Polymeric Conjugates For Angiogenesis Targeting

Polymeric conjugates have been used for targeted delivery of drugs to tumor sites143-146 because the attachment of drugs to water soluble polymers increases their aqueous solubility, reduces side effect, and overcomes multi-drug resistance; the large size of the conjugates increases the blood half-life and significantly alters the drug properties and pharmacokinetics; the conjugates can be tailor-made (i.e., side-chain content, molecular weight, charge, etc.) for specific targeting and delivery needs; they can be designed to passively (EPR) or actively target tumor sites; and site-specific drug release can be achieved by designing biodegradable spacers that can be enzymatically cleaved or that are pH sensitive. These advantages have led to the development of a wide range of polymer-anti-cancer drug conjugates, some of which are currently in clinical trials.145

N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers have shown promise as drug carriers.144,145,147,148 HPMA copolymers have been employed to modify the in vivo biodistribution of chemotherapeutic agents and enzymes. The advantages of HPMA copolymers over other water-soluble polymers is that they can be tailor-made with simple chemical modifications to regulate drug and targeting moiety content for biorecognition, internalization, or subcellular trafficking depending on specific therapeutic needs (Figure 9.2).144,149,150 The overall molecular weight of HPMA copolymers is determined by the polymerization conditions, particularly the concentration of initiator and chain transfer agents.151 Various side chain moieties (isotope chelators, targeting moieties, and drugs) (Figure 9.2) may be directly linked to the polymer chain via a biodegradable or


non-biodegradable spacer. ,

Polymer-based delivery systems have been used as carriers for passive and active targeting of drugs in the treatment of various diseases and as novel imaging agents.145,152 Without a specific targeting ligand, moderate-sized (> 30 kD) polymers can passively (via EPR) accumulate in tumor tissues.22,153 The EPR effect has been used to deliver macromolecular bioactive agents to solid tumors, including anti-angiogenic drugs.154,155

There are a number of important differences between small molecular weight drugs and polymeric conjugates of these small molecules. The advantage of polymer-based delivery


H2 3

1251 1231 124| 1311



H2 CH3

Ch2 C=O


Peptide Ch2

ch2 Ch2 Ch2

Ch2 C=O

Ch2 C=O

8Re, 99mTc


Ch2 Ch2


7Lu, 90Y, 213Bi, 210Po r--COOH


FIGURE 9.2 Structure of water-soluble HPMA copolymers for angiogenesis targeted delivery of radionuclides for imaging and therapy. The conjugate can contain side-chains of different chelating comonomers for a wide range of radionuclides for use as a single agent for both diagnosis and therapy. 1-HPMA, 2-MA-Tyr, 3-MA-GG-RGD4C, 4-MA-GG-DPK, and 5-APMA-CHX-A"-DTPA (see list of abbreviations for details). (From Mitra, A., et al., Nucl. Med Biol., 33, 43, 2006. With permission.)

systems stem from decreased extravasation in normal tissues because of the large molecular weight of the conjugates.156 Low extravasation of polymer conjugates in normal tissues generally results in reduced systemic toxicity. In this regard, the predominant liver117 and kidney120 uptake of small RGD peptides has been identified as a significant disadvantage of targeting tumor angiogenesis with small peptides.

The polymeric backbone may also provide a platform to support multivalent targeting ligands (Figure 9.1). As previously discussed, conjugation of a targeting peptide onto a polymer backbone significantly enhances the tumor to normal tissue uptake in comparison to the peptide itself. This is likely attributable to an increased target affinity because of the multivalency of the targeting moiety on the polymer backbone,157 a combination of active targeting and passive EPR effect of the macromolecular conjugate,158 and a decreased extravasation in normal tissues as a result of the large molecular weight of the conjugates.156

The strategy of targeting the tumor angiogenic endothelium using polymeric conjugates is particularly attractive where angiogenesis inhibitors show substantial toxicity at the effective dose, e.g., the fumagillin analogue TNP-470 shows extreme neurotoxicity at this level.159 Conjugation of TNP-470 to a water-soluble polymer via an enzymatically degradable spacer allows passive localization and drug release at the tumor site and prevents blood-brain barrier


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