Surface-Anchored Ticagrelor Gelatin Nanoparticles-Platelets System for Enhanced Anti-PD-L1 Therapy Response and Boosted Chemotherapeutic Efficacy of Nanomedicines

Abstract

The tumor microenvironment is characterized by immunosuppression and compromised intratumoral perfusion, which impairs the effectiveness of immune checkpoint inhibitors and nanomedicines. A significant challenge is the role of activated platelets, as they increase transfer-mediated PD-L1 expression from tumor cells and maintain the integrity of tumor vasculature. These platelets support tumor growth by stabilizing the vasculature and enabling immune evasion, as well as shielding tumor cells from immune detection. To address these platelet-mediated negative antitumor effects, we have developed bioengineered platelets (PTNPs) with surface-anchored ticagrelor-loaded gelatin nanoparticles. This study utilizes the natural tendency of platelets to localize their activated counterparts into tumors. Upon binding to tumor-associated activated platelets, the PTNPs release ticagrelor in response to the secreted matrix metalloproteinases by activated platelet, inhibiting further platelet activation. This reduction in platelet activation lessens platelet-facilitated immunosuppression and diminishes the transferred-PD-L1 expression from cancer cells to platelets, thus enhancing the immune response of anti-PD-L1 therapy. Additionally, this strategy weakens the activated platelets’ contribution to tumor vascular integrity, improving the extravasation and chemotherapeutic efficacy of nanomedicines. Our findings highlight the crucial role of platelet activation in tumor biology and introduce PTNPs as an effective approach to disrupt tumor-supporting platelet activities and enhance anticancer treatments efficacy.

Keywords

chemotherapy / immunotherapy / MMPs-responsive release / platelet-based delivery system / tumor-associated platelets

References

[1] R. L. Siegel, K. D. Miller, H. E. Fuchs, and A. Jemal, “Cancer Statistics, 2022,” CA: A Cancer Journal for Clinicians 72 (2022): 7-33.

[2] a) Q. Lu, T. Liu, Z. Han, et al., “Revolutionizing Cancer Treatment: The Power of Cell-Based Drug Delivery Systems,” Journal of Controlled Release 361 (2023): 604-620; b) O. J. Finn, “Cancer Vaccines: Between the Idea and the Reality,” Nature Reviews Immunology 3 (2003): 630-641; c) H. Wang, Q. Lu, Y. Miao, et al., “Boosting SN38-based Oral Chemotherapy to Combine Reduction-Bioactivated Structured Lipid-Mimetic Prodrug With Ascorbic Acid,” Nano Research 15 (2022): 9092-9104.

[3] a) L. J. Gay and B. Felding-Habermann, “Contribution of Platelets to Tumour Metastasis,” Nature Reviews Cancer 11 (2011): 123-134; b) H. Ye, K. Wang, Q. Lu, et al., “Nanosponges of Circulating Tumor-Derived Exosomes for Breast Cancer Metastasis Inhibition,” Biomaterials 242 (2020): 119932; c) S. Sabrkhany, M. J. E. Kuijpers, M. G. A. Oude Egbrink, and A. W. Griffioen, “Platelets as Messengers of Early-Stage Cancer,” Cancer and Metastasis Reviews 40 (2021): 563-573.

[4] a) M. Jones, M. d'Arcy Doherty, and G. M. Cohen, “Antitumour Activity of 1-Naphthol Against L1210 Leukaemia In Vivo and Ehrlich Ascites Tumour Cells In Vivo and In Vitro,” Cancer Letters 33 (1986): 347-354; b) U. Prabhakar, H. Maeda, R. K. Jain, et al., “Challenges and Key Considerations of the Enhanced Permeability and Retention Effect for Nanomedicine Drug Delivery in Oncology,” Cancer Research 73 (2013): 2412-2417.

[5] a) B. Ho-Tin-Noe, M. Demers, and D. D. Wagner, “How Platelets Safeguard Vascular Integrity,” Journal of Thrombosis and Haemostasis 9, no. 1 (2011): 56-65; b) J. Kisucka, C. E. Butterfield, D. G. Duda, et al., “Platelets and Platelet Adhesion Support Angiogenesis While Preventing Excessive Hemorrhage,” Proceedings of the National Academy of Sciences of the United States of America 103 (2006): 855-860; c) B. Ho-Tin-Noe, T. Goerge, S. M. Cifuni, D. Duerschmied, and D. D. Wagner, “Platelet Granule Secretion Continuously Prevents Intratumor Hemorrhage,” Cancer Research 68 (2008): 6851-6858.

[6] C. Hinterleitner, J. Strahle, E. Malenke, et al., “Platelet PD-L1 Reflects Collective Intratumoral PD-L1 Expression and Predicts Immunotherapy Response in Non-Small Cell Lung Cancer,” Nature Communications 12 (2021): 7005.

[7] G. Chen, A. C. Huang, W. Zhang, et al., “Exosomal PD-L1 Contributes to Immunosuppression and Is Associated With Anti-PD-1 Response,” Nature 560 (2018): 382-386.

