Targeted Drug Delivery An Introduction

With advances in nanotechnology, it is becoming increasingly possible to combine specialized delivery vehicles and targeting approaches to develop highly selective and effective cancer therapeutic and diagnostic modalities.1-4 In the case of therapeutic vehicles, drug targeting is expected to reduce the undesirable and sometimes life-threatening side effects common in anticancer therapy. Drug targeting can also enhance the efficacy of drugs because the drug is delivered directly to cancer cells, making it possible to deliver a cytotoxic dose of the drug in a controlled manner.

Cancer targeting may be achieved passively by continuously concentrating drug encapsulated nanoparticles in the tumor interstitial space due to the enhanced permeability and retention (EPR) effect.5,6 This process occurs because of a differentially large quantity of nanoparticles extravasting out of tumor microvasculature, leading to an accumulation of drugs in the tumor interstitium. Multiple factors influence the EPR, including active angiogenesis and high vascularity, defective vascular architecture, impaired lymphatic drainage, and extensive production of vascular mediators, such as bradykinin, nitric oxide, vascular endothelial growth factor (VEGF), prosta-glandins, collagenase, and peroxynitrite. The ease of vehicle extravasation is a function of the maximum size of the transvascular transport pathways in tumor microvasculature and is determined mainly through the size of open interendothelial gap junctions and trans-endothelial channels. The pore cutoff size of these transport pathways has been estimated between 400 and 600 nm, and extravasation of liposomes into tumors in vivo suggests a cutoff size in the range of 400 nm.8 As a general rule, particle extravasation is inversely proportional to size, and small particles (fewer than 200 nm size) should be most effective for extravasating the tumor microvasculature.8-10 Passive tumor targeting has several limitations, including the inability to achieve a sufficiently high level of drug concentration at the tumor site, resulting in lack of drug efficacy.11 Additionally, the lack of targeting efficiency contributes to undesirable systemic adverse effects (for reviews, see).4,12

Active tumor targeting may be achieved by both local and systemic administration of specially designed vehicles that recognize biophysical characteristics that are unique to the cancer cells. Most commonly, this represents binding of vehicles to target antigens using ligands that recognize tumor-specific or tumor-associated antigens. Some of these therapeutic conjugates are now under clinical development or are in clinical practice today. In the case of local drug delivery, such as through the injection of delivery vehicles within an organ, it is possible to achieve a desired effect within a subset of cells, as opposed to a generalized effect on all the cells of the targeted organ. In the case of cancer, the cytotoxic effects of a therapeutic agent would be directed to cancer cells while minimizing harm to noncancerous cells within and outside of the targeted organ. For example, suicide-targeted gene delivery has been demonstrated to be effective in killing prostate cancer but not healthy muscle cells in xenograft mouse models of prostate cancer.13 Similar approaches have been used to deliver docetaxel via intratumoral injection of targeted controlled release polymer vehicles to prostate cancer cells in nude mice.14 This approach is particularly useful for primary tumors that have not yet metastasized, such as localized breast or prostate cancer.

For metastatic cancers, the drug delivery vehicle would ideally be administered systemically because the location, abundance, and size of tumor metastasis within the body limits its visualization or accessibility, thus making local delivery approaches impractical. Despite the obvious advantages of systemic delivery, this approach is more challenging, and many physiological and biochemical barriers must be overcome for vehicles to reach the tumor and ultimately be capable of delivering therapeutically effective concentrations of the drugs directly to the cancer cells. One major challenge is the early systemic clearance of vehicles by the mononuclear phagocytic cells present in the liver, spleen, lung, and bone marrow.15-18 This is in part due to the large percentage of cardiac output directed to these organs, and in part due to the dense population of macrophages and monocytes that home in these organs. Additionally, a variety of factors play an important role in the ultimate success of systemic targeted approaches, including those factors related to the biochemical and physical characteristics of the nanoparticles such as: (1) the chemical properties of the controlled release polymer system and the encapsulated drug; (2) the size of the nanoparticles; (3) surface charge and surface hydrophilicity of nanoparticles; and (4) the chemical nature of the targeting molecules.19

Several classes of molecules have been utilized for targeting applications, including various forms of antibody-based molecules,20 such as chimeric human-murine antibodies, humanized antibodies, single chain Fv generated from murine hybridoma or phage display, and minibodies.58 Multivalent antibody-based targeting structures, such as multivalent minibodies, single-chain dimers and dibodies, and multispecific binding proteins, including bispecific antibodies and antibody-based fusion proteins, have all been evaluated. More recently, other classes of ligands,

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such as carbohydrates21 and nucleic acid ligands, also called aptamers,22,23 have been used as escort molecules for targeted delivery applications. The concept of nucleic acid molecules acting as ligands was first described in the 1980s when it was shown that some viruses encode small structured RNA that binds to viral and host proteins with high affinity and specificity. These RNA nucleic acid ligands had evolved over time to enhance the survival and propagation of the viruses. Subsequently, it was shown that these naturally occurring RNA ligands can inhibit the viral replication and have therapeutic benefits.24 Finally, methods were developed to perform in vitro evolution and to isolate novel nucleic acid ligands that bind to a myriad of important molecules for diverse applications in research and clinical practice.25,26

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