Introduction

During the past few decades, there have been extensive efforts in the treatment and cure of cancer that is still the second leading cause of death next to the cardiovascular diseases. With advances in research techniques, there has been a surge of therapeutic agents in the form of proteins and nucleic acids as a source of new chemical entities for the treatment of cancer.1-7 However, effective delivery of these novel agents to the target tissue has always been a problem.

The therapeutic agents used in cancer treatment are generally administered in the systemic circulation. The drug carrier, therefore, must overcome physiological barriers to reach the tumor cell in sufficient concentrations and to reside for the necessary duration to exert the pharmacological effect. These barriers include transport of the drugs within the blood vasculature and transport from the vasculature into the surrounding tumor tissues and through the interstitial spaces within the tumor. Solid tumors are characterized by vasculature that is heterogeneous in size and distribution, having a central avascular/necrotic region and vascularized peripheral region with discontinuous endothelium in the microvessels. Depending on the anatomic region of the tumor, the pore size of the endothelial junctions is found to vary from 100 to 780 nm with a mean of approximately 400 nm.8-11 Tumor vasculature is also characterized by a lack of lymphatic drainage.12-14 In addition to the complexity of tumor physiology, the development of multi-drug resistance (MDR) in tumor cells exacerbates the problem of achieving selective toxicity in tumor tissues.

Typically, a tumor consists of neoplastic cells, stromal cells, and the extracellular matrix and is associated with blood vessels, nerves, and immune cells that form an integral part of the stroma.15,16 The tumor also contains leukocytes, fibroblasts, and other extracellular elements. The majority of the infiltrated leukocytes are macrophages, more popularly referred to as tumor-associated macrophages (TAM). They have increased phagocytic activity and play an active role in tumor progression. The presence of these activated macrophages in large numbers might lead to enhanced clearance of a drug-carrying vector from the tumor microenvironment.15-18

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