[8] a) V. Giannakeas, J. Kotsopoulos, M. C. Cheung, et al., “Analysis of Platelet Count and New Cancer Diagnosis Over a 10-Year Period,” JAMA Network Open 5 (2022): e2141633; b) J. Riedl, A. Kaider, C. Marosi, et al., “Decreased Platelet Reactivity in Patients With Cancer is Associated With High Risk of Venous Thromboembolism and Poor Prognosis,” Journal of Thrombosis and Haemostasis 117 (2017): 90-98.

[9] a) J. Volz, E. Mammadova-Bach, J. Gil-Pulido, et al., “Inhibition of Platelet GPVI Induces Intratumor Hemorrhage and Increases Efficacy of Chemotherapy in Mice,” Blood 133 (2019): 2696-2706; b) M. Demers, B. Ho-Tin-Noe, D. Schatzberg, J. J. Yang, and D. D. Wagner, “Increased Efficacy of Breast Cancer Chemotherapy in Thrombocytopenic Mice,” Cancer Research 71 (2011): 1540-1549; c) Z. Zhou, B. Zhang, S. Wang, et al., “Perfluorocarbon Nanoparticles Mediated Platelet Blocking Disrupt Vascular Barriers to Improve the Efficacy of Oxygen-Sensitive Antitumor Drugs,” Small 14 (2018): e1801694; d) S. Li, Y. Zhang, J. Wang, et al., “Nanoparticle-Mediated Local Depletion of Tumour-Associated Platelets Disrupts Vascular Barriers and Augments Drug Accumulation in Tumours,” Nature Biomedical Engineering 1 (2017): 667-679.

[10] a) A. Varki, “Trousseau's Syndrome: Multiple Definitions and Multiple Mechanisms,” Blood 110 (2007): 1723-1729; b) E. Pearlstein, P. L. Salk, G. Yogeeswaran, and S. Karpatkin, “Correlation Between Spontaneous Metastatic Potential, Platelet-Aggregating Activity of Cell Surface Extracts, and Cell Surface Sialylation in 10 Metastatic-Variant Derivatives of a Rat Renal sarcoma Cell Line,” Proceedings of the National Academy of Sciences of the United States of America 77 (1980): 4336-4339.

[11] a) S. H. Yun, E. H. Sim, R. Y. Goh, J. I. Park, and J. Y. Han, “Platelet Activation: The Mechanisms and Potential Biomarkers,” BioMed Research International 2016 (2016): 060143; b) M. Koupenova, B. E. Kehrel, H. A. Corkrey, and J. E. Freedman, “Thrombosis and Platelets: An Update,” European Heart Journal 38 (2017): 785-791.

[12] a) L. Coplu, Z. T. Selcuk, I. C. Haznedaroglu, R. Dogan, and Y. Gungen, “Aplastic Pancytopenia Associated With Thymoma,” Annal of Hematology 79 (2000): 648-650; b) P. Gresele, E. Falcinelli, M. Sebastiano, and S. Momi, “Chapter Four - Matrix Metalloproteinases and Platelet Function,” Progress in Molecular Biology and Translational Science 147 (2017): 133-165.

[13] a) S. Ruan, X. Cao, X. Cun, et al., “Matrix Metalloproteinase-Sensitive Size-Shrinkable Nanoparticles for Deep Tumor Penetration and pH Triggered Doxorubicin Release,” Biomaterials 60 (2015): 100-110; b) J. Cao, P. Yang, P. Wang, et al., “Adhesion and Release″ Nanoparticle-Mediated Efficient Inhibition of Platelet Activation Disrupts Endothelial Barriers for Enhanced Drug Delivery in Tumors,” Biomaterials 269 (2021): 120620; c) J.-H. Xu, F.-P. Gao, X.-F. Liu, et al., “Supramolecular Gelatin Nanoparticles as Matrix Metalloproteinase Responsive Cancer Cell Imaging Probes,” Chemical Communications 49, no. 40 (2013): 4462-4464.

[14] I. Kazes, I. l. Elalamy, J.-D. Sraer, M. Hatmi, and G. v. Nguyen, “Platelet Release of Trimolecular Complex Components MT1-MMP/TIMP2/MMP2: Involvement in MMP2 Activation and Platelet Aggregation,” Blood 96 (2000): 3064-3069.

[15] a) Q. Lu, H. Ye, K. Wang, et al., “Bioengineered Platelets Combining Chemotherapy and Immunotherapy for Postsurgical Melanoma Treatment: Internal Core-Loaded Doxorubicin and External Surface-Anchored Anti-PD-L1 Antibody Backpacks,” Nano Letters 22 (2022): 3141-3150; b) X. Fan, K. Wang, Q. Lu, et al., “Surface-Anchored Tumor Microenvironment-Responsive Protein Nanogel-Platelet System for Cytosolic Delivery of Therapeutic Protein in the Post-Surgical Cancer Treatment,” Acta Biomaterialia 154 (2022): 412-423.

