药学学报, 2019, 54(11): 1965-1975
引用本文:
戚建平, 卢懿, 董肖椿, 赵伟利, 吴伟. 纳米药物载体体内命运研究:环境响应型荧光染料的应用[J]. 药学学报, 2019, 54(11): 1965-1975.
QI Jian-ping, LU Yi, DONG Xiao-chun, ZHAO Wei-li, WU Wei. In vivo fate study of drug nanocarriers: the applications of environment-responsive fluorescent dyes[J]. Acta Pharmaceutica Sinica, 2019, 54(11): 1965-1975.

纳米药物载体体内命运研究:环境响应型荧光染料的应用
戚建平, 卢懿, 董肖椿, 赵伟利, 吴伟
复旦大学药学院, 教育部智能化递药重点实验室, 上海 201203
摘要:
纳米制剂的体内命运研究关乎其临床转化的成败,目前所面临的最大挑战之一是如何在体内实时准确地监测纳米载体自身。传统的放射或荧光探针从被标记母体粒子解离后,依然发射信号,从而带来干扰,导致对结果的误判。环境响应探针根据纳米载体所处环境变化而切换信号,有助于将粒子信号与游离探针信号有效区分。目前应用的环境响应荧光染料主要有三大类,其原理分别基于荧光共振能量转移(FRET)、聚集诱导发光(AIE)及聚集导致淬灭(ACQ)效应。它们的共同特点是,当被包载于纳米粒中时发射荧光,而伴随着纳米载体的降解或破坏,染料分子被释放,因周围环境变化而发生信号切换或荧光淬灭。根据信号的变化可对纳米粒在生物体内的存续状态进行判断。FRET和AIE染料被广泛用于研究纳米粒和细胞的相互作用,较少应用于体内命运研究。ACQ染料对生物介质中的水敏感,具有普适性,结合各种成像设备,可更为准确地追踪纳米粒在体内的转运过程。本文对3种环境响应荧光染料的应用原理、优缺点及纳米粒体内命运研究中的应用进行了综述。
关键词:    环境响应      荧光染料      聚集导致淬灭      荧光共振能量转移      聚集诱导发光      纳米载体      体内命运      实时监测     
In vivo fate study of drug nanocarriers: the applications of environment-responsive fluorescent dyes
QI Jian-ping, LU Yi, DONG Xiao-chun, ZHAO Wei-li, WU Wei
Key Laboratory of Smart Drug Delivery of Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
Abstract:
The in vivo fate is a crucial factor that governs the successful translation of nanoformulations. However, one of the current biggest challenges is with the real-time monitoring of the body of the nanoparticles themselves. Conventional radioactive or fluorescent probes give signals even after they are disassociated from the particle matrix, generating interference to bioimaging and leading to misjudgment of results. Environment-responsive fluorescent dyes are regarded as promising tools due to signal switching in response to the changes in the environment. Currently, there are three categories of dyes in bioimaging of nanoparticles based on Förster resonance energy transfer (FRET), aggregation-induced emission (AIE) and aggregation-caused quenching (ACQ). They have similar characteristics that strong fluorescence is emitted when they are embedded in the matrix of nanocarriers, whereas the fluorescence quenches upon release from the matrix due to dissociation of nanocarriers. The fluorescence switching reflects the existing status of the nanocarriers and therefore helps to interpret the in vivo behaviors. FRET and AIE probes have been widely used in elucidating the interactions between nanoparticles and cell models. However, they show intrinsic defects in studying in vivo fate of nanoparticles. ACQ-based dyes are sensitive to water, a universal factor in the biological environment. Therefore, with the help of bioimaging equipment, the in vivo trafficking process of nanoparticles can be unraveled. This review article tends to provide an overview on the rationale, pros and cons and applications of the three categories of environment-responsive fluorescent dyes in the investigation of the in vivo fate of nanocarriers.
Key words:    environment-responsive    fluorescent dye    aggregation-caused quenching    F&246rster resonance energy transfer    aggregation-induced emission    nanocarrier    in vivo fate    real-time monitoring   
收稿日期: 2019-07-03
DOI: 10.16438/j.0513-4870.2019-0525
基金项目: 国家自然科学基金资助项目(81573363,81872815,81872826,81690263);上海市科技发展基金资助项目(19XD1400300,18410741800).
