聚合物纳米光诊疗剂的制备与应用新进展

doi:10.7517/j.issn.1674-0475.2017.04.008

摘要/Abstract

摘要：

共轭聚合物纳米颗粒是由π-共轭有机聚合物组成的尺寸在1～100 nm范围内的新型有机纳米材料。与传统的有机小分子、半导体量子点和无机纳米材料相比，聚合物纳米颗粒具有光学性质特殊、结构多样、表面易修饰和生物相容性好等优点，因而被广泛应用于生物成像、传感与检测、载药和治疗等领域。本文主要围绕聚合物纳米颗粒的制备方法、性质结构和生物相容性等方面，重点介绍了聚合物纳米颗粒作为光诊疗剂在荧光成像、光声成像，以及光动力和光热治疗领域的研究进展，并对聚合物纳米颗粒的发展前景和未来面临的挑战进行了探讨。

关键词: 聚合物纳米颗粒, 光诊疗, 荧光成像, 光声成像, 光动力治疗, 光热治疗

Abstract:

Conjugated polymer nanoparticles (PNPs), which consist of π-conjugated organic polymers, are novel organic nanomaterials with the size in the range of 1-100 nm. Compared with the traditional organic small molecules, semiconductor quantum dots and inorganic nanomaterials, the PNPs show great potential applications in biological imaging, sensing and detection, drug delivery and theranostic, due to its advantages of special optical properties, diverse structure, easy surface modification and good biocompatibility. In this paper, we present a review of current development in PNPs, including their preparation, properties, and biocompatibility. Significantly, we summarized the new progress in preparation of versatile PNPs as phototheranostics for cancer, the problems needed to solve in future.

Key words: polymer nanoparticle, phototheranostics, fluorescence imaging, photoacoustic imaging, photodynamic therapy, photothermal therapy

郭亮, 葛介超. 聚合物纳米光诊疗剂的制备与应用新进展[J]. 影像科学与光化学, 2017, 35(4): 445-463.

GUO Liang, GE Jiechao. New Progress Design and Synthesis of Versatile Polymer Nanoparticles as Phototheranostics for Cancer[J]. Imaging Science and Photochemistry, 2017, 35(4): 445-463.

