‐mediated tumor starvation therapy. The fluorescence and intersystem crossing (ISC) of Cy‐GOx are greatly inhibited, which ensures that the absorbed photon energy is mainly released by means of nonradiative transition, significantly improving its photothermal effect. Of note, this strategy can effectively realize tumor inhibition by both intratumoral injection and intravenous injection. Thus, it is believed that this design concept will provide a new strategy for improving the antioxidant capacity and photothermal effect of Cy7 in combination therapy for enhanced antitumor efficacy.
Selenium is a trace and essential micronutrient for the health of humans, animals, and microorganisms. Recently, selenium nanoparticles (SeNPs) attracted the interest of many researchers due to their biocompatibility, bioavailability, and low toxicity. Therefore, due to their higher bioactivity selenium nanoparticles are largely being used in various biomedical applications. Generally, selenium nanoparticles can be synthesized by physical, chemical, and biological methods. However, the biologically synthesized SeNPs demonstrate greater compatibility with human organs and tissues. The effect of size, shape, and the method employed for their synthesis on their applications in biological systems has been explored by many researchers. This review discusses various synthesis methods employed for their preparation and highlights their applications in the biomedical field such as in the treatment of fungal, bacterial, and parasitic infections, cancer, and diabetes. They can also act as chemopreventive agents, anti-inflammatory agents, and antioxidants. This journal is
Background
Tumor phototherapy especially photodynamic therapy (PDT) or photothermal therapy (PTT), has been considered as an attractive strategy to elicit significant immunogenic cell death (ICD) at an optimal tumor retention of PDT/PTT agents. Heptamethine cyanine dye (IR-780), a promising PDT/PTT agent, which can be used for near-infrared (NIR) fluorescence/photoacoustic (PA) imaging guided tumor phototherapy, however, the strong hydrophobicity, short circulation time, and potential toxicity in vivo hinder its biomedical applications. To address this challenge, we developed mesoporous polydopamine nanoparticles (MPDA) with excellent biocompatibility, PTT efficacy, and PA imaging ability, facilitating an efficient loading and protection of hydrophobic IR-780.
Results
The IR-780 loaded MPDA (IR-780@MPDA) exhibited high loading capacity of IR-780 (49.7 wt%), good physiological solubility and stability, and reduced toxicity. In vivo NIR fluorescence and PA imaging revealed high tumor accumulation of IR-780@MPDA. Furthermore, the combined PDT/PTT of IR-780@MPDA could induce ICD, triggered immunotherapeutic response to breast tumor by the activation of cytotoxic T cells, resulting in significant suppression of tumor growth in vivo.
Conclusion
This study demonstrated that the as-developed compact and biocompatible platform could induce combined PDT/PTT and accelerate immune activation via excellent tumor accumulation ability, offering multimodal tumor theranostics with negligible systemic toxicity.
Graphical Abstract
Photothermal therapy (PTT), which converts light energy to heat energy, has become a new research hotspot in cancer treatment. Although researchers have investigated various ways to improve the efficiency of tumor heat ablation to treat cancer, PTT may cause severe damage to normal tissue due to the systemic distribution of photothermal agents (PTAs) in the body and inaccurate laser exposure during treatment. To further improve the survival rate of cancer patients and reduce possible side effects on other parts of the body, it is still necessary to explore PTAs with high selectivity and precise treatment. In this review, we summarized strategies to improve the treatment selectivity of PTT, such as increasing the accumulation of PTAs at tumor sites and endowing PTAs with a self-regulating photothermal conversion function. The views and challenges of selective PTT were discussed, especially the prospects and challenges of their clinical applications.
Cancer has been a great threat to humans for decades. Due to the limitations of monotherapy, combinational therapies such as photothermal therapy (PTT) and immunotherapy have gained increasing attention with expectation to overcome the shortfalls of each other and obtain satisfactory therapeutic outcomes. PTT can inhibit primary tumors by thermal ablation but usually fails to achieve complete eradication and cannot prevent metastasis and recurrence. Meanwhile, the efficacy of immunotherapy is usually attenuated by the weak immunogenicity of tumor and the immunosuppressive tumor microenvironment (ITM). Therefore, many recent studies have attempted to synergize PTT with immunotherapy in order to enhance the therapeutic efficacy. In this review, we aim to summarize the cutting-edge strategies in combining nano-based PTT with immunotherapy for cancer treatment. Herein, the combination strategies were mainly classified into four categories, including 1) nano-based PTT combined with antigens to induce host immune responses; 2) nano-based PTT in combination with immune adjuvants acting as in situ vaccines; 3) nano-based PTT synergized with immune checkpoint blockade or other regulators to relieve the ITM; 4) nano-based PTT combined with CAR-T therapy or cytokine therapy for tumor treatment. The characteristics of various photothermal agents and nanoplatforms as well as the immunological mechanisms for the synergism were also introduced in detail. Finally, we discussed the existing challenges and future prospects in combined PTT and immunotherapy.
Development of versatile theranostic agents that simultaneously integrate therapeutic and diagnostic features remains a clinical urgent. Herein, we aimed to prepare uniform PEGylated (lactic-co-glycolic acid) (PLGA) microcapsules ([email protected](Fe3O4@PEG-PLGA) MCs) with superparamagnetic Fe3O4 nanoparticles embedded in the shell and Prussian blue (PB) NPs inbuilt in the cavity via a premix membrane emulsification (PME) method. On account of the eligible geometry and multiple load capacity, these MCs could be used as efficient multi-modality contrast agents to simultaneously enhance the contrasts of US, MR and PAT imaging. In-built PB NPs furnished the MCs with excellent photothermal conversion property and embedded Fe3O4 NPs endowed the magnetic location for fabrication of targeted drug delivery system. Notably, after further in-situ encapsulation of antitumor drug of DOX, (PB+DOX)@(Fe3O4@PEG-PLGA) MCs possessed more unique advantages on achieving near infrared (NIR)-responsive drug delivery and magnetic-guided chemo-photothermal synergistic osteosarcoma therapy. In vitro and in vivo studies revealed these biocompatible (PB+DOX)@(Fe3O4@PEG-PLGA) MCs could effectively target to the tumor tissue with superior therapeutic effect against the invasion of osteosarcoma and alleviation of osteolytic lesions, which will be developed as a smart platform integrating multi-modality imaging capabilities and synergistic effect with high therapy efficacy.