相关功能
PDF(601KB) Free
打印本文
0
作者相关文章
戚建平  在本刊中的所有文章
卢懿  在本刊中的所有文章
董肖椿  在本刊中的所有文章
赵伟利  在本刊中的所有文章
吴伟  在本刊中的所有文章

参考文献:
[1] Park K. Drug delivery of the future: chasing the invisible gorilla[J]. J Control Release, 2016, 240: 2-8.
[2] Etheridge ML, Campbell SA, Erdman AG, et al. The big picture on nanomedicine: the state of investigational and approved nanomedicine products[J]. Nanomedicine, 2013, 9: 1-14.
[3] Shi J, Kantoff PW, Wooster R, et al. Cancer nanomedicine: progress, challenges and opportunities[J]. Nat Rev Cancer, 2017, 17: 20-37.
[4] Tran S, DeGiovanni PJ, Piel B, et al. Cancer nanomedicine: a review of recent success in drug delivery[J]. Clin Transl Med, 2017, 6: 44.
[5] Wicki A, Witzigmann D, Balasubramanian V, et al. Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications[J]. J Control Release, 2015, 200: 138-157.
[6] Coty JB, Vauthier C. Characterization of nanomedicines: a reflection on a field under construction needed for clinical translation success[J]. J Control Release, 2018, 275: 254-268.
[7] Faria M, Bjornmalm M, Thurecht KJ, et al. Minimum information reporting in bio-nano experimental literature[J]. Nat Nanotechnol, 2018, 13: 777-785.
[8] Manaia EB, Abucafy MP, Chiari-Andreo BG, et al. Physicochemical characterization of drug nanocarriers[J]. Int J Nanomedicine, 2017, 12: 4991-5011.
[9] Park K. Facing the truth about nanotechnology in drug delivery[J]. ACS Nano, 2013, 7: 7442-7447.
[10] He H, Jiang S, Xie Y, et al. Reassessment of long circulation via monitoring of integral polymeric nanoparticles justifies a more accurate understanding[J]. Nanoscale Horiz, 2018, 3: 397-407.
[11] Shi Y, van der Meel R, Theek B, et al. Complete regression of xenograft tumors upon targeted delivery of paclitaxel via pi-pi stacking stabilized polymeric micelles[J]. ACS Nano, 2015, 9: 3740-3752.
[12] Su C, Yang H, Sun H, et al. Bioanalysis of free and liposomal amphotericin B in rat plasma using solid phase extraction and protein precipitation followed by LC-MS/MS[J]. J Pharm Biomed Anal, 2018, 158: 288-293.
[13] Su C, Liu Y, He Y, et al. Analytical methods for investigating in vivo fate of nanoliposomes: a review[J]. J Pharm Anal, 2018, 8: 219-225.
[14] Feliu N, Docter D, Heine M, et al. In vivo degeneration and the fate of inorganic nanoparticles[J]. Chem Soc Rev, 2016, 45: 2440-2457.
[15] Wang B, He X, Zhang Z, et al. Metabolism of nanomaterials in vivo: blood circulation and organ clearance[J]. ACC Chem Res, 2013, 46: 761-769.
[16] Jin Y, Kim D, Roh H, et al. Tracking the fate of porous silicon nanoparticles delivering a peptide payload by intrinsic photoluminescence lifetime[J]. Adv Mater, 2018, 30: e1802878.
[17] Hu X, Dong X, Lu Y, et al. Bioimaging of nanoparticles: the crucial role of discriminating nanoparticles from free probes[J]. Drug Discov Today, 2017, 22: 382-387.
[18] Zhu M, Nie G, Meng H, et al. Physicochemical properties determine nanomaterial cellular uptake, transport, and fate[J]. ACC Chem Res, 2013, 46: 622-631.
[19] Bertrand N, Grenier P, Mahmoudi M, et al. Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics[J]. Nat Commun, 2017, 8: 777.
[20] He X, Ma Y, Li M, et al. Quantifying and imaging engineered nanomaterials in vivo: challenges and techniques[J]. Small, 2013, 9: 1482-1491.
[21] Shaffer TM, Harmsen S, Khwaja E, et al. Stable radiolabeling of sulfur-functionalized silica nanoparticles with copper-64[J]. Nano Lett, 2016, 16: 5601-5604.
[22] Stremersch S, Brans T, Braeckmans K, et al. Nucleic acid loading and fluorescent labeling of isolated extracellular vesicles requires adequate purification[J]. Int J Pharm, 2018, 548: 783-792.
[23] Pellach M, Margel S. Preparation and characterization of uniform near IR polystyrene nanoparticles[J]. Photochem Photobiol, 2014, 90: 952-956.