参考文献

[1] Ng K K, Zheng G. Molecular interactions in organic nanoparticles for phototheranostic applications[J]. Chemical Reviews, 2015, 115(19): 11012-11042.
[2] Zhang P C, Hu C H, Ran W, Meng J, Yin Q, Li Y P. Recent progress in light-triggered nanotheranostics for cancer treatment[J]. Theranostics, 2016, 6(7): 948-968.
[3] Lim E K, Kim T, Paik S, Haam S, Huh Y M, Lee K. Nanomaterials for theranostics: recent advances and future challenges[J]. Chemical Reviews, 2014, 115(1): 327-394.
[4] Li K, Liu B. Polymer-encapsulated organic nanoparticles for fluorescence and photoacoustic imaging[J]. Chemical Society Revivews, 2014, 43(18): 6570-6597.
[5] Lee S Y, Jeon S I, Jung S, Chung I J, Ahn C H. Targeted multimodal imaging modalities[J]. Advanced Drug Delivery Reviews, 2014, 76: 60-78.
[6] Smith B R, Gambhir S S. Nanomaterials for in vivo imaging[J]. Chemical Reviews, 2017, 117(3): 901-986.
[7] Huynh E, Leung B Y, Helfield B L, Shakiba M, Gandier J A, Jin C S, Master E R, Wilson B C, Goertz D E, Zheng G. In situ conversion of porphyrin microbubbles to nanoparticles for multimodality imaging[J]. Nature Nanotechnology, 2015, 10(4): 325-332.
[8] Kuo W S, Chang C N, Chang Y T, Yang M H, Chien Y H, Chen S J, Yeh C S. Gold nanorods in photodynamic therapy, as hyperthermia agents, and in near-infrared optical imaging[J]. Angewandte Chemie International Edition, 2010, 122(15): 2771-2775.
[9] Rieffel J, Chen F, Kim J, Chen G, Shao W, Shao S, Chitgupi U, Hernandez R, Graves S A, Nickles R J. Hexamodal imaging with porphyrin-phospholipid-coated upconversion nanoparticles[J]. Advanced Materials, 2015, 27(10): 1785-1790.
[10] Elsabahy M, Heo G S, Lim S-M, Sun G, Wooley K L. Polymeric nanostructures for imaging and therapy[J]. Chemical Reviews, 2015, 115(19): 10967-11011.
[11] Chen G, Roy I, Yang C, Prasad P N. Nanochemistry and nanomedicine for nanoparticle-based diagnostics and therapy[J]. Chemical Reviews, 2016, 116(5): 2826-2885.
[12] Lucky S S, Soo K C, Zhang Y. Nanoparticles in photodynamic therapy[J]. Chemical Reviews, 2015, 115(4): 1990-2042.
[13] Chen Q, Feng L, Liu J, Zhu W, Dong Z, Wu Y, Liu Z. Intelligent albumin-MnO₂ nanoparticles as pH-/H₂O₂-responsive dissociable nanocarriers to modulate tumor hypoxia for effective combination therapy[J]. Advanced Materials, 2016, 28(33): 7129-7136.
[14] Bertout J A, Patel S A, Simon M C. The impact of O₂ availability on human cancer[J]. Nature Review Cancer, 2008, 8(12): 967-975.
[15] Jaque D, Maestro L M, Del Rosal B, Haro-Gonzalez P, Benayas A, Plaza J, Rodriguez E M, Sole J G. Nanoparticles for photothermal therapies[J]. Nanoscale, 2014, 6(16): 9494-9530.
[16] Cheng L, Wang C, Feng L, Yang K, Liu Z. Functional nanomaterials for phototherapies of cancer[J]. Chemical Reviews, 2014, 114(21): 10869-10939.
[17] Yang X, Yang M X, Pang B, Vara M, Xia Y N. Gold nanomaterials at work in biomedicine[J]. Chemical Reviews, 2015, 115(19): 10410-10488.
[18] Deng X R, Chen Y Y, Cheng Z Y, Deng K R, Hou Z Y, Liu B, Huang S S, Jin D Y, Lin J. Rational design of a comprehensive cancer therapy platform using temperature-sensitive polymer grafted hollow gold nanospheres: simultaneous chemo/photothermal/photodynamic therapy triggered by a 650 nm laser with enhanced anti-tumor efficacy[J]. Nanoscale, 2016, 8(12): 6837-6850.
[19] Lin J, Wang S J, Huang P, Wang Z, Chen S H, Niu G, Li W W, He J, Cui D X, Lu G M. Photosensitizer-loaded gold vesicles with strong plasmonic coupling effect for imaging-guided photothermal/photodynamic therapy[J]. ACS Nano, 2013, 7(6): 5320-5329.