Radiotherapy (RT) is a popular clinical therapy method for extending cancer patient survival, but is hampered by severe side effects and the weak therapy effect. Herein, responsive degradable selenium (Se) theranostic agents (Se@SiO2@Bi nanocomposites (NCs)) are fabricated, which combine computed tomography (CT) imaging and simultaneously enhance the therapeutic effects of photothermal therapy (PTT) and RT, while reducing the side effects of radiation. The Se@SiO2@Bi theranostic agents can accumulate at the tumor site, and responsively decompose to releease Se, avoiding systemic toxicity by the element. Se enhances the effect of PTT/RT, simultaneously reducing the side effects of RT. The Se@SiO2@Bi NCs as CT agents also exhibit significantly enhanced contrast imaging performance due to the high atomic number of Bi. More importantly, the Se@SiO2@Bi NCs can be rapidly excreted without long‐term toxicity, owing to responsive degradation into ultrasmall particles (<5 nm) at the tumor site. In vitro and in vivo results show that the Se@SiO2@Bi NCs can remarkably inhibit tumor cells, without causing appreciable toxicity during the treatment. This study opens a new perspective in rationally designing responsive degradable theranostic agents for future tumor therapy with enhanced therapeutic efficacy and lesser side effects.
Phototherapy such as photothermal therapy and photodynamic therapy in cancer treatment has been developed quickly over the past few years for its noninvasive nature and high efficiency. However, there are still many drawbacks in phototherapy that prevent it from clinical applications. Thus, scientists have designed different systems to overcome the issues associated with phototherapy, including enhancing the targeting ability of phototherapy, low‐temperature photothermal therapy, replacing near‐infrared light with other excitation sources, and so on. This article discusses the problems and shortcomings encountered in the development of phototherapy and highlights possible solutions to address them so that phototherapy may become a useful cancer treatment approach in clinical practice. This article aims to give a brief summary about current research advancements in phototherapy research and provides a quick guideline toward future developments in the field. This article discusses the issues and shortcomings encountered in the development of photodynamic and photothermal therapy and highlights possible solutions to address them so that phototherapy may become a useful cancer treatment approach in clinical practice.
Biomimetic materials are often capable of subtly affecting tissue development, regeneration and carcinogenesis due to their high similarity to natural tissues. Despite the benefit of using such materials in tissue engineering, their prospective use in cancer therapy has been neglected, particularly the functions and mechanisms by which biomimetic materials mediate tumor suppression. Here, we prepare hierarchically constructed bone-mimetic selenium-doped hydroxyapatite nanoparticles (B-SeHANs), which can potentially play a dual role in the postoperative treatment of bone tumors via the chemotherapy from selenium and the promotion of bone repair by hydroxyapatite, to systematically investigate the influence of bone-mimetic hierarchical construction in bone tumor inhibition by SeHANs in vivo and in vitro. We found that, compared to the non-biomimetic SeHANs, the B-SeHANs exhibited highly enhanced cellular internalization and intracellular degradation, and induced subsequent autophagy and caspase-dependent apoptosis via the ROS-mediated activation of the JNK pathway and inhibition of the Akt/mTOR pathway. We further verified that the B-SeHANs promoted autophagy and apoptosis to inhibit tumor growth while profoundly reducing bone destruction in a well-designed orthotopic tibial tumor model. The current work presents a feasible strategy for the development, evaluation and fundamental study of biomimetic mineral nanoparticles to inhibit tumor growth.
In the light of promising potency of selenium nanoparticles in biomedical applications, this is the first study to report the synergistic antibacterial activity of these nanoparticles and lysozyme. The nanohybrid system was prepared with various concentrations of each component. Resistance of Escherichia coli and Staphylococcus aureus was compared in the presence of individual Nano and Bio counterparts as well as the nanohybrid system. Upon interaction of SeNPs with Lysozyme, the nanohybrid system efficiently enhanced the antibacterial activity compared to the protein. Therefore, SeNPs play an important role in inhibition of bacterial growth at very low concentrations of protein; whereas very high amount of the protein is required to inhibit bacterial growth individually. On the other hand, lysozyme has also played a vital role in antibacterial property of SeNPs, inducing 100% inhibition at very low concentration of each component. Hence, presence of both nano and bio counterparts induced vital interplay in the Nanohybrid system. The aged samples also presented good stability of SeNPs both as the intact and complex form. Results of this effort highlight design of nanohybrid systems with synergistic antibacterial properties to overcome the emerging antibiotic resistance as well as to define fruitful applications in biomedicine and food safety.
Nonspecific absorption and clearance of nanomaterials during circulation is the major cause for treatment failure in nanomedicine‐based cancer therapy. Therefore, herein bioinspired red blood cell (RBC) membrane is employed to camouflage 2D MoSe2 nanosheets with high photothermal conversion efficiency to achieve enhanced hemocompatibility and circulation time by preventing macrophage phagocytosis. RBC–MoSe2‐potentiated photothermal therapy (PTT) demonstrates potent in vivo antitumor efficacy, which triggers the release of tumor‐associated antigens to activate cytotoxic T lymphocytes and inactivate the PD‐1/PD‐L1 pathway to avoid immunologic escape. Furthermore, in the ablated tumor microenvironment, the tumor‐associated macrophages are effectively reprogrammed to tumoricidal M1 phenotype to potentiate the antitumor action. Taken together, this biomimetic functionalization thus provides a substantial advance in personalized PTT‐triggered immunotherapy for clinical translation. Bioinspired 2D MoSe2 nanosheets with high photothermal conversion efficiency are designed to achieve efficient photothermal‐triggered cancer immunotherapy, by activating cytotoxic T lymphocytes, reprogramming of tumor‐associated macrophages to tumoricidal M1 phenotype, and inactivation of PD‐1/PD‐L1 pathway to avoid immunologic escape.
Background
Gold nanorods (AuNRs), due to the optical and electronic properties namely the surface plasma resonance, have been developed to achieve the light-mediated photothermal therapy (PTT) for cancer. However, PTT alone may suffer from inefficient tumor killing. Recently, the combination of PTT and chemotherapy has been utilized to achieve synergistic anticancer effects.
Methods
In this study, AuNRs capped with hexadecyltrimethylammonium bromide (CTAB), poly(acrylic acid) (PAA), and PEGylated anisamide (a ligand known to target the sigma receptor) have been developed to produce a range of negatively charged anisamide-targeted PEGylated AuNRs (namely Au-CTAB-PAA-PEG-AA) for the combination of PTT and chemotherapy (termed as chemo-photothermal therapy [CPTT]). Epirubicin (EPI, an anthracycline drug) was efficiently loaded onto the surface of Au800-CTAB-PAA-PEG-AA via the electrostatic interaction forming Au800-CTAB-PAA-PEG-AA.EPI complex.
Results
The resultant complex demonstrated pH-dependent drug release, facilitated nucleus trafficking of EPI, and induced antiproliferative effects in human prostate cancer PC-3 cells. When Au800-CTAB-PAA-PEG-AA.EPI complex was further stimulated with desired laser irradiation, the synergistic outcome was evident in PC-3 xenograft mice.
Conclusion
These results demonstrate a promising strategy for clinical application of CPTT in cancer.
