Original articles
Wenhui Tao, Dongyang Zhao, Guanting Li, Lingxiao Li, Songhao Li, Hao Ye, Chutong Tian, Yutong Lu, Shuying Li, Yinghua Sun, Zhonggui He, Jin Sun. Artificial tumor microenvironment regulated by first hemorrhage for enhanced tumor targeting and then occlusion for synergistic bioactivation of hypoxia-sensitive platesomes[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1487-1499

Artificial tumor microenvironment regulated by first hemorrhage for enhanced tumor targeting and then occlusion for synergistic bioactivation of hypoxia-sensitive platesomes
Wenhui Taoa, Dongyang Zhaoa, Guanting Lia, Lingxiao Lia, Songhao Lia, Hao Yea, Chutong Tiana, Yutong Lua, Shuying Lib, Yinghua Sunc, Zhonggui Hea, Jin Suna
a. Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China;
b. Department of Pharmaceutical and Engineering, College of Pharmaceutical and Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China;
c. Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
Abstract:
The unique characteristics of the tumor microenvironment (TME) could be exploited to develop antitumor nanomedicine strategies. However, in many cases, the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity. Given the amplified characteristics of TME regulated by vascular disrupting agents (VDAs), nanomedicines may achieve unexpected improved efficacy. Herein, we fabricate platelet membrane-fusogenic liposomes (PML/DP&PPa), namely "platesomes", which actively load the hypoxia-activated pro-prodrug DMG-PR104A (DP) and physically encapsulate the photosensitizer pyropheophorbide a (PPa). Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate (CA4P), PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P. First, CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention (EPR) effect, and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa. Besides, CA4P-induced vascular occlusion inhibits oxygen supply, followed by photodynamic therapy-caused acute tumor hypoxia. This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis. Thus, such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation, and provides a preferable solution to high-efficiency cancer therapy.
Key words:    Tumor microenvironment    Vascular disrupting agents    Biomimetic platesomes    Photosensitizers    Hypoxia-activated prodrugs    Nanomedicine delivery    Combination therapy    Antitumor and antimetastasis   
Received: 2021-04-18     Revised: 2021-06-20
DOI: 10.1016/j.apsb.2021.08.010
Funds: This work was financially supported by the National Natural Science Foundation of China (No. 81773656), Liaoning Revitalization Talents Program (No. XLYC1808017, China), Shenyang Youth Science and Technology Innovation Talents Program (No. RC190454, China), College Student Innovation and Entrepreneurship Training Program of Shenyang Pharmaceutical University (No. X202010163141, China).
Corresponding author: Jin Sun,E-mai:sunjin@syphu.edu.cn     Email:sunjin@syphu.edu.cn
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Authors
Wenhui Tao
Dongyang Zhao
Guanting Li
Lingxiao Li
Songhao Li
Hao Ye
Chutong Tian
Yutong Lu
Shuying Li
Yinghua Sun
Zhonggui He
Jin Sun

References:
[1] Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer 2017; 17:20-37
[2] Fang J, Nakamura H, Maeda H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 2011; 63:136-151
[3] Sun D, Zhou S, Gao W. What went wrong with anticancer nanomedicine design and how to make it right. ACS Nano 2020; 14:12281-12290
[4] Danhier F. To exploit the tumor microenvironment: since the EPR effect fails in the clinic, what is the future of nanomedicine?. J Control Release 2016; 244:108-121
[5] Chen Z, Hu Q, Gu Z. Leveraging engineering of cells for drug delivery. Acc Chem Res 2018; 51:668-677
[6] Li R, He Y, Zhang S, Qin J, Wang J. Cell membrane-based nanoparticles: a new biomimetic platform for tumor diagnosis and treatment. Acta Pharm Sin B 2018; 8:14-22
[7] Dhaliwal A, Zheng G. Improving accessibility of EPR-insensitive tumor phenotypes using EPR-adaptive strategies: designing a new perspective in nanomedicine delivery. Theranostics 2019; 9:8091-8108
[8] Hu Q, Sun W, Qian C, Wang C, Bomba HN, Gu Z. Anticancer platelet-mimicking nanovehicles. Adv Mater 2015; 27:7043-7050
[9] Hu CM J, Fang RH, Wang KC, Luk BT, Thamphiwatana S, Dehaini D, et al. Nanoparticle biointerfacing by platelet membrane cloaking. Nature 2015; 526:118-121
[10] Ye H, Wang K, Lu Q, Zhao J, Wang M, Kan Q, et al. Nanosponges of circulating tumor-derived exosomes for breast cancer metastasis inhibition. Biomaterials 2020; 242:119932
[11] Ye H, Wang K, Wang M, Liu R, Song H, Li N, et al. Bioinspired nanoplatelets for chemo-photothermal therapy of breast cancer metastasis inhibition. Biomaterials 2019; 206:1-12
[12] Zhou Y, Chen X, Cao J, Gao H. Overcoming the biological barriers in the tumor microenvironment for improving drug delivery and efficacy. J Mater Chem B 2020; 8:6765-6781
