Summary And Future Directions

There is a tremendous interest in targeted drug delivery to tumor vasculature given the genetic stability and accessibility of angiogenesis markers and the importance of angiogenesis in tumor growth and metastasis. A number of ligands targeting angiogenic markers have been identified, but the major focus has been on targeting aVb3 integrins using RGD peptides.21 Many reports of conjugating RGD ligands to a diverse group of macromolecular carrier systems have been published. These include water-soluble polymers (e.g., PEG,139 N-(2-hydroxypropyl) methacryla-mide,178 and polyethylenimine164), proteins,182,183 liposomes,184,185 and nanoparticles.165,186

With respect to future development, a broad range of angiogenesis targeting polymer conjugates can be envisioned. As additional vascular targets are identified by in vitro and in vivo methods, angiogenesis targeting may become a critically important strategy for fighting neoplastic as well as non-neoplastic diseases. The first successful human trials for imaging aVb3 integrins

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using [ F]-galacto-RGD , and the results of pre-clinical studies using macromolecular conjugates of RGD argue the validity of this concept.

It is expected that the biokinetics of copolymer-conjugates will be continuously improved by tailoring the molecular weight187-190 and/or electronegative charge190,191 of the conjugates. This flexibility in the design and synthesis of HPMA and other copolymer conjugates is likely to be important in modifying the blood half-life or reducing non-specific accumulation in normal organs, factors that should increase the conjugate therapeutic index. These may incorporate either enzy-matically hydrolysable (e.g., tetrapeptide GFLG)143 or pH sensitive (e.g., hydrazone linker)192 linkers for intracellular drug release. In addition, they will likely demonstrate targeting ligand multivalency to increase the tumor uptake and therapeutic efficacy.

It is also expected that there will be expanded use of therapeutic radionuclides to destroy angiogenic vasculature and surrounding tumor cells. Because radioactive emissions can kill at a distance from the point of radioisotope localization, they have a diameter of effectiveness that may overcome the problem of tumor heterogeneity that has plagued other molecular therapies. In short, the ever increasing interest in polymer-based therapeutics promises continued progress in angio-genesis targeted, tumor imaging, and therapy.

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