Photothermal therapy (PTT) is a promising cancer treatment modality, but PTT generally requires direct access to the source of light irradiation, thus precluding its utility against disseminated, metastatic tumors. Here, we demonstrate that PTT combined with chemotherapy can trigger potent anti-tumor immunity against disseminated tumors. Specifically, we have developed polydopamine-coated spiky gold nanoparticles as a new photothermal agent with extensive photothermal stability and efficiency. Strikingly, a single round of PTT combined with a sub-therapeutic dose of doxorubicin can elicit robust anti-tumor immune responses and eliminate local as well as untreated, distant tumors in >85% of animals bearing CT26 colon carcinoma. We also demonstrate their therapeutic efficacy against TC-1 submucosa-lung metastasis, a highly aggressive model for advanced head and neck squamous cell carcinoma (HNSCC). Our study sheds new light on a previously unrecognized, immunological facet of chemo-photothermal therapy and may lead to new therapeutic strategies against advanced cancer.
Abstract
Background: Selenium is well documented to inhibit cancer at higher doses; however, the mechanism behind this inhibition varies widely depending on the cell type and selenium species. Previously, we have demonstrated that Bacillus licheniformis JS2 derived biogenic selenium nanoparticles (SeNPs) induce non-apoptotic cell death in prostate adenocarcinoma cell line, PC-3, at a minimal concentration of 2 μg Se/ml, without causing toxicity to the primary cells. However, the mechanism behind its anticancer activity was elusive.
Results: Our results have shown that these SeNPs at a concentration of 2 μg Se/ml were able to induce reactive
oxygen species (ROS) mediated necroptosis in PC-3 cells by gaining cellular internalization. Real-time qPCR analysis showed increased expression of necroptosis associated tumor necrotic factor (TNF) and interferon regulatory factor 1 (IRF1). An increased expression of RIP1 protein was also observed at the translational level upon SeNP treatment. Moreover, the cell viability was significantly increased in the presence of necroptosis inhibitor, Necrostatin-1.
Conclusion: Data suggest that our biogenic SeNPs induce cell death in PC-3 cells by the ROS-mediated activation of necroptosis, independent to RIP3 and MLKL, regulated by a RIP1 kinase.
Among the numerous nonlinear optics effects, second harmonic generation (SHG) is always a hotspot and it is extensively used for optical frequency conversion, biomedical imaging, etc. However, SHG is forbidden in a medium with inversion symmetry under the electric-dipole approximation. Here, we demonstrated SHG from a single amorphous selenium (a-Se) nanosphere under near-infrared femtosecond pulse excitation. It was found that SH spectra are tunable with the size of a-Se nanospheres and the SHG efficiency of a single a-Se sphere with a diameter over 300 nm is estimated at 10(-8). We also established two physical mechanisms of SHG from the amorphous nanospheres. There is an electric-dipole contribution to the second-order nonlinearity in view of the inevitable structural discontinuity at the surface. The discontinuity of the normal component of the electric field strength leads to the quadrupole-type contributions arising from the large electric field gradient. The SHG process can be enhanced by resonance near the fundamental wavelength, giving rise to the detectable second harmonic (SH) spectra of a single a-Se nanosphere (d > 300 nm) or two small a-Se nanospheres (d = 200 nm) aggregated into a dimer, while the single nanosphere with smaller size (d > 300 nm) is undetectable. As an essential trace element for animals, a-Se features unique biological compatibility and has specific properties of optical nonlinearity within the optical window in biological tissue. This discovery makes a-Se nanospheres promising both in nonlinear optics and biomedicine.
The present article describes the preparation of β-emitter lutetium-177-labeled zirconia colloid and its preliminary physicochemical and biological evaluation of suitability for local radionuclide therapy. The new 177Lu-labeled therapeutic radiopharmaceutical candidate was based on the synthesis mode of a previously described zirconia nanoparticle system. The size and shape of the developed radiopharmaceutical compound were observed through a scanning electron microscope and dynamic light scattering methods. The radiocolloid had a 1.7 μm mean diameter and showed high in vitro radiochemical and colloid size stability at room temperature and during the blood sera stability test. After the in vitro characterizations, the product was investigated in the course of the treatment of a spontaneously diseased dog veterinary patient's hock joint completed with single-photon emission computed tomography (SPECT) imaging follow-up measurements and a dual-isotope SPECT imaging tests with conventional 99mTc-methanediphosphonic acid bone scintigraphy. In the treated dog, no clinical side-effects or signs of histopathological changes of the joints were recorded during the treatment. SPECT follow-up studies clearly and conspicuously showed the localization of the 177Lu-labeled colloid in the hock joint as well as detectable but negligible leakages of the radiocolloid in the nearest lymph node. On the basis of biological follow-up tests, the orthopedic team assumed that the 177Lu-labeled zirconia colloid-based local radionuclide therapy resulted in a significant and long-term improvement in clinical signs of the patient without any remarkable side-effects.
Gold nanoparticles (AuNPs) are attractive photothermal agents for cancer therapy because they show efficient local heating upon excitation of surface plasmon oscillations. The strong absorption, efficient heat conversion, high photostability, inherent low toxicity and well-defined surface chemistry of AuNPs contribute to the growing interest in their photothermal therapy (PTT) applications. The facile tunability of gold nanostructures enables engineering of AuNPs for superior near-infrared photothermal efficacy and target selectivity, which guarantee efficient and deep tissue-penetrating PTT with mitigated concerns regarding side effects by nonspecific distributions. This article discusses the current research findings with representative near-infrared-active AuNPs, which include nanoshell, nanorod, nanocage, nanostar, nanopopcorn and nanoparticle assembly systems. AuNPs successfully demonstrate potential for use in PTT, but several hurdles to clinical applications remain, including long-term toxicity and a need for sophisticated control over biodistribution and clearance. Future research directions are discussed, especially regarding the clinical translation of AuNP photosensitizers.
The development of new and improved photothermal contrast agents for the successful treatment of cancer (or other diseases) via Plasmonic Photothermal Therapy (PPTT) is a crucial part of the application of nanotechnology in medicine. Gold nanorods (AuNRs) have been found to be the most effective photothermal contrast agent, both in vitro and in vivo. Therefore, determining the optimum AuNR size needed for applications in PPTT is of great interest. In the present work, we utilized theoretical calculations as well as experimental techniques in vitro to determine this optimum AuNR size by comparing plasmonic properties and the efficacy as photothermal contrast agents of three different sizes of AuNRs. Our theoretical calculations showed that the contribution of absorbance to the total extinction, the electric field and the distance at which this field extends away from the nanoparticle surface, all govern the effectiveness of the amount of heat these particles generate upon NIR laser irradiation. Comparing between three different AuNRs (38 x 11, 28 x 8, and 17 x 5 nm), we determined that the 28 x 8 nm AuNR is the most effective in plasmonic photothermal heat generation. These results encouraged us to carry out in vitro experiments to compare the PPTT efficacy of the different sized AuNRs. The 28 x 8 nm AuNR was found to be the most effective photothermal contrast agent for PPTT of human oral squamous cell carcinoma. This size AuNR has the best compromise between the total amount of light absorbed and the fraction of which is converted to heat. In addition the distance at which the electric field extends from the particle surface is most ideal for this size AuNR, as it is sufficient to allow for coupling between the fields of adjacent particles in solution (i.e. particle aggregates), resulting in effective heating in solution.