[20] Wang J, Zhu G, You M, Song E, Shukoor M I, Zhang K, Altman M B, Chen Y, Zhu Z, Huang C Z. Assembly of aptamer switch probes and photosensitizer on gold nanorods for targeted photothermal and photodynamic cancer therapy[J]. ACS Nano, 2012, 6(6): 5070-5077.
[21] Wang S J, Huang P, Nie L M, Xing R J, Liu D B, Wang Z, Lin J, Chen S H, Niu G, Lu G M. Single continuous wave laser induced photodynamic/plasmonic photothermal therapy using photosensitizer-functionalized gold nanostars[J]. Advanced Materials, 2013, 25(22): 3055-3061.
[22] Hong G S, Diao S, Antaris A L, Dai H J. Carbon nanomaterials for biological imaging and nanomedicinal therapy[J]. Chemical Reviews, 2015, 115(19): 10816-10906.
[23] Tian B, Wang C, Zhang S, Feng L Z, Liu Z. Photothermally enhanced photodynamic therapy delivered by nano-graphene oxide[J]. ACS Nano, 2011, 5(9): 7000-7009.
[24] Yan X F, Hu H, Lin J, Jin A J, Niu G, Zhang S L, Huang P, Shen B Z, Chen X Y. Optical and photoacoustic dual-modality imaging guided synergistic photodynamic/photothermal therapies[J].Nanoscale,2015,7(6): 2520-2526.
[25] Bhaumik J, Mittal A K, Banerjee A, Chisti Y, Banerjee U C. Applications of phototheranostic nanoagents in photodynamic therapy[J]. Nano Research, 2015, 8(5): 1373-1394.
[26] Li Y P, Lin T Y, Luo Y, Liu Q Q, Xiao W C, Guo W C, Lac D, Zhang H Y, Feng C H, Wachsmann-Hogiu S. A smart and versatile theranostic nanomedicine platform based on nanoporphyrin[J]. Nature Communications, 2014, 5: 4712.
[27] Song X J, Chen Q, Liu Z. Recent advances in the development of organic photothermal nano-agents[J]. Nano Research, 2015, 8(2): 340-354.
[28] Lv G X, Guo W S, Zhang W, Zhang T B, Li S Y, Chen S Z, Eltahan A S, Wang D L, Wang Y Q, Zhang J, Wang P C, Chang J, Liang X J. Near-infrared emission CuInS/ZnS quantum dots: all-in-one theranostic nanomedicines with intrinsic fluorescence/photoacoustic imaging for tumor phototherapy[J]. ACS Nano, 2016, 10(10): 9637-9645.
[29] Hu J, Tang Y A, Elmenoufy A H, Xu H B, Cheng Z, Yang X L. Nanocomposite-based photodynamic therapy strategies for deep tumor treatment[J]. Small, 2015, 11(44): 5860-5887.
[30] Feng L H, Zhu C L, Yuan H X, Liu L B, Lv F T, Wang S. Conjugated polymer nanoparticles: preparation, properties, functionalization and biological applications[J]. Chemical Society Revivews, 2013, 42(16): 6620-6633.
[31] Yu J, Rong Y, Kuo C T, Zhou X H, Chiu D T. Recent advances in the development of highly luminescent semiconducting polymer dots and nanoparticles for biological imaging and medicine[J]. Analytical Chemistry, 2017, 89(1): 42-56.
[32] Lyu Y, Pu K Y. Recent advances of activatable molecular probes based on semiconducting polymer nanoparticles in sensing and imaging[J]. Advanced Science, 2017, 4(5): 1600481.
[33] Wu C F, Chiu D T. Highly fluorescent semiconducting polymer dots for biology and medicine[J]. Angewandte Chemie International Edition, 2013, 52(11): 3086-3109.
[34] Zhu C L, Liu L B, Yang Q, Lv F T, Wang S. Water-soluble conjugated polymers for imaging, diagnosis, and therapy[J]. Chemical Reviews, 2012, 112(8): 4687-4735.
[35] Chan Y H, Wu P J. Semiconducting polymer nanoparticles as fluorescent probes for biological imaging and sensing[J]. Particle & Particle Systems Characterization, 2015, 32(1): 11-28.
[36] Pu K Y, Chattopadhyay N, Rao J H. Recent advances of semiconducting polymer nanoparticles in in vivo molecular imaging[J]. Journal of Controlled Release, 2016, 240: 312-322.
