Abstract
Failure of conventional clinical therapies such as tumor resection and chemotherapy are mainly due to the ineffective control of tumor metastasis. Metastasis consists of three steps: (i) tumor cells extravasate from the primary sites into the circulation system via epithelial-mesenchymal transition (EMT), (ii) the circulating tumor cells (CTCs) form “micro-thrombi” with platelets to evade the immune surveillance in circulation, and (iii) the CTCs colonize in the pre-metastatic niche. Here, we design a systemic metastasis-targeted nanotherapeutic (H@CaPP) composed of an anti-inflammatory agent, piceatannol, and an anti-thrombotic agent, low molecular weight heparin, to hinder the multiple steps of tumor metastasis. H@CaPP is found efficiently impeded EMT, inhibited the formation of “micro-thrombi”, and prevented the development of pre-metastatic niche. When combined with surgical resection or chemotherapy, H@CaPP efficiently inhibits tumor metastasis and prolonged overall survival of tumor-bearing mice. Collectively, we provide a simple and effective systemic metastasis-targeted nanotherapeutic for combating tumor metastasis.
Highlights
Failure of conventional clinical therapies such as tumor resection and chemotherapy are mainly due to the ineffective control of tumor metastasis
PP was precipitated with calcium to form calcium phosphate nanoparticles (CaPP), which were further decorated with low molecular weight heparin (LMWH) via electrostatic interaction on the surface to form a systemic metastasis-targeted nanotherapeutic (H@CaPP)
D@CaPP without targeting capability was prepared by replacing LMWH with dextran to serve as the control
Summary
Failure of conventional clinical therapies such as tumor resection and chemotherapy are mainly due to the ineffective control of tumor metastasis. Due to the systematic processes, there is no effective clinical therapeutic targeting tumor metastasis yet Some therapeutic strategies such as intervening EMT process via N-cadherin antibody, targeting CTCs, and hindering the formation of a pre-metastatic niche have been proposed to combat tumor metastasis[13,14,20,26,27,28]. We designed a systemic metastasis-targeted nanotherapeutic (H@CaPP) for co-delivering an anti-inflammatory agent, piceatannol (PIC), and an anti-thrombotic agent, low molecular weight heparin (LMWH), to combat tumor metastasis by hindering the multiple steps of tumor metastasis (Fig. 1). H@CaPP successfully impeded the multiple steps of metastasis: inhibiting the EMT process in the invasion phase; hindering the formation of “micro-thrombi” in the colonization phase; suppressing pre-metastatic niche via binding to P-selectin, decreasing the adhesiveness of ECs, reversing the remodeling of extracellular matrix, and hindering the development of the immunosuppressive inflammatory site (Fig. 1). This study combined antiinflammatory drugs and anticoagulants into a targeted nanotherapeutic, providing a safe and potential strategy for adjuvant therapy of metastatic tumors
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