Developing effective cancer therapy is among the most challenging tasks confronting the scientific community today. One of the major limitation inherent to most conventional anticancer chemotherapeutic agents is that they lack of tumor selectivity.

Khaled Greish M.D., Ph.D. Research Assistant Professor, Department of Pharmaceutics & Pharmaceutical Chemistry, explains in Methods in Molecular Biologie (Jan 2010) that selective targeting with nano-sized macromolecular bioconjugates and nano-sized anticancer agents to solid tumors can be achieved by exploiting abnormalities of tumor vasculature, including hypervascularization, aberrant vascular architecture, extensive production of vascular permeability factors stimulating extravasation within tumor tissues, and lack of lymphatic drainage. The leaky nature of the tumor vasculature compared to that of healthy vessels in normal organs makes delivery possible.[1]

When administered intravenously (i.v.), nano-sized macromolecular bioconjugates and nano-sized anticancer agents escape renal clearance. Being unable to penetrate through tight endothelial junctions of normal blood vessels, their concentration builds up in the plasma giving them a long plasma half-life.  Unless they are small enough to be excreted by the kidney or stealthy enough to evade the macrophage phagocytic system (MPS), formerly the reticulo-endothelial system (RES), they tend to circulate for prolonged times.

Enhanced permeability and retention
Anticancer agents with long circulation times leak preferentially into tumor tissue through permeable tumor vessels. Due to reduced lymphatic drainage in solid tumor, they are retained in the tumor bed. This creates an ideal application for enhanced permeability and retention (EPR)-based selective anticancer nano therapies. Overtime, lack of efficient lymphatic drainage results in the tumor concentration build up, ultimately reaching several folds higher than that of the plasma.  However, success of cancer drug delivery relying on EPR effect only is still limited.

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In a number of preclinical and clinical settings this selective high local concentration of nano-sized biocompatible nano-particles or bioconjugates, including antibody-drug conjugates or ADCs in tumor tissues has proven superior in therapeutic effect with minimal side effects.

Changing design characteristics
Controlled delivery can be enhanced by changing specific design characteristics of the bioconjugate such as its size, the nature of the payload and surface features.

In a just accepted manuscript, to be published in the November 10, 2014 issue of the online edition of Bioconjugate Chemistry, published by ACS Publications), Hisataka Kobayashi , Baris Turkbey , Rira Watanabe, and Peter Choyke, discuss how they examined the basis of macromolecular or nano-sized bioconjugate delivery into cancer tissue and discuss current diagnostic methods for evaluating leakiness of the tumor vasculature.  The authors  also discuss methods to augment conventional “permeability and retention” effects for macromolecular or nano-sized bioconjugates in cancer tissue. [2]

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