[37] Szymanski C, Wu C F, Hooper J, Salazar M A, Perdomo A, Dukes A, McNeill J. Single molecule nanoparticles of the conjugated polymer MEH-PPV, preparation and characterization by near-field scanning optical microscopy[J]. Journal of Physical Chemistry B, 2005, 109(18): 8543-8546.
[38] Wu C F, Szymanski C, Cain Z, McNeill J. Conjugated polymer dots for multiphoton fluorescence imaging[J]. Journal of the American Chemical Society, 2007, 129(43): 12904-12905.
[39] Zhang X J, Yu J B, Wu C F, Jin Y H, Rang Y, Ye F M, Chiu D T. Importance of having low-density functional groups for generating high-performance semiconducting polymer dots[J]. ACS Nano, 2012, 6(6): 5429-5439.
[40] Landfester K, Montenegro R, Scherf U, Guntner R, Asawapirom U, Patil S, Neher D, Kietzke T. Semiconducting polymer nanospheres in aqueous dispersion prepared by a miniemulsion process[J]. Advanced Materials, 2002, 14(9): 651-655.
[41] Li K, Pan J, Feng S S, Wu A W, Pu K Y, Liu Y, Liu B. Generic strategy of preparing fluorescent conjugated-polymer-loaded poly (DL-lactide-co-glycolide) nanoparticles for targeted cell imaging[J]. Advanced Functional Materials, 2009, 19(22): 3535-3542.
[42] Xing C F, Xu Q L, Tang H W, Liu L B, Wang S. Conjugated polymer/porphyrin complexes for efficient energy transfer and improving light-activated antibacterial activity[J]. Journal of the American Chemical Society, 2009, 131(36): 13117-13124.
[43] Yang G M, Liu L B, Yang Q, Lv F T, Wang S. A multifunctional cationic pentathiophene: synthesis, organelle‐selective imaging, and anticancer activity[J]. Advanced Functional Materials, 2012, 22(4): 736-743.
[44] Chong H, Nie C Y, Zhu C L, Yang Q, Liu L B, Lv F T, Wang S. Conjugated polymer nanoparticles for light-activated anticancer and antibacterial activity with imaging capability[J]. Langmuir, 2012, 28(4): 2091-2098.
[45] Eggeling C, Widengren J, Rigler R, Seidel C A M. Photobleaching of fluorescent dyes under conditions used for single-molecule detection: evidence of two-step photolysis[J]. Analytical Chemistry, 1998, 70(13): 2651-2659.
[46] Wu C F, Bull B, Szymanski C, Christensen K, McNeill J. Multicolor conjugated polymer dots for biological fluorescence imaging[J]. ACS Nano, 2008, 2(11): 2415-2423.
[47] Galland C, Ghosh Y, Steinbrück A, Sykora M, Hollingsworth J A, Klimov V I, Htoon H. Two types of luminescence blinking revealed by spectroelectrochemistry of single quantum dots[J]. Nature, 2011, 479(7372): 203-207.
[48] Hoogenboom J P, Hernando J, van Dijk E M, van Hulst N F, García-Parajó M F. Power-law blinking in the fluorescence of single organic molecules[J]. ChemPhysChem, 2007, 8(6): 823-833.
[49] Tang J, Marcus R. Mechanisms of fluorescence blinking in semiconductor nanocrystal quantum dots[J]. Journal of Chemical Physics, 2005, 123(5): 054704.
[50] Clafton S N, Beattie D A, Mierczynska-Vasilev A, Acres R G, Morgan A C, Kee T W. Chemical defects in the highly fluorescent conjugated polymer dots[J]. Langmuir, 2010, 26(23): 17785-17789.
[51] Moon J H, McDaniel W, MacLean P, Hancock L F. Live-cell-permeable poly (p-phenylene ethynylene)[J].Angewandte Chemie International Edition, 2007, 46(43): 8223-8225.
[52] Ye F, White C C, Jin Y, Hu X, Hayden S, Zhang X, Gao X, Kavanagh T J, Chiu D T. Toxicity and oxidative stress induced by semiconducting polymer dots in RAW264.7 mouse macrophages[J]. Nanoscale, 2015, 7(22): 10085-10093.
[53] Wu C F, Hansen S J, Hou Q, Yu J B, Zeigler M, Jin Y H, Burnham D R, McNeill J D, Olson J M, Chiu D T. Design of highly emissive polymer dot bioconjugates for in vivo tumor targeting[J]. Angewandte Chemie International Edition, 2011, 50(15): 3430-3434.