Driven by the search for new materials with interesting and unique properties and also by the fundamental question of how atomic and molecular physical behaviour develops with increasing size, the field of nanoparticle research has grown immensely in the last two decades. Partially for these reasons, colloidal solutions of metallic (especially silver and gold) nanoparticles have long fascinated scientists because of their very intense colours. The intense red colour of colloidal gold nanoparticles is due to their surface plasmon absorption. This article describes the physical origin of the surface plasmon absorption in gold nanoparticles with emphasis on the Mie and also the Maxwell-Garnett theory and reviews the effects of particle size and shape on the resonance condition. A better understanding of the relationship between the optical absorption spectrum (in particular, the plasmon resonance) and such particle properties as its dimensions or surrounding environment can prove fruitful for the use of the plasmon absorption as an analytical tool. The plasmon resonance has also had a great impact on the Raman spectrum of surface-adsorbed molecules and a large enhancement of the fluorescence quantum yield of gold nanorods is observed. Furthermore, following the changes in the plasmon absorption induced by excitation (heating) with ultrashort laser pulses allows one to monitor the electron dynamics (electron-electron and electron-phonon interactions) in real time, which is important in understanding such fundamental questions regarding the thermal and electrical conductivity of these nanoparticles. Very intense heating with laser pulses leads to structural changes of the nanoparticles (nuclear rearrangements in the form of melting and fragmentation).
We present an axisymmetric computational model to study the heating processes of gold nanoparticles, specifically nanorods, in aqueous medium by femtosecond laser pulses. We use a two-temperature model for the particle, a heat diffusion equation for the surrounding water to describe the heat transfer processes occurring in the system, and a thermal interface conductance to describe the coupling efficiency at the particle/water interface. We investigate the characteristic time scales of various fundamental processes, including lattice heating and thermal equilibration at the particle/surroundings interface, the effects of multiple laser pulses, and the influence of nanorod orientation relative to the beam polarization on energy absorption. Our results indicate that the thermal equilibration at the particle/water interface takes approximately 500 ps, while the electron-lattice coupling is achieved at approximately 50 ps when a 48×14 nm gold nanorod is heated to a maximum temperature of 1270 K with the application of a laser pulse having 4.70 J/m(2) average fluence. Irradiation by multiple pulses arriving at 12.5 ns time intervals (80 MHz repetition rate) causes a temperature increase of no more than 3 degrees during the first few pulses with no substantial changes during the subsequent pulses. We also analyze the degree of the nanorods' heating as a function of their orientation with respect to the polarization of the incident light. Lastly, it is shown that the temperature change of a nanorod can be modeled using its volume equivalent sphere for femtosecond laser heating within 5-15% accuracy.
Owing to residual tumor tissues around the treatment margins, it is difficult to totally ablate large tumors, eliminate disseminated and metastatic nodules as well as prevent the tumor recurrence simultaneously by conventional photothermal therapy (PTT). In this work, PTT combined reactive oxygen species oxidative therapy (ROT) was conducted via mesoporous polydopamine nanosphere with nanoceria doping (MPDA-Ce). After surface anchoring with Arg-Gly-Asp (RGD) molecules, the dispersive stability and tumor targeting of this innovative nanoplatform were substantially boosted. In vitro studies revealed that the unique nanotherapeutics had satisfactory photothermal conversion efficiency (η = 51.41%), continuous nanoceria release in cytoplasm of tumor cells after acid microenvironment (pH = 5.5) induced biodegradation. Significantly, hyperthermia amplified the abundant reactive oxygen species generation under 808 nm laser irradiation that potent ROT was realized with only 27.1% cells alive. Strikingly, Indocyanine green (ICG) loaded MPDA-Ce with RGD modification shows robust tumor targeting capability in breast carcinoma bearing Balb/C mice under fluorescent imaging in the second near-infrared window. The combined treatments resulted in complete tumor cells eradication under 808 nm laser illumination both in vitro and in vivo. This work highlights the promising application of MPDA-Ce as a powerful nanoplatform for ROT and PTT combined treatment in clinical.
Considering the clinical limitations of individual approaches against metastatic lung cancer, the use of combined therapy can potentially improve the therapeutic effect of treatment. However, determination of the appropriate strategy of combined treatment can be challenging. In this study, combined chemo- and radionuclide therapy has been realized using radionuclide carriers (¹⁷⁷Lu-labeled core-shell particles, ¹⁷⁷Lu-MPs) and chemotherapeutic drug (cisplatin, CDDP) for treatment of lung metastatic cancer. The developed core-shell particles can be effectively loaded with ¹⁷⁷Lu therapeutic radionuclide and exhibit good radiochemical stability for a prolonged period of time. In vivo biodistribution experiments have demonstrated the accumulation of the developed carriers predominantly in lungs. Direct radiometry analysis did not reveal an increased absorbance of radiation by healthy organs. It has been shown that the radionuclide therapy with ¹⁷⁷Lu-MPs in mono-regime is able to inhibit the number of metastatic nodules (untreated mice = 120 ± 12 versus ¹⁷⁷Lu-MPs = 50 ± 7). The combination of chemo- and radionuclide therapy when using ¹⁷⁷Lu-MPs and CDDP further enhanced the therapeutic efficiency of tumor treatment compared to the single therapy (¹⁷⁷Lu-MPs = 50 ± 7 and CDDP = 65 ± 10 versus ¹⁷⁷Lu-MPs + CDDP = 37 ± 5). Thus, this work is a systematic research on the applicability of the combination of chemo- and radionuclide therapy to treat metastatic lung cancer.
