Targeted Inhibition of Tumor Inflammation and Tumor-Platelet Crosstalk by Nanoparticle-Mediated Drug Delivery Mitigates Cancer Metastasis

Abstract

Sowing malignant cells (the “seeds” of metastasis) to engraft secondary sites requires a conducive premetastatic niche (PMN, the “soil” of metastasis). Inflammation and tumor associated platelet (TAP) has been hijacked by primary tumors to induce PMN “soil” in distant organs, as well as facilitate the dissemination of “seeds”. This study reports a combinatory strategy with activated platelet-targeting nanoparticles to aim at the dynamic process of entire cancer metastasis, which exerts robust antimetastasis efficacy by simultaneously inhibiting tumor inflammation and tumor-platelet crosstalk. Our results reveals that the PSN peptide (a P-selectin-targeting peptide) modification enriched the accumulation of nanoparticles in primary tumor, pulmonary PMN, and metastases via capturing activated platelet. Such characteristics contribute to the efficient inhibition on almost every crucial and consecutive step of the metastasis cascade by retarding epithelial-mesenchymal transition (EMT) progression within tumors, specifically blocking the tumor-platelet crosstalk to remove the platelets “protective shield” around disseminated “seeds”, and reversing the inflammatory microenvironment to interfere with the “soil” formation. Consisting of inflammation inhibiting and TAP impeding nanoparticles, this approach prominently reduces various metastasis in abscopal lung, including spontaneous metastasis, disseminated tumor cells metastasis, and post-operative metastasis. This work provides a generalizable nanoplatform of parallel inflammation disturbance and tumor-TAP crosstalk blockade to resist metastatic tumors.

Prostate cancer cell-platelet bidirectional signaling promotes calcium mobilization, invasion and apoptotic resistance via distinct receptor-ligand pairs

“…Moreover, mouse models have demonstrated that interactions of platelets with numerous cancer cell types (e.g. mammary, colorectal, ovarian, breast) are crucial for cancer metastasis 22 , 59 , 60 . A natural corollary is to evaluate whether the presence of CD55 and/or ADGRE5 neutralizing antibodies abrogates PCa cell-platelet crosstalk and reverses metastatic potential in a nude mouse model.…”

Ultrasound-Chargeable Persistent Luminescence Nanoparticles to Generate Self-Propelled Motion and Photothermal/NO Therapy for Synergistic Tumor Treatment

“…Tissue distribution of NPs and diffusion in tumors were examined on H22 tumor-bearing mice after intravenous treatment with mSZ@PDA-NO/US, mSZ#PDA-NO/US, mSZ@PDA-NO/NIR, mSZ@PDA/US, and mSZ@PDA-NO. 65 All animal experiments were performed following the Institutional Guide for the Care and Use of Laboratory Animals of China and the protocols were approved by the Animal Care and Use Committee of Southwest Jiaotong University. Briefly, Kunming mice (∼20 g) were received from Sichuan Dashuo Biotech.…”

The role of platelets in the regulation of tumor growth and metastasis: the mechanisms and targeted therapy

“…The capture of platelets by P‐selectin was also explored. For example, nanoparticles coated with a P‐selectin‐targeting peptide (PSN peptide) were constructed, and the core of these nanoparticles was filled with ticagrelor or celecoxib 200 . Through capturing activated platelets, these PSN peptide‐modified nanocarriers have improved capability in accumulating at the primary tumor and premetastatic sites, hence robustly inhibiting platelet−tumor interaction and inflammation 200 .…”