[54] Ahmed E, Morton S W, Hammond P T, Swager T M. Fluorescent multiblock pi-conjugated polymer nanoparticles for in vivo tumor targeting[J]. Advanced Materials, 2013, 25(32): 4504-4510.
[55] Wu I C, Yu J, Ye F, Rong Y, Gallina M E, Fujimoto B S, Zhang Y, Chan Y H, Sun W, Zhou X H. Squaraine-based polymer dots with narrow, bright near-infrared fluorescence for biological applications[J]. Journal of the American Chemical Society, 2015, 137(1): 173.
[56] Rong Y, Wu C F, Yu J B, Zhang X J, Ye F M, Zeigler M, Gallina M E, Wu I C, Zhang Y, Chan Y H. Multicolor fluorescent semiconducting polymer dots with narrow emissions and high brightness[J]. ACS Nano, 2013, 7(1): 376.
[57] Zha Z B, Deng Z J, Li Y Y, Li C H, Wang J R, Wang S M, Qu E Z, Dai Z F. Biocompatible polypyrrole nanoparticles as a novel organic photoacoustic contrast agent for deep tissue imaging[J]. Nanoscale, 2013, 5(10): 4462-4467.
[58] Liang X H, Li Y Y, Li X D, Jing L J, Deng Z J, Yue X L, Li C H, Dai Z F. PEGylated polypyrrole nanoparticles conjugating gadolinium chelates for dual-modal MRI/photoacoustic imaging guided photothermal therapy of cancer[J]. Advanced Functional Materials, 2015, 25(9): 1451-1462.
[59] Liu J, Geng J L, Liao L D, Thakor N, Gao X H, Liu B. Conjugated polymer nanoparticles for photoacoustic vascular imaging[J]. Polymer Chemistry, 2014, 5(8): 2854-2862.
[60] Lyu Y, Fang Y, Miao Q Q, Zhen X, Ding D, Pu K Y. Intraparticle molecular orbital engineering of semiconducting polymer nanoparticles as amplified theranostics for in vivo photoacoustic imaging and photothermal therapy[J]. ACS Nano, 2016, 10(4): 4472-4481.
[61] Harris A L. Hypoxia-a key regulatory factor in tumour growth[J]. Nature Reviews Cancer, 2002, 2(1): 38-47.
[62] Mapp P, Grootveld M, Blake D. Hypoxia, oxidative stress and rheumatoid arthritis[J]. British Medical Bulletin, 1995, 51(2): 419-436.
[63] Wu C F, Bull B, Christensen K, McNeill J. Ratiometric single-nanoparticle oxygen sensors for biological imaging[J]. Angewandte Chemie International Edition, 2009, 48(15): 2741-2745.
[64] Fang F C. Antimicrobial reactive oxygen and nitrogen species: concepts and controversies[J]. Nature Reviews Microbiology, 2004, 2(10): 820-832.
[65] Libby P, Ridker P M, Hansson G K. Progress and cha-llenges in translating the biology of atherosclerosis[J]. Nature, 2011, 473(7347): 317-325.
[66] Bauerova K, Bezek S. Role of reactive oxygen and nitrogen species in etiopathogenesis of rheumatoid arthritis[J]. General Physiology and Biophysics, 2000, 18: 15-20.
[67] Pu K Y, Shuhendler A J, Rao J H. Semiconducting polymer nanoprobe for in vivo imaging of reactive oxygen and nitrogen species[J]. Angewandte Chemie International Edition, 2013, 52(39): 10325-10329.
[68] Chan Y-H, Wu C F, Ye F M, Jin Y H, Smith P B, Chiu D T. Development of ultrabright semiconducting polymer dots for ratiometric pH sensing[J]. Analytical Chemistry, 2011, 83(4): 1448-1455.
[69] Lu L, Rininsland F H, Wittenburg S K, Achyuthan K E, McBranch D W, Whitten D G. Biocidal activity of a light-absorbing fluorescent conjugated polyelectrolyte[J]. Langmuir, 2005, 21(22): 10154-10159.
[70] Chemburu S, Corbitt T S, Ista L K, Ji E, Fulghum J, Lopez G P, Ogawa K, Schanze K S, G. Whitten D. Light-induced biocidal action of conjugated polyelectrolytes supported on colloids[J].Langmuir,2008,24(19): 11053-11062.
[71] Corbitt T S, Ding L, Ji E, Ista L K, Ogawa K, Lopez G P, Schanze K S, Whitten D G. Light and dark biocidal activity of cationic poly (arylene ethynylene) conjugated polyelectrolytes[J]. Photochemical & Photobiological Sciences, 2009, 8(7): 998-1005.
