Surface engineering of iron oxide nanoparticles for targeted cancer therapy

Abstract

Nanotechnology provides a flexible platform for the development of effective therapeutic nanomaterials that can interact specifically with a target in a biological system and provoke a desired response. Of the nanomaterials studied, iron oxide nanoparticles have emerged as one of top candidates for cancer therapy. Their intrinsic superparamagnetism enables noninvasive magnetic resonance imaging (MRI), and their biodegradability is advantageous for in vivo applications. A therapeutic superparamagnetic iron oxide nanoparticle (SPION) typically consists of three primary components: an iron oxide nanoparticle core that serves as both a carrier for therapeutics and contrast agent for MRI, a coating on the iron oxide nanoparticle that promotes favorable interactions between the SPION and the biological system, and a therapeutic payload that performs the designated function in vivo. Often, the design may include a targeting ligand that recognizes the receptors over-expressed on the exterior surface of cancer cells. The body is a highly complex system that imposes multiple physiological and cellular barriers to foreign objects. Thus, the success of a therapeutic SPION largely relies on the design of the iron oxide core to ensure its detection in MRI and the coatings that allow the nanoparticles to bypass these barriers. Strategies to bypass the physiological barriers, such as liver, kidneys, and spleen, involve tuning the overall size and surface chemistry of the SPION to maximize blood half-life and facilitate the navigation in the body. Strategies to bypass cellular barriers include the use of targeting agents to maximize uptake of the SPION by cancer cells and the employment of materials that promote desired intracellular trafficking and enable controlled drug release. The payload can be genes, proteins, chemotherapy drugs, or a combination of these molecules. Each type of therapeutic molecule requires a specific coating design to maximize the loading and to achieve effective delivery and release. In this Account, we discuss the primary design parameters in developing therapeutic SPIONs with a focus on surface coating design to overcome the barriers imposed by the body's defense system. We provide examples of how these design parameters have been implemented to produce SPIONs for specific therapeutic applications. Although there are still challenges to be addressed, SPIONs show great promise in the successful diagnosis and treatment of the most devastating cancers. Once the critical design parameters have been optimized, these nanoparticles, combined with imaging modalities, can serve as truly multifunctional theranostic agents that not only perform a therapeutic function but also provide instant clinical feedback, allowing the physician to adjust the treatment plan.

Figure 1

Architecture of a nanotherapeutic SPION.

Figure 2

Physiological barriers encountered by a typical therapeutic nanoparticle.

Figure 3

Cellular barriers encountered by a typical therapeutic nanoparticle.

Figure 4

Targeting SPIONs in the tumor microenvironment. a) Coronal MR image of a mouse bearing xenograft tumors. b) MR images of NP-CTX and NP-RGD treated mice. c) Histological analysis of tumors showing the selective localization of NP-RGD with neovasculature and NP-CTX throughout the tumor. Color scheme for c: green, anti-CD31 (mature endothelial cell marker); blue, anti-CD61 (neovasculature marker); red, nanoparticles. Panels b and c adapted with permission from ref. Copyright 2010 Future Medicine.

Figure 5

CTX-targeted gene delivery using SPIONs. a) SPION activated with CTX for siRNA delivery in vitro and DNA delivery in vivo. b) Fluorescence images of GFP expressing cells treated with nanoparticles. Color scheme: blue, nucleus; green, membrane; red, siRNA; light green, GFP. c) Photograph of a typical xenograft mouse used for in vivo DNA delivery experiments. d) R2 map of xenograft brain tumors in mice treated with control (NP:DNA) and targeting (NP:DNA-CTX) SPIONs. e) Prussian blue stained xenograft brain tumors and f) fluorescence images of xenograft brain tumors, both showing the wider distribution of NP:DNA-CTX corresponds to higher expression of the delivered GFP gene. Scale bars correspond to 20 μm. Adapted with permission from refs.^, Copyright 2010 ACS and 2010 Elsevier.

Figure 6

Charge-reversal strategy for dual RNAi and cell-killing therapy. a) Proposed mechanism of charge-reversal strategy. b) Cell viability after treatment with various SPION formulations at neutral pH and acidic pH. c) GFP expression in cells treated with the CTX-targeted SPION under the two pH conditions. Adapted with permission from ref. Copyright 2010 ACS.

Figure 7

DOX-loaded SPIONs for overcoming MDR. a) Cartoon showing that drug resistant glioma cells (C6-ADR) overexpressing efflux pumps are able to pump out free DOX whereas DOX attached to SPIONs remains inside the cell. DOX is then released from the SPION to intercalate DNA in the nucleus, killing the cell. b) Fluorescence images of C6-ADR cells treated with free DOX (top) and NP-DOX (bottom). c) Resistance factor for free DOX and NP-DOX. Reproduced with permission from ref. Copyright 2011 Elsevier.

Figure 8

Magnetically-activated release system (MARS) for breast cancer cell treatment. (a) MARS schematic. (b) Fluorescent images (top row) and fluorescent images with differential interference contrast (bottom row) of cancer cells treated with DOX-loaded MARS without AC field (1, 2), empty MARS with AC field (3, 4), and DOX-loaded MARS with AC field (5, 6). Color scheme: green, fluorescently-labeled MARS; red, doxorubicin (DOX). The black arrows in image 6 indicate the location of apoptotic cells. (c) Cell kill associated with each treatment. Adapted with permission from ref. Copyright 2010 ACS.