Multifunctional gold nanostar conjugates for tumor imaging and combined photothermal and chemo-therapy

Uniform gold nanostars (Au NS) were conjugated with cyclic RGD (cRGD) and near infrared (NIR) fluorescence probe (MPA) or anti-cancer drug (DOX) to obtain multi-functional nanoconstructs, Au-cRGD-MPA and Au-cRGD-DOX respectively. The NIR contrast agent Au-cRGD-MPA was shown to have low cytotoxicity. Using tumor cells and tumor bearing mice, these imaging nanoparticles demonstrated favorable tumor-targeting capability mediated by RGD peptide binding to its over-expressed receptor on the tumor cells. The multi-therapeutic analogue, Au-cRGD-DOX, integrates targeting tumor, chemotherapy and photo-thermotherapy into a single system. The synergistic effect of photo-thermal therapy and chemotherapy was demonstrated in different tumor cell lines and in vivo using S180 tumor-bearing mouse models. The viability of MDA-MB-231 cells was only 40 % after incubation with Au-cRGD-DOX and irradiation with NIR light. Both tail vein and intratumoral injections showed Au-cRGD-DOX treated mice exhibiting the slowest tumor increase. These results indicate that the multifunctional nanoconstruct is a promising combined therapeutic agent for tumor-targeting treatment, with the potential to enhance the anti-cancer treatment outcomes

Design and Synthesis of Multifunctional Nanocomposites for Cancer Therapy and Bioseparation

近年来，纳米材料的生物应用研究受到越来越广泛的关注，纳米材料在疾病检测与诊断、治疗和生物分离等方面都展示出了独特的优越性与发展潜力。针对纳米材料的肿瘤治疗和生物分离应用，本论文重点发展实现相关纳米材料多功能耦合的化学途径，以优化其性能，主要开展的工作包括:(1)设计、合成钯纳米片/介孔二氧化硅纳米复合载药体系，并应用于肿瘤细胞的近红外光热疗-化学联合治疗；(2)高分子包裹的磁性纳米颗粒的合成研究及在蛋白质分离纯化中的应用。展开具体的研究内容与研究成果包括以下六个部分： 第一章：从构建纳米材料的结构角度出发，简要总结了多功能纳米复合材料在抗癌联合治疗和蛋白质的分离纯化领域中的应用进展状况，并...Recently, the bioapplications of nanomaterials have attached more and more attention. Especilly in disease diagnosis, disease therapy and bioseparation, nanomaterials exhibit unique superiority and high development potential. Aiming at nanomaterials in the application of the area of anticancer therapy and purification of proteins, this thesis sheds light on developing coupling chemical methods to ...学位：理学博士院系专业：化学化工学院化学系_纳米材料化学学号：2052009015330

Methotrexate-loaded multifunctional nanoparticles with near-infrared irradiation for the treatment of rheumatoid arthritis

Backgrounds: Despite the advances of rheumatoid arthritis (RA) therapeutics, several patients do not receive adequate treatment due to the toxicity and/or insufficient response of drugs. The aim of this study is to design photothermally controlled drug release from multifunctional nanoparticles (MNPs) at a near-infrared (NIR) irradiated site to improve therapeutic efficacy for RA and reduce side effects. Methods: Au film was deposited onto methotrexate (MTX)-loaded poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PLGA) nanoparticles, resulting in MTX-loaded MNPs. The synergistic effects of MTX-loaded MNPs with NIR irradiation were investigated using RA fibroblast-like synoviocytes (FLSs) and collagen-induced arthritis (CIA) mice. Results: Upon NIR irradiation, NIR resonance of the Au half-shell generated heat locally, accelerating MTX release from PLGA nanoparticles. In vivo NIR images of MTX-loaded MNPs indicated effective delivery of the MNPs to the inflamed joints. Moreover, in collagen-induced arthritis mice, MTX-loaded MNPs containing 1/1400 of MTX solution (repeated-dose administration) had therapeutic effects comparable to conventional treatment with MTX solution. In vitro experiments showed higher therapeutic efficacy of MTX-loaded MNPs with NIR irradiation than that of chemotherapy alone. Conclusions: A combination therapy of MTX-loaded MNP and NIR irradiation showed durable and good treatment efficacy for the suppression of arthritis in a single administration of small dose of MTX. Our results demonstrate that the treatment modality using drug-loaded MNP with NIR irradiation may be a promising therapeutic strategy for the treatment of RA and allow in vivo NIR optical imaging.ope

Enhanced EPR directed and Imaging guided Photothermal Therapy using Vitamin E Modified Toco-Photoxil

Herein we report synthesis, characterization and preclinical applications of a novel hybrid nanomaterial Toco-Photoxil developed using vitamin E modified gold coated poly (lactic-co-glycolic acid) nanoshells incorporating Pgp inhibitor d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a highly inert and disintegrable photothermal therapy (PTT) agent. Toco-Photoxil is highly biocompatible, physiologically stable PTT material with an average diameter of 130 nm that shows good passive accumulation (2.3% ID) in solid tumors when delivered systemically. In comparison to its surface modified counterparts such as IR780-Toco-Photoxil, FA-Toco-Photoxil or FA-IR780-Toco-Photoxil accumulation are merely ~0.3% ID, ~0.025% ID and ~0.005% ID in folate receptor (FR) negative and positive tumor model. Further, Toco-Photoxil variants are prepared by tuning the material absorbance either at 750 nm (narrow) or 915 nm (broad) to study optimal therapeutic efficacy in terms of peak broadness and nanomaterial’s concentration. Our findings suggest that Toco-Photoxil tuned at 750 nm absorbance is more efficient (P = 0.0097) in preclinical setting. Toco-Photoxil shows complete passiveness in critical biocompatibility test and reasonable body clearance. High tumor specific accumulation from systemic circulation, strong photothermal conversion and a very safe material property in body physiology makes Toco-Photoxil a superior and powerful PTT agent, which may pave its way for fast track clinical trial in future

Mitochondrial targeting theranostic nanomedicine and molecular biomarkers for efficient cancer diagnosis and therapy.