[24] Huang M, Yu R, Xu K, et al. An arch-bridge-type fluorophore for bridging the gap between aggregation-caused quenching (ACQ) and aggregation-induced emission (AIE)[J]. Chem Sci, 2016, 7: 4485-4491.
[25] Wang T, Wang L, Li X, et al. Size-dependent regulation of intracellular trafficking of polystyrene nanoparticle-based drug-delivery systems[J]. ACS Appl Mater Interfaces, 2017, 9: 18619-18625.
[26] Hollis CP, Weiss HL, Leggas M, et al. Biodistribution and bioimaging studies of hybrid paclitaxel nanocrystals: lessons learned of the EPR effect and image-guided drug delivery[J]. J Control Release, 2013, 172: 12-21.
[27] Lee B, Park BG, Cho W, et al. BOIMPY: fluorescent boron complexes with tunable and environment-responsive light-emitting properties[J]. Chemistry, 2016, 22: 17321-17328.
[28] Yang Z, Cao J, He Y, et al. Macro-/micro-environment-sensitive chemosensing and biological imaging[J]. Chem Soc Rev, 2014, 43: 4563-4601.
[29] Suetsugu A, Shimizu M, Saji S, et al. Visualizing the tumor microenvironment by color-coded imaging in orthotopic mouse models of cancer[J]. Anticancer Res, 2018, 38: 1847-1857.
[30] Yang X, Shen S, Guo L, et al. An enzyme-responsive "Turn-on" fluorescence polymeric superamphiphile as a potential visualizable phosphate prodrug delivery vehicle[J]. Macromol Biosci, 2018, 18: e1800045.
[31] Förster T. Zwischenmolekulare energiewanderung und fluoreszenz[J]. Ann Phys-berlin, 1948, 437: 55-75.
[32] Lovell JF, Chen J, Jarvi MT, et al. FRET quenching of photosensitizer singlet oxygen generation[J]. J Phys Chem B, 2009, 113: 3203-3211.
[33] Li H, Luo Y, Sun X. Fluorescence resonance energy transfer dye-labeled probe for fluorescence-enhanced DNA detection: an effective strategy to greatly improve discrimination ability toward single-base mismatch[J]. Biosens Bioelectron, 2011, 27: 167-171.
[34] Morton SW, Zhao X,Quadir MA, et al. FRET-enabled biological characterization of polymeric micelles[J]. Biomaterials, 2014, 35: 3489-3496.
[35] Chen T, Li C, Li Y, et al. Small-sized mPEG-PLGA nanoparticles of schisantherin A with sustained release for enhanced brain uptake and anti-parkinsonian activity[J]. ACS Appl Mater Interfaces, 2017, 9: 9516-9527.
[36] Akita H, Kudo A, Minoura A, et al. Multi-layered nanoparticles for penetrating the endosome and nuclear membrane via a step-wise membrane fusion process[J]. Biomaterials, 2009, 30: 2940-2949.
[37] Zou P, Chen H, Paholak HJ, et al. Noninvasive fluorescence resonance energy transfer imaging of in vivo premature drug release from polymeric nanoparticles[J]. Mol Pharm, 2013, 10: 4185-4194.
[38] Zhao Y, Fay F, Hak S, et al. Augmenting drug-carrier compatibility improves tumour nanotherapy efficacy[J]. Nat Commun, 2016, 7: 11221.
[39] Saha J, Datta Roy A, Dey D, et al. Role of quantum dot in designing FRET based sensors[J]. Mater Today, 2018, 5: 2306-2313.
[40] Yan F, Bai Z, Chen Y, et al. Ratiometric fluorescent detection of copper ions using coumarin-functionalized carbon dots based on FRET[J]. Sensor Actuator Chem, 2018, 275: 86-94.
[41] Chen H, Kim S, Li L, et al. Release of hydrophobic molecules from polymer micelles into cell membranes revealed by Förster resonance energy transfer imaging[J]. Proc Natl Acad Sci U S A, 2008, 105: 6596-6601.
[42] Li D, Zhuang J, Yang Y, et al. Loss of integrity of doxorubicin liposomes during transcellular transportation evidenced by fluorescence resonance energy transfer effect[J]. Colloids Surf B Biointerfaces, 2018, 171: 224-232.
