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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2018, Vol. 12 Issue (6) : 667-677    https://doi.org/10.1007/s11684-017-0583-y
REVIEW |
Platelet membrane-based and tumor-associated platelet- targeted drug delivery systems for cancer therapy
Yinlong Zhang1,2, Guangna Liu1,2, Jingyan Wei1(), Guangjun Nie2,3()
1. College of Pharmaceutical Science, Jilin University, Changchun 130021, China
2. CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
3. University of Chinese Academy of Sciences, Beijing 100049, China
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Abstract

Platelets have long been known to play critical roles in hemostasis by clumping and clotting blood vessel injuries. Recent experimental evidence strongly indicates that platelets can also interact with tumor cells by direct binding or secreting cytokines. For example, platelets have been shown to protect circulating cancer cells in blood circulation and to promote tumor metastasis. In-depth understanding of the role of platelets in cancer progression and metastasis provides promising approaches for platelet biomimetic drug delivery systems and functional platelet-targeting strategies for effective cancer treatment. This review highlights recent progresses in platelet membrane-based drug delivery and unique strategies that target tumor-associated platelets for cancer therapy. The paper also discusses future development opportunities and challenges encountered for clinical translation.

Keywords platelet-mimicking delivery systems      tumor-associated platelets      cancer therapy      EPR effect     
Corresponding Authors: Jingyan Wei,Guangjun Nie   
Just Accepted Date: 03 January 2018   Online First Date: 09 April 2018    Issue Date: 03 December 2018
 Cite this article:   
Yinlong Zhang,Guangna Liu,Jingyan Wei, et al. Platelet membrane-based and tumor-associated platelet- targeted drug delivery systems for cancer therapy[J]. Front. Med., 2018, 12(6): 667-677.
 URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-017-0583-y
http://academic.hep.com.cn/fmd/EN/Y2018/V12/I6/667
Fig.1  Proposed design mechanism of platelet membrane-based drug delivery systems. (A) Natural or genetically engineered platelet membrane-based drug loading. (B) Platelet membrane-coated polymer-based drug loading.
Fig.2  Schematic illustration of the possible mechanism of enhanced antitumor activity of Dox-loaded platelet drug delivery system. Tumor-bearing mice are injected with Dox platelets by the tail vein. Dox platelets passively target tumor cells through tumor cell-induced platelet aggregation. Dox induces tumor cell apoptosis through regulating expressions of apoptosis-related genes. Reprinted from Ref. 8 with permission.
Fig.3  (A) Schematic illustration of antiPD-L1 delivery to primary-tumor resection sites by platelets, where TCR is T cell receptor, and MHC is the major histocompatibility complex; (B) In vivo bioluminescence imaging of B16–F10 tumors after removal of primary tumors. Three representative mice per treatment group are shown. Reprinted from Ref. 11 with permission.
Fig.4  Schematic of lentiviral transduction of aIIb-TRAIL construct into mouse hematopoietic stem/progenitor cells followed by bone marrow transplantation via retroorbital injection. Reprinted from Ref. 13 with permission.
Fig.5  Schematic preparation of platelet membrane-coated nanoparticle. Poly(lactic-coglycolic acid) (PLGA) nanoparticles are enclosed entirely in human platelet-derived plasma membrane. The resulting particles possess platelet-mimicking properties for immunocompatibility, sub-endothelium binding, and pathogen adhesion. Reprinted from Ref. 14 with permission.
Fig.6  Schematic synthesis of RBC-PNPs. Membrane material is derived from both RBCs and platelets and then fused together. The resulting fused membrane is used to coat PLGA polymeric cores to produce [RBC-P]NPs. Reprinted from Ref. 15 with permission.
Fig.7  Schematic design of drug-loaded PM-NV for targeting and sequential drug delivery. (A) Main components of TRAIL-Dox-PM-NV: TRAIL-conjugated PM derived from platelets; Dox-NV. (i) Centrifugation of whole blood; (ii) platelet isolation; (iii) PM extraction. (B) In vivo elimination of CTCs and sequential delivery of TRAIL and Dox. TRAIL-Dox-PM-NV captured CTCs via specific affinity of P-selectin and overexpressed CD44 receptors and subsequently triggered TRAIL/Dox-induced apoptosis signaling pathways. (i) Interaction of TRAIL and death receptors trigger apoptosis signaling; (ii) TRAIL-Dox-PM-NV internalization; (iii) TRAIL-Dox-PM-NV dissociation mediated by the lyso-endosome acidity; (iv) release and accumulation of Dox in the nuclei; (v) intrinsic apoptosis triggered by Dox. Reprinted from Ref. 16 with permission.