Combined chemo-photothermal therapy of gold nanorods (GNRs) for cancer treatment shows better therapeutic efficiency than mono-chemotherapy, which has gained worldwide interests of scientists and clinician in both laboratory and clinic application. However, high cytotoxicity, declined delivery efficiency, and unsatisfactory therapy effect of the GNRs are still challenging in anti-cancer treatment. Herein, a series of pH-sensitively zwitterionic polypeptide conjugated GNRs were synthesized via a gold–thiol interaction for combination of chemo-photothermal therapy in cervical cancer treatment. The acid-labile hydrazone bond was utilized to incorporate the doxorubicin (DOX) for pH-sensitive drug release under tumoral environment. The as prepared GNRs conjugates demonstrated pH-triggered surface charge conversion from negative to positive when transporting from blood circulation to tumor extracellular environment, which can facilitate the cellular uptake via electrostatic interaction. After cellular internalization, the drug release was promoted by cleavage of the hydrazone in GNRs conjugates under cancer intracellular acid environment. As the effective near-infrared (NIR) photothermal materials, the as prepared GNRs conjugates can absorb NIR photo energy and convert it into heat under irradiation, which can efficiently kill the tumor cells. In cell assay, the GNRs conjugates displayed excellent biocompatibility against normal cell, enhanced cancer cell uptake, and remarkable cancer cell killing effects. In HeLa tumor-bearing mice, the GNRs conjugates demonstrated enhanced tumor inhibition efficacy by combination of chemo-photothermal therapy.
Photothermal therapy (PTT) is hampered by limited light penetration depth and cell thermoresistance induced by over-expressed heat shock proteins (HSPs). Herein, we proposed a tumor-specific enhanced NIR-II PTT through the starvation mediated thermal sensitization strategy. A semiconducting polymer with superior NIR-II fluorescence imaging (FI) performance and NIR-II PTT efficacy was synthesized and encapsulated into folate modified liposomes, together with a glycolysis inhibitor, 2-deoxy-d-glucose (2DG). Upon specifically targeting folate receptors and guidance of NIR-II FI, spatiotemporal 2DG release could be achieved by the trigger of NIR-II photothermal effect. The released 2DG could not only deplete the energy supply of tumor cells by inhibiting tumor anaerobic glycolysis, but also decrease the ATP levels and hamper the production of HSPs, ultimately enhancing the tumor thermal sensitivity toward PTT. Owing to the sensitization effect of 2DG, tumor cells with overexpressed folate receptors could be significantly damaged by NIR-II PTT with an enhanced therapeutic efficiency. The work provided a promising strategy for specific starvation/NIR-II PTT synergistic therapy towards tumors.
Lycium barbarum polysaccharides (LBP) with different molecular weights (LBP1, LBP2 and LBP3) of 92,441 Da, 7714 Da, and 3188 Da were used as stabilizers and capping agents to prepare uniformly dispersed selenium nanoparticles (SeNPs), and determined the storage stability. In addition, the anti-fatigue activity of LBP-decorated SeNPs with the best stability (LBP1-SeNPs) was estimated by using forced swimming test. The results showed that LBP1-SeNPs exhibited smaller particle size and more excellent stability than those of LBP2-SeNPs and LBP3-SeNPs when the storage time was extended to 30 days, and the average particle size was maintained at about 105.4 nm. The exhaustion swimming time of all tested dose groups of LBP1-SeNPs was significantly longer than the control group (p < 0.05), and the high-dose group among them was even obviously longer than the positive group (p < 0.05). The results of glycogen, blood urea nitrogen (BUN), blood lactic acid (BLA), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were further confirmed that LBP1-SeNPs could relieve fatigue by increasing the reserve of glycogen, enhancing antioxidant enzyme levels and regulating metabolic mechanism. These results demonstrated that LBP1-SeNPs could be developed as a potential anti-fatigue nutritional supplement.
A group of patients with adult-type soft tissue sarcoma is at high risk of local recurrence and distant metastases. Age, tumour site, histological subtype, tumour size and grade have been identified as the most important independent adverse prognostic factors. Macroscopically complete tumour resection is considered as the mainstay of treatment with the addition of preoperative or postoperative radiotherapy for extremity or trunk localisation. Retroperitoneal localisation requires compartmental resection and is associated with a worse prognosis. Here, radiotherapy is of no proven value. Perioperative chemotherapy is considered to treat micrometastatic disease not detectable at the time of diagnosis. The neoadjuvant application gives the risk of distant metastasis the greatest importance as therapy is carried out at the earliest possible time, whereas adjuvant chemotherapy is delayed by surgery and the necessary wound healing. With reported response rates up to 30%, both the operability may be improved and the risk of intraoperative tumour cell dissemination may be reduced, resulting also in reduced local relapse rates. However, the potential risk of early tumour progression may counteract this benefit. Optimised strategies with multimodality approaches including chemotherapy, regional hyperthermia (RHT) and immunotherapeutic agents have been shown to improve survival in high-risk patients. Here, we focus on the data from available randomised studies investigating the use of perioperative chemotherapy in patients with high-risk adult-type soft tissue sarcoma, including the use of RHT for local enhancement of chemotherapy effect and immune induction.
Alpha therapy provides an outstanding prospect in the treatment of recalcitrant and micrometastatic cancers. However, side effects on the normal tissues and organs (especially, kidneys) due to the release of daughter isotopes from α-emitters remain a bottleneck. In this work, calcium carbonate core-shell particles of different sizes were considered as isotope carriers for encapsulation of ²²⁵Ac (highly powerful alpha-emitter that generates 4 net alpha particle isotopes in a short decay chain) in order to achieve in vitro and in vivo retention of ²²⁵Ac and its daughter isotopes. According to the in vitro studies, the developed calcium carbonate core-shell particles were able to retain ²²⁵Ac and its daughter isotopes (²²¹Fr and ²¹³Bi) exhibited good stability in biological media and dose-dependent biocompatibility (over 30 d). The SPECT imaging demonstrated the size-dependent distribution of ²²⁵Ac-doped core-shell particles. Further, in vivo studies confirmed the high retention efficiency of calcium carbonate core-shell particles, which was demonstrated in normal Wistar rats (up to 10 d). Interestingly, the radioactivity accumulation in kidney and urine was significantly less for encapsulated ²²⁵Ac than in case of non-encapsulated form of ²²⁵Ac (²²⁵Ac conjugated with albumin), indicating the absence of radioisotope leakage from the developed particles. Thus, our study validates the application of ²²⁵Ac-doped core-shell particles to sequester α-emitter (²²⁵Ac) and its decay products in order to reduce their systemic toxicity during alpha therapy.
Low tumor mutational burden and absence of T cells within the tumor sites are typical characteristics of “cold immune tumors” that paralyzes the immune system. The strategy of reversing “cold tumors” to “hot tumors” infiltrated high degree of T cells in order to activate anti-tumor immunity has attracted lots of attentions. Herein, immunogenic core–shell [email protected] NPs is fabricated by gold-selenium coordination bond to realize nanoparticles-mediated local photothermal-triggered immunotherapy. As expected, incorporation of gold nanostars (AuNSs) with improved photothermal stability and conversion efficiency promotes the disintegration and transformation of selenium nanoparticles (SeNPs), thus leading to enhanced cancer cells apoptosis by producing higher hyperthermia. Moreover, the results of in vivo experiments demonstrate that the synergy between SeNPs-mediated chemotherapy and AuNSs-induced photothermal therapy not only generated a localized antitumor-immune response with excellent cancer killing effect under the presence of tumor-associated antigens, but also effectively reprogrammed the tumor associated macrophages (TAMs) from M2 to M1 phenotype with tumoricidal activity to devour distant tumors. Without a doubt, this study not only provides a potent strategy to reverse the immunosuppressive tumor microenvironment, but also offers a new insight for potential clinical application in tumor immunotherapy.
