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WIREs Nanomed Nanobiotechnol
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Cancer‐associated‐platelet‐inspired nanomedicines for cancer therapy

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Abstract Platelets, with hemostasis and thrombosis activities, are one of the key components in the blood circulation. As a guard, they rapidly respond to any abnormal blood vessel injury signal and release their granules' contents, which induce their adhesion and aggregation on wound site for hemostasis. Recently, increasing evidence has indicated that platelets are critically involved in the growth and metastasis of cancer cells by releasing a variety of cytokines and chemokines to stimulate cancer cell proliferation and various angiogenic regulators to accelerate tumor angiogenesis. Platelets also secrete active transforming growth factor beta (TGF‐β) to promote the epithelial–mesenchymal transition of cancer cells and their extravasation from primary site, and form microthrombus on the surface of cancer cells to protect them from immune attack and high‐speed shear force in the circulation. Therefore, blocking platelet–cancer cell interaction may be an attractive strategy to treat primary tumor and/or prevent cancer metastasis. However, systemic inhibition or depletion of platelets brings risk of severe bleeding complication. Cancer‐associated‐platelets‐targeted nanomedicines and biomimetic nanomedicines coated with platelet membrane can be used for targeted anticancer drug delivery, due to their natural targeting ability to tumor cells and platelets. In the current review, we first summarized the platelet mechanisms of action in physiological condition and their multiple roles in cancer progression and conventional antiplatelet therapeutics. We then highlighted the recent progress on the design and fabrication of cancer‐associated‐platelet‐targeted nanomedicines and platelet membrane coating nanomedicines for cancer therapy. Finally, we discussed opportunities and challenges and offered our thoughts for the future development. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology‐Inspired Nanomaterials > Lipid‐Based Structures
Roles of platelets in cancer progression. Platelets can stimulate tumor growth and angiogenesis through the secretion of growth factors and pro‐angiogenic contents in tumor microenvironment (TME) at primary tumor site. Release of TGF‐β from activated platelets can induce epithelial–mesenchymal transition (EMT) transition in cancer cells prior to entering the blood circulation. Following intravasation, many detached cancer cells may enter bloodstream and closely contact with various circulating blood cells, like platelets. Once activated, the platelet cytoskeleton collapses followed by extensive shape change, depending upon the trigger stimulus. Activated platelets can interact with cancer cells through a variety of receptors (GPIIb/IIIa‐fibrinogen and P‐selectin) to protect tum cancer or cells from elimination by immune cells and physical stress. The metastatic cancer cells can use the attached platelets to adhere to P‐selectin expressed by activated endothelial cells lining the blood vessel walls. Following adhesion to the endothelium, the metastatic tum cancer or cells escape the bloodstream at the secondary site to begin to form a secondary tumor site. Platelets can also promote the formation of neutrophil extracellular traps (NETs) and associated immunothrombosis via release of platelet granule cytokines, as well as direct contact with neutrophils via cell surface receptors. NETs contribute to systemic effects of the whole process of tumor progression by promoting metastasis, thrombosis, and organ failure
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Schematic illustration of the preparation of PEOz‐platesome‐dox and its proposed anticancer mechanism. (a) PEOz‐platesome‐dox was generated by coextrusion of PEOz‐liposome‐dox and PNV. (b) After intravenous injection, PEOz‐platesome‐dox is expected to target the cancer through molecular interactions between platelet membrane and cancer cell substituents, such as platelet CD62p and its cognate receptor, tumoral CD44. The incorporation of pH‐sensitive lipids into the platesome would allow its cargo (dox) to be rapidly released at the tumor site in response to the acidic pH of the TME and/or lysosomal compartments. The released dox kills cancer cells by inhibiting the cellular DNA replication. Reprinted from G. Liu, Zhao, et al. (2019) with permission
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Design features and the proposed mechanism of action of PLP–D–R in caner blood vessels in vivo. (a) Schematic of the MMP2‐responsive nanoparticles. The Dox‐loaded core nanoparticles (P–D) were assembled from the PEI–(PLGA)2 block copolymer, onto the surface of which the antibody R300 was absorbed to form P–D–R. A shell comprising MMP2 cleavable peptides (for targeted MMP2 responsiveness), lecithins and PEGylated phospholipids (for steric stabilization) was layered onto the surface of the core nanoparticles. (b) The shell layer of the resulting PLP–D–R is cleaved within cancers by MMP2, which is overexpressed on the surface of cancer endothelial and stroma cells, consequently exposing R300 and leading to its release locally. R300 binds to platelet‐surface receptors and facilitates the formation of platelet microaggregates and subsequent depletion. The absence of platelets in cancers induces openings in the vessel walls, which provide ready access for the Dox‐encapsulated core nanoparticles to enter the tumor. Reprinted from reference (S. Li et al., 2017) with permission