[43] Chen T, He B, Tao J, et al. Application of Forster resonance energy transfer (FRET) technique to elucidate intracellular and in vivo biofate of nanomedicines[J]. Adv Drug Deliv Rev, 2019, 143: 177-205.
[44] Wang Y, Zhang Y, Wang J, et al. Aggregation-induced emission (AIE) fluorophores as imaging tools to trace the biological fate of nano-based drug delivery systems[J]. Adv Drug Deliv Rev, 2019, 143: 161-176.
[45] Hong Y, Lam JW, Tang BZ. Aggregation-induced emission: phenomenon, mechanism and applications[J]. Chem Commun (Camb), 2009, 29: 4332-4353.
[46] Luo J, Xie Z, Lam JWY, et al. Aggregation-induced emission of 1-methyl-1,2,3,4,5-pentaphenylsilole[J]. Chem Commun (Camb), 2001, 21: 1740-1741.
[47] Chen JI, Wu WC. Fluorescent polymeric micelles with aggregation-induced emission properties for monitoring the encapsulation of doxorubicin[J]. Macromol Biosci, 2013, 13: 623-632.
[48] Hu X, Zhang J, Yu Z, et al. Environment-responsive aza-BODIPY dyes quenching in water as potential probes to visualize the in vivo fate of lipid-based nanocarriers[J]. Nanomedicine, 2015, 11: 1939-1948.
[49] Ye JH, Wang ZH, Liu J. A novel fluorescent sensor for Ag+ and Fe3+ based on aggregation-induced emission[J]. Adv Mater Res, 2013, 821-822: 909-912.
[50] Tong H, Hong Y, Dong Y, et al. Protein detection and quantitation by tetraphenylethene-based fluorescent probes with aggregation-induced emission characteristics[J]. J Phys Chem B, 2007, 111: 11817.
[51] Liow SS, Dou Q, Kai D, et al. Long-term real-time in vivo drug release monitoring with AIE thermogelling polymer[J]. Small, 2017, 13: 1603404.
[52] Zhang C, Jin S, Li S, et al. Imaging intracellular anticancer drug delivery by self-assembly micelles with aggregation-induced emission (AIE micelles)[J]. ACS Appl Mater Interfaces, 2014, 6: 5212-5220.
[53] Birks JB. Photophysics of Aromatic Molecules[M]. London: Wiley- InterScience, 1970.
[54] Förster T, Kasper K. Ein konzentrationsumschlag der fluoreszenz des pyrens[J]. Z Phys Chem (Munich), 1955, 59: 976-980.
[55] Ma X, Sun R, Cheng J, et al. Fluorescence aggregation-caused quenching versus aggregation-induced emission: a visual teaching technology for undergraduate chemistry students[J]. J Chem Edu, 2015, 93: 345-350.
[56] Zhai D, Xu W, Zhang L, et al. The role of "disaggregation" in optical probe development[J]. Chem Soc Rev, 2014, 43: 2402-2411.
[57] Kunzler J, Samha L, Zhang R, et al. Investigation of the effect of concentration on molecular aggregation of cyanine dyes in aqueous solution[J]. Am J Undegrad Res, 2011, 9: 1-4.
[58] Hong Y, Lam JW, Tang BZ. Aggregation-induced emission[J]. Chem Soc Rev, 2011, 40: 5361-5388.
[59] Qi J, Hu X, Dong X, et al. Towards more accurate bioimaging of drug nanocarriers: turning aggregation-caused quenching into a useful tool[J]. Adv Drug Deliv Rev, 2019, 143: 206-225.
[60] He H, Zhang J, Xie Y, et al. Bioimaging of intravenous polymeric micelles based on discrimination of integral particles using an environment-responsive probe[J]. Mol Pharm, 2016, 13: 4013-4019.
[61] Hu X, Fan W, Yu Z, et al. Evidence does not support absorption of intact solid lipid nanoparticles via oral delivery[J]. Nanoscale, 2016, 8: 7024-7035.
[62] Eggeling C, Widengren J, Rigler R, et al. Photobleaching of fluorescent dyes under conditions used for single-molecule detection: evidence of two-step photolysis[J]. Anal Chem, 1998, 70: 2651-2659.
[63] Cheung S, O’Shea DF. Directed self-assembly of fluorescence responsive nanoparticles and their use for real-time surface and cellular imaging[J]. Nat Commun, 2017, 8: 1885.
[64] Ma Y, He H, Xia F, et al. In vivo fate of lipid-silybin conjugate nanoparticles: implications on enhanced oral bioavailability[J]. Nanomedicine, 2017, 13: 2643-2654.
