Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumor vasculature permeability and drug delivery

Tumor vasculature is critically dependent on platelet mediated hemostasis and disruption of the same can augment delivery of nano-formulation based chemotherapeutic agents which depend on enhanced permeability and retention for tumor penetration. Here, we evaluated the role of Clopidogrel, a well-known inhibitor of platelet aggregation, in potentiating the tumor cytotoxicity of cisplatin nano-formulation in a murine breast cancer model. In vivo studies in murine syngeneic 4T1 breast cancer model showed a significant greater penetration of macromolecular fluorescent nanoparticles after clopidogrel pretreatment. Compared to self-assembling cisplatin nanoparticles (SACNs), combination therapy with clopidogrel and SACN was associated with a 4 fold greater delivery of cisplatin to tumor tissue and a greater reduction in tumor growth as well as higher survival rate. Clopidogrel enhances therapeutic efficiency of novel cisplatin based nano-formulations agents by increasing tumor drug delivery and can be used as a potential targeting agent for novel nano-formulation based chemotherapeutics.

[1]  Xing‐dong Zhang,et al.  Computer simulation of biomolecule–biomaterial interactions at surfaces and interfaces , 2015, Biomedical materials.

[2]  Joseph W. Nichols,et al.  EPR: Evidence and fallacy. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[3]  R. Jain,et al.  Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. , 2013, Cancer research.

[4]  A. Pandey,et al.  P2Y12 receptor inhibition augments cytotoxic effects of cisplatin in breast cancer , 2013, Medical Oncology.

[5]  A. Sood,et al.  Platelets increase the proliferation of ovarian cancer cells. , 2012, Blood.

[6]  A. Pandey,et al.  Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity , 2012, Proceedings of the National Academy of Sciences.

[7]  R. Jain,et al.  Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner , 2012, Nature nanotechnology.

[8]  W. Chiu,et al.  Paraneoplastic thrombocytosis in ovarian cancer. , 2012, The New England journal of medicine.

[9]  Daniel A. Heller,et al.  Treating metastatic cancer with nanotechnology , 2011, Nature Reviews Cancer.

[10]  Jun Fang,et al.  The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. , 2011, Advanced drug delivery reviews.

[11]  D. Wagner,et al.  Increased efficacy of breast cancer chemotherapy in thrombocytopenic mice. , 2011, Cancer research.

[12]  C. Holmes,et al.  The platelet contribution to cancer progression , 2011, Journal of thrombosis and haemostasis : JTH.

[13]  Hillary Holback,et al.  Intratumoral Drug Delivery with Nanoparticulate Carriers , 2011, Pharmaceutical Research.

[14]  R. Jain,et al.  Delivering nanomedicine to solid tumors , 2010, Nature Reviews Clinical Oncology.

[15]  Joseph M. DeSimone,et al.  Strategies in the design of nanoparticles for therapeutic applications , 2010, Nature Reviews Drug Discovery.

[16]  M. Schön,et al.  Constitutive and functionally relevant expression of JAM-C on platelets , 2010, Thrombosis and Haemostasis.

[17]  Ji Luo,et al.  Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction , 2009, Cell.

[18]  D. Wagner,et al.  Platelet granule secretion continuously prevents intratumor hemorrhage. , 2008, Cancer research.

[19]  M. Dewhirst,et al.  Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. , 2006, Journal of the National Cancer Institute.

[20]  Kristian Pietras,et al.  High interstitial fluid pressure — an obstacle in cancer therapy , 2004, Nature Reviews Cancer.

[21]  R. Jain Delivery of molecular and cellular medicine to solid tumors. , 2001, Advanced drug delivery reviews.

[22]  M. Seyfarth,et al.  Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement , 2001, Heart.

[23]  G. Hortobagyi,et al.  Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  R. Jain,et al.  Delivery of molecular and cellular medicine to solid tumors. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[25]  Rakesh K Jain,et al.  Delivery of molecular and cellular medicine to solid tumors. , 1997, Advanced drug delivery reviews.

[26]  R. Jain,et al.  Delivery of Molecular and Cellular Medicine to Solid Tumors , 1997, Advanced drug delivery reviews.

[27]  R. Jain,et al.  Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. , 1994, Cancer research.

[28]  B. Smith,et al.  Aspirin does not inhibit adenosine diphosphate-induced platelet alpha- granule release , 1993 .

[29]  A. Pandey,et al.  Sequential application of a cytotoxic nanoparticle and a PI3K inhibitor enhances antitumor efficacy. , 2014, Cancer research.

[30]  P. Salama [Thrombosis and cancer]. , 2004, Anales del sistema sanitario de Navarra.

[31]  B. Smith,et al.  Aspirin does not inhibit adenosine diphosphate-induced platelet alpha-granule release. , 1993, Blood.