Fig.8  Schematic design of tPA-Ald-PM-NP-bort and sequentially targeting to bone microenvironment and MM cells. (A) Main components of tPA-Ald-PM-NP-bort: platelet-derived platelet membrane; PNPs made of acid-responsive modified dextran. (B) After intravenous injection, tPA-Ald-PM-NP-bort can sequentially target bone microenvironment through efficient binding between Ald and calcium ions and home to MM cells via specific affinity of P-selectin and overexpressed CD44 receptors. After internalization, tPA-Ald-PM-NP-bort matrix can be dissociated by lyso-endosome acidity, releasing the encapsulated bortezomib. Reprinted from Ref. 17 with permission.
Fig.9  Schematic illustration of two-sequential-module-based drug delivery systems and enhanced drug accumulation. Signaling transmission NCA is composed of an arginine-glycine-aspartic peptide-decorated nanocarrier, which can (i) target tumor blood vessels, (ii) release encapsulated TNF-a, and (iii) induce vasculature inflammation. Execution of biomimetic NCB involves a platelet membrane-coated dextran nanocarrier with incorporation of an acidity-degradable modality. (iii) NCB can respond to amplified targeting signal induced by NCA, accumulating at the tumor site and subsequently releasing an encapsulated anticancer drug. Reprinted from Ref. 18 with permission.
Fig.10  Design of CREKA-Lipo-T nanoparticles and their proposed antimetastatic mechanism within tumor tissues. (A) Proposed mechanism of action of CREKA-Lipo-T nanoparticles. Normally, tumor growth factor (TGF)-b secreted by platelets induces transition of tumor cells to a mesenchymal-like phenotype (I). Platelets can also protect tumor cells against attack from natural killer (NK) cells (II). At distant sites, platelets assist metastatic cells to cross the local endothelium by secreting numerous cytokines. Following treatment, CREKA-Lipo-T actively targets microthrombi in tumor vessel walls and releases ticagrelor slowly and locally. Ticagrelor binds to tumor-associated platelets and inhibits their functions. The release of TGF-b from platelets and the interaction between platelets and tumor cells are abolished, leading to decreased epithelial–mesenchymal-like transition of tumor cells and thus inhibiting their invasion capacity. When tumor cells are present in circulation, compromised platelets fail to adhere to tumor cells and cannot shield tumor cells from NK cell attack. X indicates that a process was abolished by treatment. (B) Conjugation between 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (PEG) and CREKA peptide using Michael addition reaction under anaerobic conditions. (C) Schematic diagram of CREKA-Lipo-T nanoparticle synthesis. Reprinted from Ref. 24 with permission.
Fig.11  Design features and proposed mechanism of action of PLP-D-R in tumor blood vessels in vivo. (A) Schematic illustration of MMP2-responsive nanoparticles. Dox-loaded core nanoparticles (P-D) were assembled from PEI-(PLGA)2 block copolymer, wherein the antibody R300 was absorbed on its surface (P-D-R). A shell comprising MMP2-cleavable peptides (for targeted MMP2 responsiveness), lecithins, and PEGylated (PEG) phospholipids (for steric stabilization) was layered into the surface of core nanoparticles. (B) Shell layer of the resulting PLP-D-R was cleaved within tumors by MMP2, which is overexpressed on the surface of tumor endothelial and stroma cells, consequently exposing R300 and leading to its release locally. R300 binds to platelet-surface receptors and facilitates formation of platelet microaggregates and subsequent depletion. Absence of platelets in tumors induces openings in the vessel walls, enhancing permeability and retention effect, which provide ready access for Dox-encapsulated core nanoparticles to enter tumors. Reprinted from Ref. 27 with permission.
Fig.12  (A) Immunofluorescence staining of endothelial cells (CD31; red) in MCF7 tumor sections 24 h after administration of saline, R300, PLP-D, or PLP-D-R. Nuclei were stained with Hoechst 33342 (blue). White arrows indicate endothelial damage. (B) Scanning electron micrographs of blood vessels in MCF7 tumors 24 h after injection of saline, R300, PLP-D, or PLP-D-R. Disruption of vascular endothelial integrity in R300 and PLP-D-R-treated tumors is exemplified by widened breaches on the vascular barrier (magnified below, red arrows) compared with endothelium in controls. (C) High-resolution TEM images of blood vessels in MCF7 tumors 24 h after injection of saline, R300, PLP-D, or PLP-D-R, showing disrupted endothelium (red arrows) in R300- and PLP-D-R-treated groups. In the R300-treated group, the arrows show the exposed basement membrane in the endothelial gap, whereas in the PLP-D-R-treated group, RBCs (green arrows) leaked from the vessel through the breach between endothelial cells. RBC, red blood cells; EN, endothelium; NU, nuclei of endothelial cells. Reprinted from Ref. 27 with permission.