[65] Xia F, Fan W, Jiang S, et al. Size-dependent translocation of nanoemulsions via oral delivery[J]. ACS Appl Mater Interfaces, 2017, 9: 21660-21672.
[66] Kamaly N, Yameen B, Wu J, et al. Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release[J]. Chem Rev, 2016, 116: 2602-2663.
[67] Geng J, Zhu Z, Qin W, et al. Near-infrared fluorescence amplified organic nanoparticles with aggregation-induced emission characteristics for in vivo imaging[J]. Nanoscale, 2014, 6: 939-945.
[68] He Z, Wan X, Schulz A, et al. A high capacity polymeric micelle of paclitaxel: implication of high dose drug therapy to safety and in vivo anti-cancer activity[J]. Biomaterials, 2016, 101: 296-309.
[69] Ahn HK, Jung M, Sym SJ, et al. A phase II trial of Cremorphor EL-free paclitaxel (Genexol-PM) and gemcitabine in patients with advanced non-small cell lung cancer[J]. Cancer Chemoth Pharm, 2014, 74: 277-282.
[70] Zhang Y, Li Q, Welsh WJ, et al. Micellar and structural stability of nanoscale amphiphilic polymers: implications for anti-atherosclerotic bioactivity[J]. Biomaterials, 2016, 84: 230-240.
[71] Sun X, Wang G, Zhang H, et al. The blood clearance kinetics and pathway of polymeric micelles in cancer drug delivery[J]. ACS Nano, 2018, 12: 6179-6192.
[72] Sakai-Kato K, Nishiyama N, Kozaki M, et al. General considerations regarding the in vitro and in vivo properties of block copolymer micelle products and their evaluation[J]. J Control Release, 2015, 210: 76-83.
[73] Ke XY, Ng VWL, Gao SJ, et al. Co-delivery of thioridazine and doxorubicin using polymeric micelles for targeting both cancer cells and cancer stem cells[J]. Biomaterials, 2014, 35: 1096-1108.
[74] Chen H, Kim S, He W, et al. Fast release of lipophilic agents from circulating PEG-PDLLA micelles revealed by in vivo Förster resonance energy transfer imaging[J]. Langmuir, 2008, 24: 5213-5217.
[75] Li Y, Song X, Yi X, et al. Zebrafish: a visual model to evaluate the biofate of transferrin receptor-targeted 7 peptide-decorated coumarin 6 micelles[J]. ACS Appl Mater Interfaces, 2017, 9: 39048-39058.
[76] Zhang J, Li C, Zhang X, et al. In vivo tumor-targeted dual-modal fluorescence/CT imaging using a nanoprobe co-loaded with an aggregation-induced emission dye and gold nanoparticles[J]. Biomaterials, 2015, 42: 103-111.
[77] Pridgen EM, Alexis F, Farokhzad OC. Polymeric nanoparticle drug delivery technologies for oral delivery applications[J]. Expert Opin Drug Deliv, 2015, 12: 1459-1473.
[78] Fonte P, Araújo F, Silva C, et al. Polymer-based nanoparticles for oral insulin delivery: revisited approaches[J]. Biotechnol Adv, 2015, 33: 1342-1354.
[79] Li D, Zhuang J, He H, et al. Influence of particle geometry on gastrointestinal transit and absorption following oral administration[J]. ACS Appl Mater Interfaces, 2017, 9: 42492-42502.
[80] Qin W, Ding D, Liu J, et al. Biocompatible nanoparticles with aggregation-induced emission characteristics as far-red/near-infrared fluorescent bioprobes for in vitro and in vivo imaging applications[J]. Adv Funct Mater, 2012, 22: 771-779.
[81] Wu WC, Chen CY, Tian Y, et al. Enhancement of aggregation-induced emission in dye-encapsulating polymeric micelles for bioimaging[J]. Adv Funct Mater, 2010, 20: 1413-1423.
[82] Wu W, Mao D, Hu F, et al. A highly efficient and photostable photosensitizer with near-infrared aggregation-induced emission for image-guided photodynamic anticancer therapy[J]. Adv Mater, 2017, 29: 1700548.
[83] He H, Xie Y, Lv Y, et al. Bioimaging of intact polycaprolactone nanoparticles using aggregation-caused quenching probes: size-dependent translocation via oral delivery[J]. Adv Healthc Mater, 2018, 7: e1800711.
