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Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy

Mi Kyung Yu, Jinho Park, Sangyong Jon 

Cell Dynamics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, 261 Chemdangwagi-ro, Gwangju 500-712, Republic of Korea.

How to cite this article:
Yu MK, Park J, Jon S. Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy. Theranostics2012; 2(1):3-44. doi:10.7150/thno.3463. Available from http://www.thno.org/v02p0003.htm

Abstract

Nanomaterials offer new opportunities for cancer diagnosis and treatment. Multifunctional nanoparticles harboring various functions including targeting, imaging, therapy, and etc have been intensively studied aiming to overcome limitations associated with conventional cancer diagnosis and therapy. Of various nanoparticles, magnetic iron oxide nanoparticles with superparamagnetic property have shown potential as multifunctional nanoparticles for clinical translation because they have been used asmagnetic resonance imaging (MRI) constrast agents in clinic and their features could be easily tailored by including targeting moieties, fluorescence dyes, or therapeutic agents. This review summarizes targeting strategies for construction of multifunctional nanoparticles including magnetic nanoparticles-based theranostic systems, and the various surface engineering strategies of nanoparticles for in vivoapplications.

Keywords: Multifunctional nanoparticles, magnetic nanoparticles, targeting ligand, bioconjugation, surface engineering, long circulation

Introduction

Top
Introduction
2. Types of targeting moieties
3. Methods of conjugating the...
4. Surface engineering...
5. Conclusions and perspectives
Acknowledgements
References

Cancer remains one of the most deadly diseases in the world, and the number of new cases increases each year [1]. Despite rapid advances in diagnostic procedures and treatments, the overall survival rate from cancer has not improved substantially over the past 30 years [2]. There is a need, therefore, to develop novel approaches for the accurate detection of early-stage of cancer and for targeted therapies based on the cancer-specific markers, which could lead to personalized medicine. Recent advances in nanomaterials have explored passive and active targeting strategies for enhancing intratumoral drug concentrations while limiting the unwanted toxicity to healthy tissue [3-5]. The targeted delivery of nanomaterials can overcome difficulties associated with conventional free anticancer drugs, including insolubility under aqueous conditions, rapid clearance, and a lack of selectivity, resulting in nonspecific toxicity toward normal cells and lower the dose of drugs delivered to the cancer cells [6]. Inorganic nanomaterials with a variety of unique intrinsic physical properties have attracted growing interest for use in biomedical imaging applications [7,8]. Among the imaging nanoprobes, magnetic iron oxide nanoparticles have been widely used as MRI contrast agents for cancer imaging, helping to provide anatomical details and furthermore real-time monitoring of the therapeutic response [9,10]. In this review, we first discuss selective targeting strategies using nanoparticles for achieving effective cancer detection and treatment; secondly, we discuss the various targeting moieties used as 'escort' molecules to specific tumor tissues; third, we discuss methods of conjugating the functional moieties to nanoparticles; finally, we discuss strategies for optimizing the nanoparticle surfaces for in vivoapplications. We highlight the potential utility of magnetic nanoparticle-based theranostic systems, which thus far are shown to be suitable for clinical use.

Passive and active targeting

Most nanoparticles are expected to accumulate in tumors due to the pathophysiologic characteristics of tumor blood vessels. Delivery of nutrients to an actively growing tumor with a volume greater than 2 mm³ becomes diffusion-limited, and new blood vessel formation is required to supply nutrients and oxygen [11]. The incomplete tumor vasculature results in leaky vessels with enlarged gap junctions of 100 nm to 2 μm, depending on the tumor type, and macromolecules easily access the tumor interstitium [12-14]. Tumors also have a compound retention time higher than that of normal tissues because tumors lack a well-defined lymphatic system [15,16]. These features provide an enhanced permeability and retention (EPR) effect, which constitutes an important mechanism for the passive targeting and selective accumulation of nanoparticles in the tumor interstitium. Doxil^®, a poly(ethylene glycol)-coated (PEGylated) liposomal system for doxorubicin (Dox) delivery, and Abraxane^®, albumin-bound paclitaxel nanoparticles for the treatment of metastatic breast cancer, are representative examples of US food and Drug Administration (FDA)-approved nanocarrier-based drugs for cancer therapy. These agents circulate in the body with a half-life about 100 times longer than that of free anticancer drugs while simultaneously reducing systemic toxicity [17-21].

However, passive targeting approaches suffer from several limitations. Targeting cancer cells using the EPR effect is not feasible in all tumors because the degree of tumor vascularization and porosity of tumor vessels can vary with the tumor type and status [12,22]. In addition, cancer cells can display a reduced number of specific interactions that lead to internalization of nanoparticles. In addition to preventing interactions between nanoparticles and opsonins, PEGylated surfaces can also reduce interactions between nanoparticles and cell surfaces [23-26]. The lack of control can lead to drug expulsion and induce cancer cells to develop resistance toward a variety of drugs (multiple drug resistance, MDR), which inevitably reduces any therapeutic effects [27]. One approach to overcoming these limitations is to attach targeting moieties to the nanoparticle surfaces. Nanoparticles that present targeting moieties can bind to target cells through ligand-receptor interactions that induce receptor-mediated endocytosis and drug release inside the cell. Efficient binding and internalization requires that receptors are expressed exclusively on target cancer cells (10⁴-10⁵ copies per cell) relative to normal cells, and expression should be homogenous across all targeted cells [28]. This delivery strategy achieves a high targeting specificity and delivery efficiency, while avoiding nonspecific binding and the MDR efflux mechanism [29]. At present, several targeted delivery systems are under clinical trials, such as transferrin receptor targeted cytotoxic platinum-based oxaliplatin in a liposome (MBP-426), transferrin receptor targeted cyclodextrin-containing nanoparticles with siRNA payload (CALAA-01), or prostate-specific membrane antigen (PSMA) targeted polymeric nanoparticles containing docetaxel (BIND-014). Table 1 lists the nanoparticle-based drugs that are approved or under clinical development. Although ligand-mediated targeting technologies have not yet made a considerable clinical impact on human health, it will soon be feasible to develop targeted nanoparticle candidates for clinical translation [30]..........................