Hollow mesoporous particles for drug delivery and cancer therapy have attracted significant attention over recent decades. Here, we develop a simple and highly efficient strategy for preparing fluorescent hollow mesoporous carbon spheres (HMCSs). Compared with typical carbon materials such as fullerene C60, carbon nanotubes, reduced graphene oxide, and carbon nanohorns; HMCSs showed fewer effects on cell cycle distribution and lower toxicity to cells. Ten different drugs were incorporated into the HMCSs, and the maximum loading efficiency reached 42.79 ± 2.7%. Importantly, microwaves were found to improve the photothermal effect generated by HMCSs when combined with 980-nm laser irradiation. The cell killing and tumor growth inhibition efficiencies of HMCSs and drug-loaded HMCSs under co-irradiation with laser and microwaves were significantly improved compared with those under laser irradiation alone. After local administration HMCSs were only distributed in tissue at the injection site. HMCSs showed almost no toxicity in mice after local injection and could be completely removed from the injection site.
The design of magnetic nanostructures whose magnetic heating efficiency remains unaffected at the tumor site is a fundamental requirement to further advance magnetic hyperthermia in clinic. This work demonstrates that the confinement of magnetic nanoparticles (NPs) into a submicrometric cavity is a key strategy to enable a certain degree of nanoparticle motion and minimize aggregation effects, consequently preserving the magnetic heat loss of iron oxide nanocubes (IONCs) under different conditions, including intracellular environments. We fabricated magnetic Layer-by-Layer (LbL) self-assembled polyelectrolyte submicrometric capsules using three different approaches, and we studied their heating efficiency as obtained in aqueous dispersions and once internalized by tumor cells. First, IONCs were added to the hollow cavities of LbL submicrocapsules, allowing the IONCs to move to a certain extent in the capsule cavities. Second, IONCs were co-encapsulated into solid calcium carbonate cores coated with LbL polymer shells. Third, IONCs were incorporated within the polymer layers of the LbL capsule walls. In aqueous solution, the higher specific absorption rate (SAR) values were related to the ones of free IONCs, while lower SAR values were recorded for capsule/core assemblies. However, after uptake by cancer cell lines (SKOV-3 cells), the SAR values of the free IONCs were significantly lower than those observed for capsule/core assemblies, especially after prolonged incubation periods (24 and 48 hours). These results show that IONCs packed into submicrocavities preserve the magnetic losses, as SAR values remained almost invariable. Conversely, free IONCs without the protective capsule shell agglomerated and their magnetic losses are strongly reduced. Indeed, IONC loaded capsules and free IONCs reside inside endosomal and lysosomal compartments after cellular uptake, show magnetic losses strongly reduced due to the immobilization and aggregation in centrosymmetrical structures in the intracellular vesicles. The confinement of IONCs into submicrometric cavities is a key strategy to provide a sustained and predictable heating dose inside biological matrices.
Light-sensitive yolk-shell nanoparticles (YSNs) as remote-controlled and stimuli-responsive theranostic platforms provide an attractive method for synergistic cancer therapy. Herein, a kind of novel stimuli-responsive multifunctional YSNs has been successfully constructed by integrating star-shaped gold (Au star) nanoparticles as the second near-infrared (NIR-II) photothermal yolks, and biodegradable crystalline zeolitic imidazolate framework-8 (ZIF-8) as the shells. In this platform, chemotherapeutic drug (doxorubicin hydrochloride, DOX) was encapsulated into the cavity between Au star and ZIF-8, which can be controlled release due to the degradation process of ZIF-8 in the low-pH tumor microenvironment. Upon the 1064 nm (NIR-II biowindow) laser irradiation, gold [email protected] ([email protected]) nanoparticles exhibited outstanding synergistic anti-cancer effect based on their photothermal and promoted cargo release properties. Moreover, the strong NIR region absorbance endows the [email protected] of NIR thermal imaging and photoacoustic (PA) imaging properties. This work contributes to design a stimuli-responsive “all-in-one” nanocarrier that realizes bimodal imaging diagnosis and chemo- photothermal synergistic therapy.
Growth in the knowledge of cancer biology has led to the emergence and evolution of cancer nanomedicines by providing the rationale for leveraging nanotechnology to develop better treatment options. The discovery of nanometer-sized intercellular openings in the defective angiogenic tumor vasculature contributed to the development of an idea for the well-known cancer passive targeting regime, enhanced permeability and retention (EPR) effect, of the nanomedicines. Recently, reactive oxygen species (ROS) have been highlighted as one of the key players that underlie the acquisition of the various hallmarks of cancer. As ROS are associated with all stages of cancer, their applications in cancer treatment based on the following concentration-dependent implications have attracted much attention: (1) low to moderate levels of ROS as key signaling molecules, (2) elevated levels of ROS in cancer cells as one of the unique characteristics of cancer, and (3) excessive levels of ROS as cytotoxic agents. Considering ROS from a different point of view, various cancer nanomedicines have been designed to achieve spatiotemporal control of therapeutic action, the main research focus in this area. This Account includes our efforts and preclinical achievements in development of nanomedicines for a range of ROS-mediated cancer therapies. It begins with general background regarding cancer nanomedicines, the significance of ROS in cancer, and a brief overview of ROS-mediated approaches for cancer therapy. Then, this Account highlights the two key roles of ROS that define therapeutic purposes of cancer nanomedicines: (1) ROS as drug delivery enhancers and (2) ROS as cell death inducers. The former inspired us to develop nitric oxide-generating nanoparticles for improved EPR effect, endogenous ROS-responsive polymeric micelles for enhanced intracellular drug delivery, and exogenous ROS-activated micelles for subcellular localization via photochemical internalization. While refining conventional chemotherapy, recent researches also have focused on the latter, the cytotoxic ROS, to advance alternative treatment modalities such as oxidation therapy, photodynamic therapy (PDT), and sonodynamic therapy (SDT). In particular, we have been motivated to develop polymeric nanoreactors containing enzymes to produce H2O2 for oxidation therapy, photosensitizer-loaded gold-nanoclustered polymeric nanoassemblies for photothermally activated PDT overcoming the oxygen dependency of PDT, and hydrophilized TiO2 nanoparticles and Au-TiO2 nanocomposites as novel sonosensitizers for improved SDT efficiency. The integration of nanomedicine and ROS-mediated therapy has emerged as the new paradigm in the treatment of cancer, based on promising proof-of-concept demonstrations in preclinical studies. Further efforts to ensure clinical translation along with more sophisticated cancer nanomedicines to address relevant challenges are expected to be made in the coming years.