1 Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature 2008; 453(7193): 314–321
https://doi.org/10.1038/nature07039 pmid: 18480812
2 Furie B, Furie BC. Thrombus formation in vivo. J Clin Invest 2005; 115(12): 3355–3362
https://doi.org/10.1172/JCI26987 pmid: 16322780
3 Ho-Tin-Noé B, Goerge T, Cifuni SM, Duerschmied D, Wagner DD. Platelet granule secretion continuously prevents intratumor hemorrhage. Cancer Res 2008; 68(16): 6851–6858
https://doi.org/10.1158/0008-5472.CAN-08-0718 pmid: 18701510
4 Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer 2011; 11(2): 123–134
https://doi.org/10.1038/nrc3004 pmid: 21258396
5 Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013; 19(11): 1423–1437
https://doi.org/10.1038/nm.3394 pmid: 24202395
6 Mammadovabach E, Zigrino P, Brucker C, Bourdon C, Freund M, Arcangelis AD, Abrams SI, Orend G, Gachet C, Mangin PH. Platelet integrin a6b1 controls lung metastasis through direct binding to cancer cell–derived ADAM9. JCI Insight 2016; 1(14): e88245
https://doi.org/10.1172/jci.insight.88245 pmid: 27699237
7 Yu LX, Yan L, Yang W, Wu FQ, Ling Y, Chen SZ, Tang L, Tan YX, Cao D, Wu MC, Yan HX, Wang HY. Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein. Nat Commun 2014; 5: 5256
https://doi.org/10.1038/ncomms6256 pmid: 25348021
8 Xu P, Zuo H, Chen B, Wang R, Ahmed A, Hu Y, Ouyang J. Doxorubicin-loaded platelets as a smart drug delivery system: an improved therapy for lymphoma. Sci Rep 2017; 7: 42632
https://doi.org/10.1038/srep42632 pmid: 28198453
9 Nurden AT, Nurden P, Sanchez M, Andia I, Anitua E. Platelets and wound healing. Front Biosci 2008; 13: 3532–3548
pmid: 18508453
10 Nieswandt B, Hafner M, Echtenacher B, Männel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999; 59(6): 1295–1300
pmid: 10096562
11 Wang C, Sun W, Ye Y, Hu Q, Bomba HN, Gu Z. In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy. Nat Biomed Eng 2017; 1: 0011
12 Daly ME. Determinants of platelet count in humans. Haematologica 2011; 96(1): 10–13
https://doi.org/10.3324/haematol.2010.035287 pmid: 21193429
13 Li J, Sharkey CC, Wun B, Liesveld JL, King MR. Genetic engineering of platelets to neutralize circulating tumor cells. J Control Release 2016; 228: 38–47
https://doi.org/10.1016/j.jconrel.2016.02.036 pmid: 26921521
14 Hu CM, Fang RH, Wang KC, Luk BT, Thamphiwatana S, Dehaini D, Nguyen P, Angsantikul P, Wen CH, Kroll AV, Carpenter C, Ramesh M, Qu V, Patel SH, Zhu J, Shi W, Hofman FM, Chen TC, Gao W, Zhang K, Chien S, Zhang L. Nanoparticle biointerfacing by platelet membrane cloaking. Nature 2015; 526(7571): 118–121
https://doi.org/10.1038/nature15373 pmid: 26374997
15 Dehaini D, Wei X, Fang RH, Masson S, Angsantikul P, Luk BT, Zhang Y, Ying M, Jiang Y, Kroll AV, Gao W, Zhang L. Erythrocyte-platelet hybrid membrane coating for enhanced nanoparticle functionalization. Adv Mater 2017 29(16):1606209
https://doi.org/10.1002/adma.201606209 pmid: 28199033
16 Hu Q, Sun W, Qian C, Wang C, Bomba HN, Gu Z. Anticancer platelet-mimicking nanovehicles. Adv Mater 2015; 27(44): 7043–7050
https://doi.org/10.1002/adma.201503323 pmid: 26416431