[13] Yang S, Gao H. Nanoparticles for modulating tumor microenvironment to improve drug delivery and tumor therapy. Pharmacol Res 2017; 126:97-108
[14] Zhang W, Wang F, Hu C, Zhou Y, Gao H, Hu J. The progress and perspective of nanoparticle-enabled tumor metastasis treatment. Acta Pharm Sin B 2020; 10:2037-2053
[15] Dark GG, Hill SA, Prise VE, Tozer GM, Pettit GR, Chaplin DJ. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Res 1997; 57:1829-1834
[16] Tozer GM, Kanthou C, Parkins CS, Hill SA. The biology of the combretastatins as tumour vasculartargeting agents. Int J Exp Pathol 2002; 83:21-38
[17] Tozer GM, Prise VE, Wilson J, Cemazar M, Shan S, Dewhirst MW. Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability. Cancer Res 2001; 61:6413-6422
[18] Satterlee AB, Rojas JD, Dayton PA, Huang L. Enhancing nanoparticle accumulation and retention in desmoplastic tumors via vascular disruption for internal radiation therapy. Theranostics 2017; 7:253-269
[19] Volz J, Mammadova-Bach E, Gil-Pulido J, Nandigama R, Remer K, Sorokin L, et al. Inhibition of platelet GPVI induces intratumor hemorrhage and increases efficacy of chemotherapy in mice. Blood 2019; 133:2696-2706
[20] Song W, Tang Z, Zhang D, Li M, Gu J, Chen X. A cooperative polymeric platform for tumor-targeted drug delivery. Chem Sci 2016; 7:728-736
[21] Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 2011; 10:417-427
[22] Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004; 4:437-447
[23] Sharma A, Arambula JF, Koo S, Kumar R, Singh H, Sessler JL,et al. Hypoxia-targeted drug delivery. Chem Soc Rev 2019; 48:771-813
[24] Kling J. Hypoxia-activated prodrugs forge ahead in cancer. Nat Biotechnol 2012; 30:381
[25] Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer 2011; 11:393-410
[26] Zhao D, Tao W, Li S, Li L, Sun Y, Li G, et al. Light-triggered dual-modality drug release of self-assembled prodrug-nanoparticles for synergistic photodynamic and hypoxia-activated therapy. Nanoscale Horiz 2020; 5:886-894
[27] Zhang L, Wang Z, Zhang Y, Cao F, Dong K, Ren J, et al. Erythrocyte membrane cloaked metal-organic framework nanoparticle as biomimetic nanoreactor for starvation-activated colon cancer therapy. ACS Nano 2018; 12:10201-10211
[28] Yang S, Tang Z, Hu C, Zhang D, Shen N, Yu H, et al. Selectively potentiating hypoxia levels by Combretastatin A4 nanomedicine: toward highly enhanced hypoxia-activated prodrug Tirapazamine therapy for metastatic tumors. Adv Mater 2019; 31:e1805955
[29] Yang Z, Chi D, Wang Q, Guo X, Lv Q, Wang Y. Improved antitumor activity and tolerability of cabazitaxel derived remote-loading liposomes. Int J Pharm 2020; 589:119814
[30] Zhao D, Tao W, Li S, Chen Y, Sun Y, He Z, et al. Apoptotic body-mediated intercellular delivery for enhanced drug penetration and whole tumor destruction. Sci Adv 2021; 7:eabg0880
[31] Pitchaimani A, Nguyen TDT, Aryal S. Natural killer cell membrane infused biomimetic liposomes for targeted tumor therapy. Biomaterials 2018; 160:124-137
[32] He Y, Li R, Li H, Zhang S, Dai W, Wu Q, et al. Erythroliposomes: integrated hybrid nanovesicles composed of erythrocyte membranes and artificial lipid membranes for pore-forming toxin clearance. ACS Nano 2019; 13:4148-4159
[33] Litvinov RI, Barsegov V, Schissler AJ, Fisher AR, Bennett JS, Weisel JW, et al. Dissociation of bimolecular αIIbβ3-fibrinogen complex under a constant tensile force. Biophys J 2011; 100:165-173
[34] Sanchez-Gaytan BL, Fay F, Hak S, Alaarg A, Fayad ZA, Perez-Medina C, et al. Real-time monitoring of nanoparticle formation by FRET imaging. Angew Chem Int Ed Engl 2017; 56:2923-2926
[35] Hanley WD, Napier SL, Burdick MM, Schnaar RL, Sackstein R, Konstantopoulos K. Variant isoforms of CD44 are P- and L-selectin ligands on colon carcinoma cells. FASEB J 2006; 20:337-339
[36] Zhou Z, Zhang B, Wang S, Zai W, Yuan A, Hu Y, et al. Perfluorocarbon nanoparticles mediated platelet blocking disrupt vascular barriers to improve the efficacy of oxygen-sensitive antitumor drugs. Small 2018; 14:e1801694
[37] Tao W, He Z. ROS-responsive drug delivery systems for biomedical applications. Asian J Pharm Sci 2018; 13:101-112
[38] Wieczorek E, Mlynarczyk DT, Kucinska M, Dlugaszewska J, Piskorz J, Popenda L, et al. Photophysical properties and photocytotoxicity of free and liposome-entrapped diazepinoporphyrazines on LNCaP cells under normoxic and hypoxic conditions. Eur J Med Chem 2018; 150:64-73
[39] Sadzuka Y, Tokutomi K, Iwasaki F, Sugiyama I, Hirano T, Konno H, et al. The phototoxicity of photofrin was enhanced by PEGylated liposome in vitro. Cancer Lett 2006; 241:42-48
[40] Li L, Liu Y, Li H, Guo X, He X, Geng S, et al. Rational design of temperature-sensitive blood-vessel-embolic nanogels for improving hypoxic tumor microenvironment after transcatheter arterial embolization. Theranostics 2018; 8:6291-6306
[41] Rankin EB, Giaccia AJ. Hypoxic control of metastasis. Science 2016; 352:175-180
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