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      pH-Responsive Aerobic Nanoparticles for Effective Photodynamic Therapy

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          Abstract

          Rationale: Photodynamic therapy (PDT), an O 2-dependent treatment for inhibition of cancer proliferation, suffers from the low therapeutic effect in clinical application due to the hypoxic microenvironment in tumor cells.

          Methods: To overcome this obstacle, a stimuli-responsive drug delivery system with O 2 self-sufficiency for effective PDT was developed. In this study, pH-responsive aerobic nanoparticles were prepared by the electrostatic interaction between the O 2-evolving protein Catalase and Chitosan. Subsequently, the photosensitizer Chlorin e6 (Ce6) was encapsulated in the nanoparticles.

          Results: The nanoparticles exhibited high stability in aqueous medium and efficient cellular uptake by tumor cells facilitating their accumulation in tumors by enhanced permeability and retention (EPR) effect. In acidic environment, irradiation caused disassembly of the nanoparticles resulting in the quick release of Catalase and the photosensitizer with continuous formation of cytotoxic singlet oxygen ( 1O 2) greatly enhancing the PDT efficacy in hypoxic tumor tissues both in vitro and i n vivo biological studies.

          Conclusion: Due to the unique O 2 self-sufficiency, the nanoparticles, upon irradiation, exhibited higher anticancer activity than free Ce6 both in vitro and in vivo. Our work has identified a new pH-triggered strategy to overcome hypoxia for effective PDT against cancer cells.

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          Most cited references24

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          Beyond the Barriers of Light Penetration: Strategies, Perspectives and Possibilities for Photodynamic Therapy

          Photodynamic therapy (PDT) is a photochemistry based treatment modality that involves the generation of cytotoxic species through the interactions of a photosensitizer molecule with light irradiation of an appropriate wavelength. PDT is an approved therapeutic modality for several cancers globally and in several cases has proved to be effective where traditional treatments have failed. The key parameters that determine PDT efficacy are 1. the photosensitizer (nature of the molecules, selectivity, and macroscopic and microscopic localization etc.), 2. light application (wavelength, fluence, fluence rate, irradiation regimes etc.) and 3. the microenvironment (vascularity, hypoxic regions, stromal tissue density, molecular heterogeneity etc.). Over the years, several groups aimed to monitor and manipulate the components of these critical parameters to improve the effectiveness of PDT treatments. However, PDT is still misconstrued to be a surface treatment primarily due to the limited depths of light penetration. In this review, we present the recent advances, strategies and perspectives in PDT approaches, particularly in cancer treatment, that focus on increasing the 'damage zone' beyond the reach of light in the body. This is enabled by a spectrum of approaches that range from innovative photosensitizer excitation strategies, increased specificity of phototoxicity, and biomodulatory approaches that amplify the biotherapeutic effects induced by photodynamic action. Along with the increasing depth of understanding of the underlying physical, chemical and physiological mechanisms, it is anticipated that with the convergence of these strategies, the clinical utility of PDT will be expanded to a powerful modality in the armamentarium for the management of cancer.
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            Supramolecular photonic therapeutic agents.

            A new approach to achieving selectivity for photodynamic therapy based upon the reversible off/on switching of the key therapeutic property (singlet oxygen generation) of a supramolecular photonic therapeutic agent (SPTA) in response to an external stimulus in the surrounding microenvironment is described. A series of SPTA analogues with pH responsive receptors of varying pKa are presented, in which the generation of singlet oxygen is shown to be dependent upon a proton source. For example, systems have been constructed such that the excited state energy of the photosensitizer can be decayed by a rapid photoinduced electron transfer (PET) mechanism, resulting in virtually no singlet oxygen being generated, but when the amine receptor is protonated the PET mechanism does not operate and singlet oxygen is produced. In vitro efficacy demonstrated that the SPTA derivatives can be activated within cells and one analogue is measured to have an EC50 value of 5.8 nM when assayed in the MRC5 cell line.
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              Hypoxia inducible factor (HIF-1a and HIF-2a) expression in early esophageal cancer and response to photodynamic therapy and radiotherapy.

              Hypoxia inducible factor 1a and 2a (HIF-1a and HIF-2a) are key proteins regulating cellular response to hypoxia. Because the efficacy of photodynamic therapy (PDT) is dependent on the presence of oxygen, the assessment of HIF-1a and HIF-2a expression may be of value in predicting clinical response to PDT. Using recently produced MoAbs, we examined the expression of HIF1a and HIF2a in a series of 37 early-stage esophageal cancers treated with PDT and with additional radiotherapy in case of incomplete response after PDT. Strong expression of the HIF1a and of HIF2a proteins in all optical fields examined was noted in 51% and in 13% of cases, respectively. High expression was associated with a low complete response (CR) rate and with the absence of bcl-2 protein expression. On the contrary, bcl-2 expression was associated with a high CR rate. Combined analysis of HIF1a and bcl-2 protein expression revealed that of 16 cases with high HIF1a expression and the absence of bcl-2 reactivity, only 1 (7%) responded completely to PDT (P = 0.007). Bivariate analysis showed that HIF1a expression was independently related to response to PDT (P = 0.04; t ratio = 2.8), whereas bcl-2 approached significance (P = 0.07; t-ratio = 1.8). The final response to radiotherapy was high (70%) and independent of the HIF and bcl-2 status, which may be a result of reoxygenation after cellular depletion mediated by PDT. The present study suggests that assessment of HIF and of bcl-2 expression are important predictors of in vivo sensitivity to PDT. Modulation of PDT response with bioreductive drugs and/or drugs targeting bcl-2 (i.e., taxanes) may prove of significant therapeutic importance in a subgroup of patients with high HIF expression.
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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2017
                13 October 2017
                : 7
                : 18
                : 4537-4550
                Affiliations
                [1 ]Department of Oral & Maxillofacial-Head & Neck Oncology, Shanghai Key Laboratory of Stomatology Cosmetic Laser Center, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P. R. China.
                [2 ]School of Chemistry and Chemical Engineering, Shanghai Key Lab of Electrical Insulation and Thermal Aging, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China.
                [3 ]School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, P. R. China.
                Author notes
                ✉ Corresponding authors: Xinyuan Zhu, Ph.D., School of Chemistry and Chemical Engineering, Shanghai Key Lab of Electrical Insulation and Thermal Aging, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, P. R. China. Guoyu Zhou, Ph.D., and Zhiyuan Zhang, Ph.D., Department of Oral &Maxillofacial-Head Neck Oncology, Shanghai Jiao Tong University School of Medicine, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, P. R. China. E-mail: xyzhu@ 123456sjtu.edu.cn , guoyuzhou@ 123456hotmail.com , zhzhy0502@ 123456163.com

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                thnov07p4537
                10.7150/thno.19546
                5695147
                29158843
                f97fdee6-fb61-452a-b5b7-9c366bf45d3a
                © Ivyspring International Publisher

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 7 February 2017
                : 28 August 2017
                Categories
                Research Paper

                Molecular medicine
                ph-responsive,nanoparticles,catalase,hydrogen peroxide,photodynamic therapy
                Molecular medicine
                ph-responsive, nanoparticles, catalase, hydrogen peroxide, photodynamic therapy

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