[84] Meng F, Wang J, Ping Q, et al. Quantitative assessment of nanoparticle biodistribution by fluorescence imaging, revisited[J]. ACS Nano, 2018, 12: 6458-6468.
[85] Wan B, Dai Y, Liu D, et al. Intraocular fate of polycaprolactone nanoparticles administered via intravitreal and various periocular routes: bioimaging of integral nanoparticles using environment-sensitive fluorophores[J]. J Biomed Nanotechnol, 2017, 13: 960-972.
[86] Qi J, Lu Y, Wu W. Absorption, disposition and pharmacokinetics of solid lipid nanoparticles[J]. Curr Drug Metab, 2012, 13: 418-428.
[87] Mu H, Hoy CE. The digestion of dietary triacylglycerols[J]. Prog Lipid Res, 2004, 43: 105-133.
[88] Porter CJ, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs[J]. Nat Rev Drug Discov, 2007, 6: 231.
[89] Huang Z, Huang Y, Ma C, et al. Endotracheal aerosolization device for laboratory investigation of pulmonary delivery of nanoparticle suspensions: in vitro and in vivo validation[J]. Mol Pharm, 2018, 15: 5521-5533.
[90] Zhao Y, van Rooy I, Hak S, et al. Near-infrared fluorescence energy transfer imaging of nanoparticle accumulation and dissociation kinetics in tumor-bearing mice[J]. ACS Nano, 2013, 7: 10362-10370.
[91] Bouchaala R, Mercier L, Andreiuk B, et al. Integrity of lipid nanocarriers in bloodstream and tumor quantified by near-infrared ratiometric FRET imaging in living mice[J]. J Control Release, 2016, 236: 57-67.
[92] Yang J, Dong Z, Liu W, et al. Discriminating against injectable fat emulsions with similar formulation based on water quenching fluorescent probe[J]. Chinese Chem Lett, 2019. DOI: 10.1016/j.cclet.2019.07.016.
[93] Su R, Fan W, Yu Q, et al. Size-dependent penetration of nanoemulsions into epidermis and hair follicles: implications for transdermal delivery and immunization[J]. Oncotarget, 2017, 8: 38214.
[94] Ahmad E, Feng Y, Qi J, et al. Evidence of nose-to-brain delivery of nanoemulsions: cargoes but not vehicles[J]. Nanoscale, 2017, 9: 1174-1183.
[95] Junyaprasert VB, Morakul B. Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs[J]. Asian J Pharm Sci, 2015, 10: 13-23.
[96] Pawar VK, Singh Y, Meher JG, et al. Engineered nanocrystal technology: in-vivo fate, targeting and applications in drug delivery[J]. J Control Release, 2014, 183: 51-66.
[97] Hollis CP, Weiss HL, Evers BM, et al. In vivo investigation of hybrid paclitaxel nanocrystals with dual fluorescent probes for cancer theranostics[J]. Pharm Res, 2014, 31: 1450-1459.
[98] Zhao R, Hollis CP, Zhang H, et al. Hybrid nanocrystals: achieving concurrent therapeutic and bioimaging functionalities toward solid tumors[J]. Mol Pharm, 2011, 8: 1985-1991.
[99] Gao W, Lee D, Meng Z, et al. Exploring intracellular fate of drug nanocrystals with crystal-integrated and environment-sensitive fluorophores[J]. J Control Release, 2017, 267: 214-222.
[100] Wang T, Qi J, Ding N, et al. Tracking translocation of self-discriminating curcumin hybrid nanocrystals following intravenous delivery[J]. Int J Pharm, 2018, 546: 10-19.
[101] Shen C, Yang Y, Shen B, et al. Self-discriminating fluorescent hybrid nanocrystals: efficient and accurate tracking of translocation via oral delivery[J]. Nanoscale, 2018, 10: 436-450.
[102] Xie Y, Shi B, Xie F, et al. Epithelia transmembrane transport of orally administered ultrafine drug particles evidenced by environment sensitive fluorophores in cellular and animal studies[J]. J Control Release, 2018, 270: 65-75.
[103] Dai T, Jiang K, Lu W. Liposomes and lipid disks traverse the BBB and BBTB as intact forms as revealed by two-step Forster resonance energy transfer imaging[J]. Acta Pharm Sin B, 2018, 8: 261-271.
相关文献:
1.樊敦, 余敬谋, 黄皓, 金一.环境响应性递释系统在基因与药物共传递应用中的研究进展[J]. 药学学报, 2017,52(5): 713-721