Mitochondria play a crucial part in the cell's ability to adapt to the changing microenvironments and their dysfunction is associated with an extensive array of illnesses, including cancer. Mitochondrial dysfunction has been identified as a potential therapeutic target for cancer therapy. The objective of this article is to give an in-depth analysis of cancer treatment that targets the mitochondrial genome at the molecular level. Recent studies provide insights into nanomedicine techniques and theranostic nanomedicine for mitochondrial targeting. It also provides conceptual information on mitochondrial biomarkers for cancer treatment. Major drawbacks and challenges involved in mitochondrial targeting for advanced cancer therapy have also been discussed. There is a lot of evidence and reason to support using nanomedicine to focus on mitochondrial function. The development of a delivery system with increased selectivity and effectiveness is a prerequisite for a theranostic approach to cancer treatment. If given in large amounts, several new cancer-fighting medicines have been created that are toxic to healthy cells as well. For effective therapy, a new drug must be developed rather than an old one. When it comes to mitochondrial targeting therapy, theranostic techniques offer valuable insight

Development of Hybrid Nanoplatforms for Theranostic Applications

There is a need of new approaches in which cancer and other diseases are adressed. These new methods must be capable to reduce doses, treatment times, and damage to healty tissues. Furthermore, it is desirable that these systems function as diagnosis and imaging agents, so the evolution of the disease can be visualized in real time and decisions about treatment regimes can be made as soon as possible. The combination of therapeutic and diagnostic/imaging agents in one system creates a new concept called theranostics; hence, a theranostic system can treat the disease and, at the same time, work as a diagnostic and imaging agent. The objective of this thesis has been the synthesis, characterization and evaluation of different multifunctional theranostic nanoplatforms that can be applied in cancer treatment, diagnosis and imaging. The processes used to prepare them have involved low energy consumption and most of the materials were biocompatible. The results obtained from their physicochemical characterization and performance in vitro and in vivo suggest that these nanoplatforms could be used as anticancer treatments with more effective results, allowing lower doses, treatment times, and combined therapies applied locally and simultaneously

Drug-loaded Gold Plasmonic Nanoparticles for In Vivo Therapy of Multidrug Resistance in Cancer and Rheumatoid Arthritis

의과대학/박사Gold (Au) plasmonic nanoparticles (NPs) containing doxorubicin (DOX) for the treatment of multidrug resistance (MDR) in cancer were developed. To investigate the possibility of treating multidrug-resistant tumors with targeted chemo-photothermal treatment, in vitro and in vivo studies were conducted using a doxorubicin (DOX)-resistant DLD-1 cell line (DLD-1/DOX) and nude mice with human xenograft tumors, respectively. The chemo-photothermal treatment consisted of DOX-loaded-poly(lactic-co-glycolic acid, PLGA)-Au half-shell nanoparticles with targeting moieties of anti-death receptor-4 monoclonal antibody conjugated to the Au surface. The cells or xenografted tumors treated with nanoparticles were exposed to near infrared light for 10 min, which caused an increase in temperature to 45 °C. Chemo-photothermal treatment resulted in a large reduction in the rate of tumor xenograft growth on DLD-1/DOX tumor-bearing mice with a much smaller dose of DOX than conventional DOX chemotherapy. These results demonstrate that targeted chemo-photothermal treatment can provide high therapeutic efficacy and low toxicity in the treatment of multidrug-resistant tumors. RGD-attached gold (Au) plasmonic nanoparticles (NPs) containing methotrexate (MTX) for the treatment of rheumatoid arthritis (RA) were also developed. The MTX is the most widely used disease modifying anti-rheumatic drug (DMARD) for the treatment of RA, and RGD peptide (arginine-glycine-aspartic acid) is a targeting moiety for inflammation. Upon near-infrared (NIR) irradiation, heat is locally generated due to Au half shells, and the drug release rate is enhanced, delivering heat and drug to the inflamed joints simultaneously. RA is a chronic inflammatory disease characterized by synovial inflammation in multiple joints within the penetration depth of NIR light. When combined with NIR irradiation, these nanoparticles containing a much smaller dosage of MTX (1/930 of MTX solution) showed greater therapeutic effects than that of a conventional treatment with MTX solution in collagen-induced arthritic (CIA) mice. This novel drug delivery system is a good way to maximize therapeutic efficacy and minimize dosage-related MTX side effects in the treatment of RA. Furthermore, these multifunctional nanoparticles could be applied to other DMARDs for RA or other inflammatory diseases. Similar results were obtained using MTX-loaded PLGA gold (Au)/iron (Fe)/gold (Au) half-shell nanoparticles conjugated with RGD, which can be applied for magnetic targeted chemo-photothermal treatment, and in vivo multimodal imaging of RA. The Fe half-shell layer embedded between the Au half-shell layers enables in vivo T2 -magnetic resonance (MR) imaging in addition to NIR absorbance imaging. Furthermore, the delivery of the nanoparticles to the inflammation region in CIA mice, and their retention can be enhanced under external magnetic field. When combined with consecutive NIR irradiation and external magnetic field application, these nanoparticles provide enhanced therapeutic effects with an MTX dosages of only 0.05% dosage compared to free MTX therapy for the treatment of RA.ope