Introduction

Despite significant progress in the surgical treatment, radiotherapy, and chemotherapy of solid tumors (e.g., breast, colon, lung, and prostate), too few patients survive long term. This critical unmet need has been the long term focus of a wide range of therapies directed at the malignant cancer cell phenotype, its dysfunctional apoptotic signaling pathways, and survival adaptations. To enhance drug effectiveness and decrease non-specific toxicities, many of these agents have been designed to specifically target tumor cell antigens, receptors, and tumor microenvironmental markers.

In contrast to direct targeting of specific tumor cell markers, targeting endothelial cells supporting tumor angiogenesis provides an alternative, broadly applicable method for cancer diagnosis and therapy. - All growing tumors require an augmented blood supply, so angiogenesis is a critical common denominator for therapeutic attack. Two distinct types of vessel targeted therapies have evolved.6 The first general group, the anti-angiogenic agents, inhibit tumor-induced neovascularization by preventing proliferation, migration, and differentiation of

endothelial cells.7-9 Anti-angiogenic drugs have been carried through substantial development to clinical trials.7'10-12 Bevacuzimab (Avastin), an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, has been approved for the treatment of colorectal cancer.13 The second type, the antivascular agents, cause rapid and selective occlusion of existing tumor blood vessels, leading to tumor ischemia and extensive hemorrhagic necrosis.5,14,15 Although still in preclinical development, antivascular-targeted therapeutics produce a characteristic pattern of necrosis after administration to mice and rats with solid tumors.16,17 They cause a widespread central necrosis that can extend to as much as 95% of the tumor. -

Indeed, over the past 5-10 years, there has been a rapid development of small molecular therapies directed against neovascular angiogenesis. These molecules are typically smaller than 2 kDa and show very low to absent immunogenicity, high target affinity, rapid targeting, and fast blood clearance. Small molecular agents have been directed at a number of angiogenesis-related targets and have been coupled to moieties to support scintigraphic, optical, and magnetic resonance imaging (MRI).19,20 Other modifications have supported delivery of drugs, tumor enzyme-cleaved prodrugs, and therapeutic radionuclides. This rich foundation provides the infrastructure upon which polymer-based conjugates have allowed further strides. Well-designed polymer conjugates demonstrate improved pharmacokinetics with prolonged blood residence, lower non-specific tissue penetration, and increased passive tumor localization because of enhanced permeability, and retention; i.e., the EPR effect. Polymer conjugates bearing targeting ligands often demonstrate high tumor affinity via multivalent interactions.23 Relative to smaller molecular platforms, they can also carry higher diagnostic and therapeutic agent payloads (Figure 9.1).

Biological Payload (Diagnostic or Therapeutic)

FIGURE 9.1 Schematic of angiogenesis-targeted conjugates. (a) Conjugate of cyclic RGD peptide with a therapeutic or a diagnostic agent. Chemotherapeutic or antiangiogenic drugs can be linked via biodegradable linkers, whereas imaging agents or radionuclides are generally attached via non-biodegradable linkers. (b) Particulate systems such as liposomes and nanoparticles are conjugated to cyclic RGD peptides via a nonbiodegradable linker, and the therapeutic or diagnostic agents are encapsulated. (c) Polymeric conjugates have cyclic RGD peptides linked onto the side chains via non-biodegradable linker, whereas biodegradable linkers can be used for drugs and non-biodegradable linkers for imaging agents or radionuclides.

Biological Payload (Diagnostic or Therapeutic)

FIGURE 9.1 Schematic of angiogenesis-targeted conjugates. (a) Conjugate of cyclic RGD peptide with a therapeutic or a diagnostic agent. Chemotherapeutic or antiangiogenic drugs can be linked via biodegradable linkers, whereas imaging agents or radionuclides are generally attached via non-biodegradable linkers. (b) Particulate systems such as liposomes and nanoparticles are conjugated to cyclic RGD peptides via a nonbiodegradable linker, and the therapeutic or diagnostic agents are encapsulated. (c) Polymeric conjugates have cyclic RGD peptides linked onto the side chains via non-biodegradable linker, whereas biodegradable linkers can be used for drugs and non-biodegradable linkers for imaging agents or radionuclides.

Recent advances provide a clear indication that polyvalent, moderate molecular weight ligand-polymer conjugates will provide the platform to target angiogenesis and deliver a broad range of effective therapies. This chapter presents an overview of tumor angiogenesis, strategies for targeting angiogenic vasculature, and current developments in angiogenesis-targeted polymeric conjugates for diagnosis and therapy.

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