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Cancer‐associated‐platelet‐targeting nanomedicines and platelet membrane coating nanomedicines. (a) Nanoparticles targeting activated platelets. These platelets can stimulate tumor angiogenesis, enhances vascular permeability, and promote the formation of metastatic tumors. Targeting and destroying them can be an effective way to control metastasis. (b) A schematic illustration for preparing platelet membrane biomimetic nanotechnology. To prepare nanoparticles coated with platelet membranes, a blood sample will be collected and the platelets will be separated. Then their membranes will be extracted and used to cover the nanoparticles. (c) Nanoparticles targeting to circulating tumor cells (CTC). The same as platelets, it has been indicated that the tissue factor (TF), adenosine diphosphate (ADP), or thrombin secreted from CTC can induce platelets aggregation. By targeting CTC, one can not only stop them from releasing these materials, but also target deliver other therapeutics to prevent metastasis
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Platelet receptors, its inhibitors and blockers, and platelet‐targeted pharmacologic drugs used to treat cancer. Various transmembrane receptors are expressed and involved in platelet–platelet and platelet–cancer cell interactions. Aspirin, a reversible inhibitor of cyclooxygenase (COX)‐1, is widely used against platelets. COX‐1, which is highly produced by cancer cells, is involved in arachidonic acid (AA) metabolism to prostaglandin (PG) H2. By TxA2 synthase (TXAS), PGH2 can be turned into thromboxane (Tx)A2 which is a pro‐aggregatory agent. Interaction between podoplanin and CLEC‐2, can induce platelet aggregation. Anti‐PLAG3 and ‐PLAG4 mAb can specifically prevent this process. Platelets can be activated by ADP via P2Y1 and P2Y12 receptors. Two groups of ADP blockers, including thienopyridines and the new generation of the drugs, can strongly bind to P2Y1 and P2Y12 to block platelet aggregation. Various isoforms of phosphodiesterases exist in platelets, and their inhibitors are dipyridamole as PDE3‐PDE5 inhibitor, cilostazol as PDE3 inhibitor and EHNA as PDE2 inhibitor. EP3 is a subtype of prostaglandin E2 (PGE2) which can be inhibited via its antagonist, DG‐041. Expression of platelet fibrinogen receptors can be affected by various substances (e.g. GPIIb/IIIa, ADP, collagen, arachidonic acid, or epinephrine); therefore, inhibition of platelet‐ fibrinogen binding can vary regarding their targets. αIIbβ3 blockers are abciximab, eptifibatide, tirofiban, XV454, and 7C3 F(ab)2; αvβ3 blockers include SB‐273005, SH066, SC‐68448, and vitaxin; revacept, kistomin, and glaucocalyxin are the therapeutics targeting GPVI. P‐selectin is another receptor on cancer cell plasma membrane, which is inhibited by heparin. Iloprost is an agonist of prostacyclin (IP) receptor for PGI2. Thrombin which leads to platelet activation, bind specifically onto protease‐activated receptors (PARs). PAR‐1 and PAR‐4 are expressed on human platelets which are blocked respectively by vorapaxar and atopaxar, and BMS‐986120 and BMS‐986141
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Schematic representation of platelet and cancer cell surface receptors. Platelets surface receptors interact with cancer cell or metastasis‐related ligands on cells or extracellular compartments via the different types of cell receptor and extracellular matrix (ECM) proteins as intermediaries. The glycoprotein GPIb‐IX‐V and GPVI are responsible for initial platelet adhesion and activation in blood by binding to their main ligand, von Willebrand factor (vWF) and collagen. On inactivated platelets, integrins are presented in a low affinity state. Platelet activation leads to conformational changes that enable high‐affinity interactions with ECM proteins and with other cells. One of the most important integrins is αIIbβ3 (GPIIb/IIIa) which enhance platelet adhesion and aggregation via fibronectin, fibrinogen and vWF. P‐selectin is expressed on activated platelets that bind to PSGL‐1 (expressed on leukocytes) and regulate the initial interactions between activated platelets and leukocytes. PAR receptors bind to thrombin that stimulates platelets and increases their adhesion to tumor cells. ADP acts through P2Y1 and P2Y12 receptors (G‐protein‐coupled receptors) which leads to shape change, aggregation, and thromboxane A2 production by platelets. CLEC‐2‐podoplanin interaction facilitates hematogenous tumor metastasis
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Therapeutic Approaches and Drug Discovery > Emerging Technologies
Biology-Inspired Nanomaterials > Lipid-Based Structures

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