17 Hu Q, Qian C, Sun W, Wang J, Chen Z, Bomba HN, Xin H, Shen Q, Gu Z. Engineered nanoplatelets for enhanced treatment of multiple myeloma and thrombus. Adv Mater 2016; 28(43): 9573–9580
https://doi.org/10.1002/adma.201603463 pmid: 27626769
18 Hu Q, Sun W, Qian C, Bomba HN, Xin H, Gu Z. Relay drug delivery for amplifying targeting signal and enhancing anticancer efficacy. Adv Mater 2017; 29(13): 1605803
https://doi.org/10.1002/adma.201605803 pmid: 28160337
19 Li J, Ai Y, Wang L, Bu P, Sharkey CC, Wu Q, Wun B, Roy S, Shen X, King MR. Targeted drug delivery to circulating tumor cells via platelet membrane-functionalized particles. Biomaterials 2016; 76: 52–65
https://doi.org/10.1016/j.biomaterials.2015.10.046 pmid: 26519648
20 Cho MS, Bottsford-Miller J, Vasquez HG, Stone R, Zand B, Kroll MH, Sood AK, Afshar-Kharghan V. Platelets increase the proliferation of ovarian cancer cells. Blood 2012; 120(24): 4869–4872
https://doi.org/10.1182/blood-2012-06-438598 pmid: 22966171
21 Cooke NM, Spillane CD, Sheils O, O’Leary J, Kenny D. Aspirin and P2Y12 inhibition attenuate platelet-induced ovarian cancer cell invasion. BMC Cancer 2015; 15(1): 627
https://doi.org/10.1186/s12885-015-1634-x pmid: 26353776
22 Klement GL, Yip TT, Cassiola F, Kikuchi L, Cervi D, Podust V, Italiano JE, Wheatley E, Abou-Slaybi A, Bender E, Almog N, Kieran MW, Folkman J. Platelets actively sequester angiogenesis regulators. Blood 2009; 113(12): 2835–2842
https://doi.org/10.1182/blood-2008-06-159541 pmid: 19036702
23 Rachidi S, Metelli A, Riesenberg B, Wu BX, Nelson MH, Wallace C, Paulos CM, Rubinstein MP, Garrett-Mayer E, Hennig M, Bearden DW, Yang Y, Liu B, Li Z. Platelets subvert T cell immunity against cancer via GARP-TGFb axis. Sci Immunol 2017; 2(11): 7911
https://doi.org/10.1126/sciimmunol.aai7911 pmid: 28763790
24 Zhang Y, Wei J, Liu S, Wang J, Han X, Qin H, Lang J, Cheng K, Li Y, Qi Y, Anderson GJ, Sukumar S, Li S, Nie G. Inhibition of platelet function using liposomal nanoparticles blocks tumor metastasis. Theranostics 2017; 7(5): 1062–1071
https://doi.org/10.7150/thno.17908 pmid: 28435448
25 Ho-Tin-Noé B, Goerge T, Wagner DD. Platelets: guardians of tumor vasculature. Cancer Res 2009; 69(14): 5623–5626
https://doi.org/10.1158/0008-5472.CAN-09-1370 pmid: 19584268
26 Kisucka J, Butterfield CE, Duda DG, Eichenberger SC, Saffaripour S, Ware J, Ruggeri ZM, Jain RK, Folkman J, Wagner DD. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage. Proc Natl Acad Sci USA 2006; 103(4): 855–860
https://doi.org/10.1073/pnas.0510412103 pmid: 16418262
27 Li S, Zhang Y, Wang J, Zhao Y, Ji T, Zhao X, Ding Y, Zhao X, Zhao R, Li F, Yang X, Liu S, Liu Z, Lai J, Whittaker AK, Anderson GJ, Wei J, Nie G. Nanoparticle-enabled local depletion of tumor-associated platelets disrupts tumor vascular barriers and augments tumor drug accumulation. Nat Biomed Eng 2017;1:667–679
https://doi.org/DOI: 10.1038/s41551-017-0115-8
28 Ishikawa S, Miyashita T, Inokuchi M, Hayashi H, Oyama K, Tajima H, Takamura H, Ninomiya I, Ahmed AK, Harman JW, Fushida S, Ohta T. Platelets surrounding primary tumor cells are related to chemoresistance. Oncol Rep 2016; 36(2): 787–794
https://doi.org/10.3892/or.2016.4898 pmid: 27349611
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