Recent advances in nanomedicine make it auspicious for cancer diagnosis and treatment. A possible non-invasive photothermal therapy (PTT) for cancer treatment could be constructed by combining the nanomedicine and laser. PTT employs photothermal agents (PTAs) with high photothermal conversion efficacy for converting light into heat to selectively kill cancer cells under the help of lasers. Because of the unique Surface Plasmon Resonance (SPR) phenomenon and the tunable near-infrared (NIR) region absorption, noble metal nanoparticles like gold nanoparticles can be applied as a PTA for PTT. Gold nanoparticles (AuNPs) offer the enhanced absorption and scattering properties, the optical properties tunability, and specific tumor targeting capability, therefore, AuNPs based PTT turns to be furthermore promising. However, drawbacks such as long retention time, cytotoxicity, and insufficient cancer cells targeting restrict the application of AuNPs as PTTs. This review overviews research of the PTT applications of various modified AuNPs in previous publications. With the advancement of chemical synthesis technology, AuNPs of various shapes and sizes can be synthesized with desired properties, which can achieve multimodal cancer treatment with enhanced anti- tumor effect. In this review, we summarized the major features of five principal types of AuNPs: gold nanorods, gold nanoshells, gold nanospheres, gold nanocages, and gold nanostars with different sizes, discussed their advantages and disadvantages in PTT. We also detailed the surface modification of AuNPs which could be beneficial for the performance of AuNPs based PTT. In addition, depending on properties of AuNPs and lasers, the underlying mechanism of cell death triggered by NIR laser can be different, which also affects the anti-cancer effects and outcomes of PTT. However, controlling cell death through a desired cell death mechanism to achieve desired PTT outcome is still a challenge.
Imaging-guided photothermal therapy (PTT) is an attractive strategy to improve the diagnosis accuracy and treatment outcomes by monitoring the accumulation of photothermal agents in tumors in real-time and determining the best treatment window. Taking advantage of the superior imaging quality of NIR II fluorescence imaging and remote-controllable phototherapy modality of PTT, we developed a facile macromolecular fluorophore (PF) by conjugating small molecule NIR-II fluorophore (Flav7) with amphiphilic polypeptide. The PF can form uniform micelles in aqueous solution, which exhibit slight negative charge. In vitro experimental results showed that the PF nanoparticles showed satisfactory photophysical properties, prominent photothermal conversion effciency (42.3%), excellent photothermal stability, negligible cytotoxicity and remarkable photothermal toxicity. Meanwhile, the PF can visualize and feature the tumors by NIR-II fluorescence imaging owing to prolonged blood circulation time and enhanced accumulation in tumors. Moreover, in vivo studies revealed that the PF nanoparticles achieved excellent photothermal ablation effect to tumors with low dose of NIR-II dye and light irradiation, and the process can be traced by NIR fluorescence imaging.
Sophisticated self-assembly may endow materials with a variety of unique functions that are highly desirable for therapeutic nanoplatform. Herein, we report the co-assembly of two structurally-defined telodendrimers, each comprised of hydrophilic linear PEG and hydrophobic cholic acid cluster as a basic amphiphilic molecular subunit. One telodendrimer has four added indocyanine green derivatives, leading to excellent photothermal properties; the other telodendrimer has four sulfhydryl groups designed for efficient inter-subunit cross-linking, contributing to superior stability during circulation. The co-assembled nanoparticle (CPCI-NP) possesses superior photothermal conversion efficiency as well as efficient encapsulation and controlled release of cytotoxic molecules and immunomodulatory agents. CPCI-NP loaded with doxorubicin has proven to be a highly efficacious combination photothermal/chemo-therapeutic nanoplatform against orthotopic OSC-3 oral cancer xenograft model. When loaded with imiquimod, a potent small molecule immunostimulant, CPCI-NP was found to be highly effective against 4T1 syngeneic murine breast cancer model, particularly when photothermal/immuno-therapy is given in combination with PD-1 checkpoint blockade antibody. Such triple therapy not only eradicates the light-irradiated primary tumors, but also activates systemic anti-tumor immunoactivity, causing tumor death at light-unexposed distant tumor sites. This co-assembled multi-functional, versatile, and easily scalable photothermal immuno-nanoplatform shows great promise for clinical translation.
We have previously demonstrated that selenium nanoparticles (SeNPs) administered via oral route possess similar capacities of increasing selenoenzyme activities as the extensively examined sodium selenite, selenomethionine and methylselenocysteine, and yet display the lowest toxicity among these selenium compounds in mouse models. However, the low toxicity of SeNPs found in mammalian systems would lead to the interpretation that the punctate distribution of elemental selenium found in cultured cancer cells subjected to selenite treatment that triggers marked cytotoxicity represents a detoxifying mechanism. The present study found that SeNPs could be reduced by the thioredoxin- or glutaredoxin-coupled glutathione system to generate ROS. Importantly, ROS production by SeNPs in these systems was more efficient than by selenite, which has been recognized as the most redox-active selenium compound for ROS production. This is because multiple steps of reduction from selenite to selenide anion are required; whereas only a single step reduction from the elemental selenium atom to selenide anion is needed to trigger redox cycling with oxygen to produce ROS. We thus speculated that accumulation of SeNPs in cancer cells would result in a strong therapeutic effect, rather than serves a detoxification function. Indeed, we showed herein that preformed SeNPs generated a potent therapeutic effect in a mouse model due to rapid, massive and selective accumulation of SeNPs in cancer cells. Overall, for the first time, we demonstrate that SeNPs have a stronger pro-oxidant property than selenite and hyper-accumulation of SeNPs in cancer cells can generate potent therapeutic effects.
Optical properties of well-known bulk materials can be significantly modified by decreasing dimensions to nm-size. Using Molecular Beam Epitaxy (MBE) and e-beam Physical Vapour Deposition (PVD) we have fabricated 20–30 nm-thick amorphous Ge, Te and Se films. The permittivities of investigated layers have been extracted from measurements of the Ψ and Δ ellipsometric azimuths. We found that for all of the investigated films, the intensity of all bands in the permittivity spectrum is smaller than for bulk materials or thick (> 100 nm) films. Using the acquired optical constants along with the permittivity of a 20 nm-thick silver film, we have applied the Maxwell-Garnett equation to predict the permittivities of a silver film with Ge, Se or Te segregated in its structure. Implementing the parameters of 20 nm-thick Ge results in an 81 nm redshift of the segregation-induced band with respect to the experimental value, while implementing the parameters of 2 nm-thick Ge film results in a 95 nm blueshift of this band.