[16] a) V. Dymicka-Piekarska, O. M. Koper-Lenkiewicz, J. Zinczuk, E. Kratz, and J. Kaminska, “Inflammatory Cell-Associated Tumors. Not Only Macrophages (TAMs), Fibroblasts (TAFs) and Neutrophils (TANs) Can Infiltrate the Tumor Microenvironment. The Unique Role of Tumor Associated Platelets (TAPs),” Cancer Immunology and Immunotherapy 70 (2021): 1497-1510; b) L. Amo, E. Tamayo-Orbegozo, N. Maruri, et al., “Involvement of Platelet-Tumor Cell Interaction in Immune Evasion. Potential Role of Podocalyxin-Like Protein 1,” Frontiers in Oncology 4 (2014): 245; c) X. Wang, S. Zhao, Z. Wang, and T. Gao, “Platelets Involved Tumor Cell EMT During Circulation: Communications and Interventions,” Cell Communication and Signaling 20 (2022): 82.

[17] Z. Feng, G. Chen, M. Zhong, et al., “An Acid-Responsive MOF Nanomedicine for Augmented Anti-Tumor Immunotherapy Via a Metal Ion Interference-Mediated Pyroptotic Pathway,” Biomaterials 302 (2023): 122333.

[18] Y. Wang, B. Zhang, Q. Xi, et al., “Gemcitabine Nano-Prodrug Reprograms Intratumoral Metabolism and Alleviates Immunosuppression for Hepatocellular Carcinoma Therapy,” Nano Today 53 (2023): 102009.

[19] a) W. Ma, R. Sun, L. Tang, et al., “Bioactivable STING Nanoagonists to Synergize NIR-II Mild Photothermal Therapy Primed Robust and Long-Term Anticancer Immunity,” Advanced Materials 35 (2023): e2303149; b) K. Wang, X. Zhang, H. Ye, et al., “Biomimetic Nanovaccine-Mediated Multivalent IL-15 Self-Transpresentation (MIST) for Potent and Safe Cancer Immunotherapy,” Nature Communications 14 (2023): 6748.

[20] a) H. Ye, K. Wang, J. Zhao, et al., “In Situ Sprayed Nanovaccine Suppressing Exosomal PD-L1 by Golgi Apparatus Disorganization for Postsurgical Melanoma Immunotherapy,” ACS Nano 17 (2023): 10637-10650; b) Y. Lu, H. Ye, J. Zhao, et al., “Small EV-Based Delivery of CpG ODNs for Melanoma Postsurgical Immunotherapy,” Journal of Controlled Release 363 (2023): 484-495.

[21] a) Y. Han, Q. Liu, J. Hou, et al., “Tumor-Induced Generation of Splenic Erythroblast-Like Ter-Cells Promotes Tumor Progression,” Cell 173 (2018): 634-648.e12; b) W. H. Woglom, “The Size of the Spleen in Immune Mice,” Journal of Cancer Research 4 (1919): 281-323; c) N. T. Le Na, S. Duc Loc, N. L. Minh Tri, et al., “Nanomelanin Potentially Protects the Spleen From Radiotherapy-Associated Damage and Enhances Immunoactivity in Tumor-Bearing Mice,” Materials 12 (2019): 1725.

[22] M. Haemmerle, R. L. Stone, D. G. Menter, V. Afshar-Kharghan, and A. K. Sood, “The Platelet Lifeline to Cancer: Challenges and Opportunities,” Cancer Cell 33 (2018): 965-983.

[23] Z. M. Ruggeri and G. L. Mendolicchio, “Adhesion Mechanisms in Platelet Function,” Circulation Research 100 (2007): 1673-1685.

[24] T. Goerge, B. Ho-Tin-Noe, C. Carbo, et al., “Inflammation Induces Hemorrhage in Thrombocytopenia,” Blood 111 (2008): 4958-4964.

[25] X. Pang, P. Yang, L. Wang, et al., “Human Serum Albumin Nanoparticulate System With Encapsulation of gefitinib for Enhanced Anti-Tumor Effects in Non-Small Cell Lung Cancer,” Journal of Drug Delivery Science and Technology 52 (2019): 997-1007.

[26] a) H. Ye, K. Wang, M. Wang, et al., “Bioinspired Nanoplatelets for Chemo-Photothermal Therapy of Breast Cancer Metastasis Inhibition,” Biomaterials 206 (2019): 1-12; b) J. Zhao, H. Ye, Q. Lu, et al., “Inhibition of Post-Surgery Tumour Recurrence via a Sprayable Chemo-Immunotherapy Gel Releasing PD-L1 Antibody and Platelet-Derived Small EVs,” Journal of Nanobiotechnology 20 (2022): 62.

RIGHTS & PERMISSIONS

2025 The Author(s). Exploration published by Henan University and John Wiley & Sons Australia, Ltd.