A Platelet-Mimetic Paradigm for Metastasis-Targeted Nanomedicine Platforms

Abstract

There is compelling evidence that beyond their traditional role in hemostasis and thrombosis, platelets play a significant role in mediating hematologic mechanisms of tumor metastasis by directly and indirectly interacting with pro-metastatic cancer cells. With this rationale, we hypothesized that platelets can be an effective paradigm to develop nanomedicine platforms that utilize platelet-mimetic interaction mechanisms for targeted diagnosis and therapy of metastatic cancer cells. Here we report on our investigation of the development of nanoconstructs that interact with metastatic cancer cells via platelet-mimetic heteromultivalent ligand-receptor pathways. For our studies, pro-metastatic human breast cancer cell line MDA-MB-231 was studied for its surface expression of platelet-interactive receptors, in comparison to another low-metastatic human breast cancer cell line, MCF-7. Certain platelet-interactive receptors were found to be significantly over-expressed on the MDA-MB-231 cells and these cells showed significantly enhanced binding interactions with active platelets compared to MCF-7 cells. Based upon these observations, two specific receptor interactions were selected and corresponding ligands were engineered onto the surface of liposomes as model nanoconstructs, to enable platelet-mimetic binding to the cancer cells. Our model platelet-mimetic liposomal constructs showed enhanced targeting and attachment of MDA-MB-231 cells compared to the MCF-7 cells. These results demonstrate the promise of utilizing platelet-mimetic constructs in modifying nanovehicle constructs for metastasis-targeted drug as well as modifying surfaces for ex-vivo cell enrichment diagnostic technologies.

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

“…Inspired by these molecular interactions, nanotechnologies have sought to mimic activated platelets by conjugating antibodies or peptide sequences that recognize cancer cells [33, 34]. Nevertheless, existing platelet biomimetic strategies represent a bottom-up approach and may have certain limitations: the bottom-up approach is largely inadequate in duplicating a complex protein makeup of natural platelets on a synthetic substrate.…”

Genetic engineering of platelets to neutralize circulating tumor cells

“…In addition, other groups have also attempted to functionalize platelet-derived cancer targeting peptides or platelet membrane to the surface of nanoparticles [51, 52]. The ability of targeting cancer cells was tested in in vitro cell culture or mouse models bearing solid tumors.…”

Platelet-mimetic strategies for modulating the wound environment and inflammatory responses

“…[36][37][38] Current research in the field of platelet-mimetic technologies utilizes a wide variety of strategies including both naturally derived platelet derivatives and synthetic platelet strategies. In subsequent sections, we review various strategies that encompass a large range of approaches to achieve various goals such as wound targeting, drug delivery, and immune system evasion through platelet membrane cloaking.…”

“…61 Similar heteromultivalent ligand-receptor pathway surface-decorated nanoconstructs were later used by this group to target and deliver anticancer drugs to metastatic MDA-MB-231 and MCF-7 cancer cells ( Figure 6). 37 …”