Targeted drug delivery to circulating tumor cells via platelet membrane-functionalized particles

Abstract

Circulating tumor cells (CTCs) are responsible for metastases in distant organs via hematogenous dissemination. Fundamental studies in the past decade have suggested that neutralization of CTCs in circulation could represent an effective strategy to prevent metastasis. Current paradigms of targeted drug delivery into a solid tumor largely fall into two main categories: unique cancer markers (e.g. overexpression of surface receptors) and tumor-specific microenvironment (e.g. low pH, hypoxia, etc.). While relying on a surface receptor to target CTCs can be greatly challenged by cancer heterogeneity, targeting of tumor microenvironments has the advantage of recognizing a broader spectrum of cancer cells regardless of genetic differences or tumor types. The blood circulation, however, where CTCs transit through, lacks the same tumor microenvironment as that found in a solid tumor. In this study, a unique “microenvironment” was confirmed upon introduction of cancer cells of different types into circulation where activated platelets and fibrin were physically associated with blood-borne cancer cells. Inspired by this observation, synthetic silica particles were functionalized with activated platelet membrane along with surface conjugation of tumor-specific apoptosis-inducing ligand cytokine, TRAIL. Biomimetic synthetic particles incorporated into CTC-associated micro-thrombi in lung vasculature and dramatically decreased lung metastases in a mouse breast cancer metastasis model. Our results demonstrate a “Trojan Horse” strategy of neutralizing CTCs to attenuate metastasis.

The Landscape of Circulating Tumor Cell Research in the Context of Epithelial-Mesenchymal Transition

“…Importantly, depletion of platelets or inhibition of TGF-β secretion solely in platelets drastically reduced distant metastases [67] . Another way to target CTC-platelet interactions could be targeted drug delivery to CTCs via platelet membranefunctionalized particles, as shown for a major tumor-killing cytokine, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), conjugated to the platelet membrane-coated silica particles which dramatically decreased lung metastases in a mouse BC metastasis model [179] . Taking into account the presented data, platelets are a promising therapeutic target for the attenuation of metastatic events.…”

Genetic engineering of platelets to neutralize circulating tumor cells

“…Recently, we published a work that utilized platelet-CTC interactions in the blood to deliver the cancer-killing protein TRAIL to CTCs by coating silica particles with platelet membrane [50]. In addition, other groups have also attempted to functionalize platelet-derived cancer targeting peptides or platelet membrane to the surface of nanoparticles [51, 52].…”

“…It is responsible for the tumoricidal activity of these immune cells [21]. (2) TRAIL exerts a tumor cell-specific apoptotic effect by recognizing death receptors (DRs) highly expressed on the surface of cancer cells [22–24]. Previous studies have successfully modified mesenchymal stem cells (MSCs) and neural stem cells (NSCs) to express TRAIL to kill solid tumors in mice [7, 25, 26].…”

The Promise of Circulating Tumor Cells for Precision Cancer Therapy

“…TNF-related apoptosis-inducing ligand (TRAIL) is a cytokine known to induce apoptosis specifically in tumor cells. Using synthetic silica particles functionalized with activated platelet membrane with surface conjugation of TRAIL or platelets genetically modified to express surface-bound TRAIL, Li and colleagues demonstrated selective killing of cancer cells in vitro and a significant metastatic reduction in mouse models of prostate and breast cancer metastasis [158,159]. This is the first demonstration of a Trojan-horse approach to neutralize CTCs and attenuate future science group…”