[72] Zhou Z, Corbitt T S, Parthasarathy A, Tang Y, Ista L K, Schanze K S, Whitten D G. "End-only" functionalized oligo (phenylene ethynylene) s: synthesis, photophysical and biocidal activity[J]. Journal of Physical Chemistry Letter, 2010, 1(21): 3207-3212.
[73] Chang K W, Tang Y, Fang X F, Yin S Y, Xu H, Wu C F. Incorporation of porphyrin to pi-conjugated backbone for polymer-dot-sensitized photodynamic therapy[J]. Biomacromolecules, 2016, 17(6): 2128-2136.
[74] Zhou X B, Liang H, Jiang P F, Zhang K Y, Liu S J, Yang T S, Zhao Q, Yang L J, Lv W, Yu Q. Multifunctional phosphorescent conjugated polymer dots for hypoxia imaging and photodynamic therapy of cancer cells[J]. Advanced Science, 2016, 3(2): 1500155.
[75] Chen M, Fang X L, Tang S H, Zheng N F. Polypyrrole nanoparticles for high-performance in vivo near-infrared photothermal cancer therapy[J]. Chemical Communications, 2012, 48(71): 8934-8936.
[76] Yang K, Xu H, Cheng L, Sun C Y, Wang J, Liu Z. In vitro and in vivo near-infrared photothermal therapy of cancer using polypyrrole organic nanoparticles[J]. Advanced Materials, 2012, 24(41): 5586-5592.
[77] Abel S B, Molina M A, Rivarola C R, Kogan M J, Barbero C A. Smart polyaniline nanoparticles with thermal and photothermal sensitivity[J]. Nanotechnology, 2014, 25(49): 495602.
[78] Zhou J, Lu Z G, Zhu X J, Wang X J, Liao Y, Ma Z F, Li F. NIR photothermal therapy using polyaniline nanoparticles[J]. Biomaterials, 2013, 34(37): 9584-9592.
[79] Cheng L, Yang K, Chen Q, Liu Z. Organic stealth nanoparticles for highly effective in vivo near-infrared photothermal therapy of cancer[J]. ACS Nano, 2012, 6(6): 5605-5613.
[80] Zha Z B, Yue X L, Ren Q S, Dai Z F. Uniform polypy-rrole nanoparticles with high photothermal conversion efficiency for photothermal ablation of cancer cells[J]. Advanced Materials, 2013, 25(5): 777-782.
[81] Lyu Y, Xie C, Chechetka S A, Miyako E, Pu K Y. Semiconducting polymer nanobioconjugates for targeted photothermal activation of neurons[J]. Journal of the American Chemical Society, 2016, 138(29): 9049-9052.
[82] Geng J L, Sun C Y, Liu J, Liao L D, Yuan Y Y, Thakor N, Wang J, Liu B. Biocompatible conjugated polymer nanoparticles for efficient photothermal tumor therapy[J]. Small, 2015, 11(13): 1603-1610.
[83] Feng G X, Fang Y, Liu J, Geng J L, Ding D, Liu B. Multifunctional conjugated polymer nanoparticles for image-guided photodynamic and photothermal therapy[J]. Small, 2017, 13(3): 1602807.
[84] Ge J C, Lan M H, Zhou B J, Liu W M, Guo L, Wang H, Jia Q Y, Niu G L, Huang X, Zhou H Y, Meng X M, Wang P F, Lee C S, Zhang W J, Han X D. A graphene quantum dot photodynamic therapy agent with high singlet oxygen generation[J].Nature Communications,2014,5: 4596.
[85] Guo L, Ge J C, Liu Q, Jia Q Y, Zhang H Y, Liu W M, Niu G L, Liu S, Gong J R, Hackbarth S, Wang P F. Versatile polymer nanoparticles as two-photon-triggered photosensitizers for simultaneous cellular, deep-tissue imaging, and photodynamic therapy[J]. Advanced Healthcare Materials, DOI: 10.1002/adhm.201601431.
[86] Guo L, Niu G L, Zheng X L, Ge J C, Liu W M, Jia Q Y, Zhang P P, Zhang H Y, Wang P F. Single near-infrared emissive polymer nanoparticle as a versatile phototheranostic[J]. Advanced Science, DOI: 10.1002/advs.201700085.
[87] Guo L, Liu W M, Niu G L, Zhang P P, Zheng X L, Jia Q Y, Zhang H Y, Ge J C, Wang P F. Polymer nanoparticles with high photothermal conversion efficiency as robust photoacoustic and thermal theranostics[J]. Journal of Mate-rials Chemistry B, 2017, 5(15): 2832-2839.