Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Mar;12(3):375-92.
doi: 10.1517/17425247.2015.966684. Epub 2014 Oct 1.

Leukocytes as carriers for targeted cancer drug delivery

Michael J Mitchell  1 , Michael R King
Affiliations
Review

Leukocytes as carriers for targeted cancer drug delivery

Michael J Mitchell et al. Expert Opin Drug Deliv. 2015 Mar.

Abstract

Introduction: Metastasis contributes to over 90% of cancer-related deaths. Numerous nanoparticle platforms have been developed to target and treat cancer, yet efficient delivery of these systems to the appropriate site remains challenging. Leukocytes, which share similarities to tumor cells in terms of their transport and migration through the body, are well suited to serve as carriers of drug delivery systems to target cancer sites.

Areas covered: This review focuses on the use and functionalization of leukocytes for therapeutic targeting of metastatic cancer. Tumor cell and leukocyte extravasation, margination in the bloodstream, and migration into soft tissue are discussed, along with the potential to exploit these functional similarities to effectively deliver drugs. Current nanoparticle-based drug formulations for the treatment of cancer are reviewed, along with methods to functionalize delivery vehicles to leukocytes, either on the surface and/or within the cell. Recent progress in this area, both in vitro and in vivo, is also discussed, with a particular emphasis on targeting cancer cells in the bloodstream as a means to interrupt the metastatic process.

Expert opinion: Leukocytes interact with cancer cells both in the bloodstream and at the site of solid tumors. These interactions can be utilized to effectively deliver drugs to targeted areas, which can reduce both the amount of drug required and various nonspecific cytotoxic effects within the body. If drug delivery vehicle functionalization does not interfere with leukocyte function, this approach may be utilized to neutralize tumor cells in the bloodstream to prevent the formation of new metastases, and also to deliver drugs to metastatic sites within tissues.

Keywords: cancer; leukocyte; metastasis; nanomedicine.