The design of novel, effective drug delivery systems is one of the most promising ways to improve the treatment of socially important diseases. This paper reports on an innovative approach to the production of composite microcontainers (microcapsules) bearing advanced protective functions. Cerium oxide (CeO2) nanoparticles were incorporated into layer-by-layer (LbL) polyelectrolyte microcapsules as a protective shell for an encapsulated enzyme (luciferase of Photinus pyralis), preventing its oxidation by hydrogen peroxide – the most abundant type of reactive oxygen species (ROS). The protective effect depends on CeO2 loading in the shell: at a low concentration, CeO2 nanoparticles only scavenge ROS, while a higher content leads to a decrease in access for both ROS and the substrate to the enzyme in the core. By varying the concentration of the nanoparticles in the shell, it is possible to control the level of core shielding – from ROS filtering, to complete blocking. A comprehensive analysis of microcapsules by transmission electron microscopy (TEM), scanning electron microscopy (SEM), atomic force microscopy (AFM), confocal laser scanning microscopy (CLSM) and energy-dispersive X-ray spectroscopy (EDX) techniques was carried out. Composite microcapsules decorated with CeO2 nanoparticles and encapsulated luciferase were shown to be easily taken up by rat B50 neuronal cells; they are non-toxic and are able to protect cells from the oxidative stress induced by hydrogen peroxide. The approach demonstrated that the active protection of microencapsulated substances by CeO2 nanoparticles can be used in the development of new drug delivery and diagnostic systems.
This chapter first provides a brief understanding of optical spectroscopy and microscopy by focusing on popular linear techniques. These concepts are further extended to nonlinear spectroscopy/microscopy methods, which utilize coherent excitation of the target molecules to exhibit diverse modalities, thereby probing different properties of a sample. Moreover, in certain nonlinear techniques, the use of a coherent source for exciting the sample leads to the emission of coherent signal, which provides enhancement of signal to multiple orders of magnitude over linear techniques. Combining signals obtained from multiple techniques enriches information, thus helping in creating a superior microscopic image. Hence, the concept of multimodality is rapidly gaining recognition in the field of applied microscopy.
Herein, a donor-acceptor-donor (D-A-D) structured small molecule (DPP-TPA) is designed and synthesized for photoacoustic imaging (PAI) guided photodynamic/photothermal synergistic therapy. In the diketopyrrolopyrrole (DPP) molecule, thiophene group is contained to increase the intersystem crossing (ISC) ability through the heavy atom effect. Simultaneously, triphenylamine (TPA) is introduced for bathochromic shift absorption as well as charge transport capacity enhancement. After formation of nanoparticles (NPs, ~76 nm) by reprecipitation, the absorption of DPP-TPA NPs further displays obvious bathochromic-shift with the maximum absorption peak at 660 nm. What's more, the NPs architecture enhances the D-A-D structure, which greatly increases the charge transport capacity and impels the charge to generate heat by light. DPP-TPA NPs present high photothermal conversion efficiency ( = 34.5%) and excellent singlet oxygen (1O2) generation ( = 33.6%) under 660 nm laser irradiation. PAI, with high spatial resolution and deep bio-tissue penetration, indicates DPP-TPA NPs can rapidly target to the tumor sites within 2 hours by the enhanced permeability and retention (EPR) effect. Importantly, DPP-TPA NPs could effectively hinder the tumor growth by photodynamic/photothermal synergistic therapy in vivo even at a low dosage (0.2 mg/kg) upon laser irradiation (660 nm 1.0 W/cm2). This study illuminates the photothermal conversion mechanism of small organic NPs and demonstrates the promising application of DPP-TPA NPs in PAI guided phototherapy.
A new theranostic platform is developed based on biocompatible polyacrylic acid (PAA)-Co9 Se8 nanoplates. PAA-Co9 Se8 nanoplates are successfully utilized for photoacoustic imaging (PAI)/MRI dual-modal imaging. Moreover, the PAA-Co9 Se8 -DOX showed pH-responsive chemotherapy and enabled the combination of photothermal therapy and chemotherapy to receive superior antitumor efficacy. This work promises further exploration of the 2D nanoplatforms for theranostic applications.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
A combined thermal model for transient temperature field in a tumor and ambient tissue during laser heating of embedded gold nanoparticles is developed. The approach considered is based on coupling of the particular models for the absorbed radiation power and transient temperature field. A modified two-flux approximation is used for the radiative transfer in a scattering tissue containing absorbing gold nanoshells. The spectral properties of silica-core gold nanoshells are calculated using the Mie theory. The transient energy equation for composite human tissue takes into account the metabolic heat generation and heat conduction, the heat transfer with blood perfusion through capillary tubes, the continuous or periodic laser heating, and also heat transfer of a human body with ambient medium. A simplified example problem for a superficial human cancer is solved numerically to illustrate the relative role of the problem parameters on the transient temperature field in a human body during hyperthermia treatment.
We report a dramatically improved synthesis of colloidal gold nanorods (NRs) using a binary surfactant mixture composed of hexadecyltrimethylammonium bromide (CTAB) and sodium oleate (NaOL). Both thin (diameter < 25 nm) and thicker (diameter > 30 nm) gold NRs with exceptional monodispersity and broadly tunable longitudinal surface plasmon resonance can be synthesized using seeded growth at reduced CTAB concentrations (as low as 0.037 M). The CTAB-NaOL binary surfactant mixture overcomes the difficulty of growing uniform thick gold NRs often associated with the single-component CTAB system and greatly expands the dimensions of gold NRs that are accessible through a one-pot seeded growth process. Gold NRs with large overall dimensions and thus high scattering/absorption ratios are ideal for scattering-based applications such as biolabeling as well as enhancement of optical processes.
Light-responsive microcapsules constructed by layer-by-layer self-assembly are used as microcarriers to deliver different macromolecules inside cells. The microcapsules carry the macromolecules as cargo in their cavity, while their walls are modified with agglomerated gold nanoparticles. Microcapsules are incorporated by living cells and are then located in lysosomal compartments. Controlled release of the encapsulated material from the interior of the capsule to the cytosol is possible upon NIR-light irradiation. This is based on local heating of the gold nanoparticles upon NIR light and disruption of the capsule wall, what results on release of encapsulated materials. We illustrate several key advances in controlled release induced by light. First, we demonstrate that capsules can be opened individually, which allows for sequentially releasing cargo from different capsules within one single cell. Second, by using a pH-indicator as cargo the claim of release from the acidic lysosomal compartments to the neutral cytosol is experimentally evident which until now has been only speculated. Third, green fluorescent protein (GFP) is released to the cytosol while retaining its functionality. This demonstrates that proteins can be released without destruction by the local heating. Fourth, GFP is also administered in biodegradable capsules, which leads to a different release mechanism compared to externally triggering for light-responsive microcapsules.