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Relighting Photosensitizers by Synergistic Integration of Albumin and Perfluorocarbon for Enhanced Photodynamic Therapy Hao Ren, Jiaqi Liu, Fenhong Su, Sizhan Ge, Ahu Yuan, Weimin Dai, Jinhui Wu, and Yiqiao Hu ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b14885 • Publication Date (Web): 09 Jan 2017 Downloaded from http://pubs.acs.org on January 10, 2017
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ACS Applied Materials & Interfaces
Relighting Photosensitizers by Synergistic Integration of Albumin and Perfluorocarbon for Enhanced Photodynamic Therapy Hao Ren1,†, Jiaqi Liu1,†, Fenhong Su1, Sizhan Ge1, Ahu Yuan1,2,3,4,5, Weimin Dai1,Jinhui Wu1,2,3,4,5*,Yiqiao Hu1,2,3,4,5*
Affiliations: 1
State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing
University, Nanjing 210093, China 2
State Key Laboratory of Natural Medicines, China Pharmaceutical University,
Nanjing 210009, China 3
Jiangsu Key Laboratory for Nano Technology, Nanjing University, Nanjing 210093,
China 4
Institute of Drug R&D, Medical School of Nanjing University, Nanjing 210093, China
5
Jiangsu R&D platform for controlled & targeted drug delivery, Nanjing University,
Nanjing 210093, China
*: Corresponding Author Email:
[email protected] and
[email protected] †: These authors contributed equally to this work
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ABSTRACT Photodynamic therapy (PDT) is hampered by poor water solubility and skin phototoxicity of photosensitizers (PSs). Incorporation of PSs into nanocarrier (Nano-PDT) has been designed to overcome these problems. However, self-quenching of PSs highly condensed in Nano-PDT significantly reduced singlet oxygen (1O2) generation, resulting in unsatisfactory PDT efficacy. Here, we developed a novel tripleffect Nano-PDT, which has a special core-shell nanostructure by synergistic integration of perfluorotributylamine (PFTBA) and human serum albumin (HSA) to improve PDT. It has three mechanisms to relight quenched PSs, generating more 1
O2.First, PSs uniformly dispersed in the shell, preventing self-quenching caused by
π-π stacking. Second, HSA as nanocarrier extends the triplet state lifetimes of PSs, increasing the amount of 1O2. Third, PFTBA as core dissolves and protects1O2 to extend the duration time of action of 1O2. Compared with PS-encapsulated Nano-PDT, the self-quenching of PSs in tripleffect Nano-PDT can be effectively overcome. The fluorescence and 1O2 generationof PSare increased by approximately 100-fold and 15-fold, respectively. After intravenous injection into tumor-bearing mice, the tumor growth is significantly inhibited, while the PS-encapsulated Nano-PDTalmost has no effect. The novel tripleffect Nano-PDT may guide improvement of existing clinical PDT and future PDT design. KEYWORDS: photodynamic therapy, self-quenching, tripleffect, human serum albumin, perfluorocarbon, core-shell structure
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ACS Applied Materials & Interfaces
INTRODUCTION Photodynamic therapy (PDT) is a promising alternative approach for treatment of solid tumor and other diseases 1-2. In PDT, photosensitizers (PSs) are irradiated by light of a specific wavelength and then produce a number of toxic singlet oxygen (1O2) to kill cells3. Compared with other treatment method such as chemotherapy and radiotherapy, PDT is minimally invasive and toxic4. It avoids systematic treatment since treatment occurs only where light is delivered. However, a number of shortages related to conventional PDT hampered their success in clinical use5-6. Firstly, water solubility of most PSs is too low to be administered7. For example, Hypericin (HYP) is a naturally occurring red plant pigment extracted from Hypericum perforatum. It has drawn increased interest due to its high quantum yields of 1O28. However, its hydrophobicity leads to difficulties in administration, but also leads to a decline in PDT 9. Secondly, nonspecific tissue distribution of PSs induces unexpected side effects such as skin photoxicity10-11. For example, photofrinas first generation PS was nonspecific distributed in skin12. Patients treated by photofrinhave to wear protective clothes and stay in the dark room for a long time after treatment to avoid skin phototoxicity4, 13. To overcome these difficulties, incorporation of PSs in nanostructured drug delivery system (Nano-PDT) such as polymeric nanoparticles, liposomes, etc. is a potential method
14-15
. It may improve delivery of poorly water-soluble PSs, and
facilitate transcytosis of PSs across endothelial barriers2, 16. It has also beenachieved great interest to combine chemotherapy for effective cancer treatment17-19. However, encapsulation of PSs into nanocarriers induces the aggregation of PSs, resulting in their 3
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reduced PDT efficacy, because the condensed PSs in nanoparticles are more easily to form aggregates than free PSs through π-π stacking20-24. Therefore, the currently main challenge in design of Nano-PDT is confining PSs inside nanoparticles at high concentrations without affecting their
1
O2 quantum yield. Some groups have
developed supramolecular dendrimer PSs in which the core of PSs is surrounded by large dendritic wedges 25-27. However, besides the complicated synthesis process, PSs cannot be loaded at high efficiency due to the steric hindrance of dendritic wedges. Other groups designed PSs-based nanoscale metal-organic framework (NMOF) to avoid the π-π stacking of PSs28-30.However, the biocompatibility and biosafety of NMOF have to be extensively evaluated before it can be used in human beings. Herein, our aim is to develop a simple method to confine PSs inside nanoparticles at high concentrations without affecting their 1O2 quantum yield. In our mind, to be used in human beings in the future, the preparation method should be simple so that it can be produced in large-scale and nanocarrier should be biocompatible and biosafety. Human serum albumin (HSA) has been successfully approved by FDA for the delivery of paclitaxel (Abraxane®)31-32. Our lab developed a series nanodelivery system based on albumin and found that the loading can be extremely high (~80% w/w)33-35. Using the same method, PSs can be also loaded inside HSA at extremely high efficiency (>70% w/w), which is much higher than that using lipid as nanocarrier (