PubMed Disclaimer

Conflict of interest statement

Declaration of interest

The authors were supported by the Cornell Center on the Microenvironment and Metastasis through Award Number U54CA143876 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1
Figure 1. Tumor cell and leukocyte trafficking similarities
(A) Margination in the vascular system. Deformable red blood cells drive leukocytes and CTCs to a marginated position near the vessel wall, due to their higher drift velocity away from walls. (B) Adhesion to inflamed blood vessels. Upon the onset of inflammation, endothelial cells upregulate E-selectin expression, which can cause free-flowing, selectin ligand-bearing leukocytes to adhesively interact with the endothelial cell wall. CTCs are also known to express sialylated carbohydrate ligands on their surface, which can adhere to selectins on the surface of the endothelium. (C) Transmigration into tissues. Upon firm adhesion to the endothelial cell wall, leukocytes are known to transmigrate into the extravascular space and migrate along chemoattractant gradients to the site of inflammation. CTCs also respond to chemoattractants and transmigrate to inflammatory sites, where they may then survive and form micrometastases. CTC: Circulating tumor cell; ES: E-selectin.
Figure 2
Figure 2. Approaches to functionalize leukocytes with drug delivery vehicles (DDVs)
(A) Receptor–ligand interactions to attach DDVs to the leukocyte surface. (B) Covalent binding of maleimide-bearing DDVs to thiol groups on the protein-covered leukocyte surface. (C) Selectin-coated DDVs bind to leukocytes within the circulation under flow conditions. (D) Internalization of DDVs by phagocytic leukocytes.
Figure 3
Figure 3. Cellular ‘Trojan Horse’ mechanism to deliver nanoparticle-based therapeutics to solid tumors
(A) Monocytes and/or macrophages that typically infiltrate solid tumors internalize therapeutic and/or diagnostic nanoparticles for delivery into tumor sites. (B) Monocytes and macrophages containing gold nanoshells can be photoablated by near-infrared (NIR) light, inducing cell death and releasing therapeutics and/or nanoshells for uptake into tumor cells. (C) Tumor cell death then occurs via (1) therapeutic delivery in tumor cells or (2) heating of nanoshell-containing tumor tissue by NIR. hv: Near-infrared light; NIR: Near-infrared.
Figure 4
Figure 4. Functionalized natural killer (NK) cells to target lymph node micrometastases
(A,B) Liposomes with maleimide groups (A) react with thiolated apoptosis-inducing ligand TRAIL and anti-CD57 antibodies. (C) Liposomes functionalized to surface of NK cells via antibody binding to CD57. (D) Micrographs of fluorescent liposomes functionalized to the NK cell surface. Scale bar = 100 μm. (E) Schematic of functionalized NK cell intervention in an in vitro model of lymph node micrometastasis. (F) Brightfield and fluorescent micrographs of functionalized NK cells inducing cancer cell apoptosis in an in vitro model of lymph node micrometastases comprised of MDA-MB-231, COLO 205, and LNCaP cancer cells. Cells are labeled with Annexin-V (green) and propidium iodide (red) after 12 and 24 h to assess cell viability. Scale bar = 100 μm. Figure parts reproduced by permission of The Royal Society of Chemistry [156]. DSPE: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine; HSPC: hydrogenated soy phosphatidylcholine; NK: Natural killer.
Figure 5
Figure 5. Unnatural killer cells to target and kill cancer cells in flowing human blood in vitro and in the peripheral circulation of mice in vivo
(A) Schematic of E-selectin (ES) and TRAIL (ES/TRAIL) functionalized liposome synthesis. (B) Confocal micrographs of fluorescent ES/TRAIL liposomes functionalized to the surface of leukocytes after exposure to blood flow. Scale bar = 5 μm. Green: ES/TRAIL liposome. Blue: leukocyte nucleus. (C) Micrographs of COLO 205 cells (white) after treatment with ES/TRAIL liposomes (left) or ES-conjugated liposomes in blood under shear flow for 2 h. Scale bar = 50 μm. (D) Flow cytometry of COLO 205 cancer cells after treatment with ES/TRAIL or ES liposomes in blood under shear flow in a cone-and-plate viscometer (shear rate: 188 s−1) for 2 h. Unsheared: viable untreated cancer cell control. (E) Comparison of fraction of viable COLO 205 and PC-3 cancer cells after treatment with ES/TRAIL liposomes in buffer versus blood. n = 3 for all samples. Bars represent the mean ± SD in each treatment group. ***p < 0.0001 (unpaired t test). (F) Fraction of viable COLO 205 and PC-3 cancer cells after treatment with ES/TRAIL liposomes in blood with varying percentages of hematocrit. Hematocrit was varied, whereas other blood components remained constant, based on a normal hematocrit of 45%. Plasma indicates removal of all blood cells. n = 3 for all samples. Bars represent the mean ± SD in each treatment group. *p < 0.05 (one-way ANOVA with Tukey’s post-test). (G) Schematic of two-step mechanism involving functionalization of leukocytes with liposomes (left), which then contact circulating cancer cells and activate the death receptor (right). (H) Schematic of in vivo mouse experiment to functionalize leukocytes via systemic delivery of ES/TRAIL liposomes, followed by targeting of circulating cancer cells in the bloodstream. (I) Representative micrographs of COLO 205 cancer cells removed from mouse circulation after treatment with ES/TRAIL liposomes (upper left), sTRAIL (upper right), ES liposomes (lower left), and buffer (lower right) injections. Scale bar = 20 μm. (J) Leukocytes functionalized with fluorescent ES/TRAIL liposomes (green) upon removal from mouse circulation 2.5 h after systemic injection. Scale bar = 50 μm. (K) Schematic of mouse lung and example two-photon excited fluorescence (2PEF) image stack from mouse lung where Hoechst-labeled COLO 205 cells (green) are arrested in vasculature of lung (visible by autofluorescence, yellow). Scale bar = 80 μm. (L) 2PEF images of Hoescht-labeled COLO 205 cells (green) with Alexa Fluor 568-labeled Annexin-V apoptosis probe (red) for each experimental group. Red arrows point to apoptotic COLO 205 cells (red and green colocalized), and blue arrows indicate non-apoptotic COLO 205 cells (green only). White circles indicate regions of autofluorescence from lung tissue. Scale bar = 30 μm.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331:1559–64. - PubMed
    1. Schroeder A, Heller DA, Winslow MM, et al. Treating metastatic cancer with nanotechnology. Nat Rev Cancer. 2011;12(1):39–50. This article broadly reviews current research, opportunities, and challenges in combining aspects of engineering, cancer biology, and medicine to develop nanotechnology platforms to treat metastatic cancer. - PubMed
    1. Safra T, Muggia F, Jeffers S, et al. Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol. 2000;11:1029–33. - PubMed
    1. Prabhakar U, Maeda H, Jain RK, et al. Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res. 2013;73(8):2412–17. - PMC - PubMed
    1. Christofori G. New signals from the invasive front. Nature. 2006;441(7092):444–50. - PubMed

Publication types

MeSH terms