In contrast to crosslinking in the core or periphery of the micelle, Intezyne has developed pH-reversible crosslinking technology in the middle block of the triblock copolymer. Crosslinking of this middle layer of the micelle is advantageous since it does not interfere with the core region, which is where the drug resides. The chemistry utilized to crosslink the polymer chains together,
and thus stabilizes the micelle, is based on metal acetate chemistry (Figure 2). It is well known that a number of metal ions can interact with carboxylic acids to form metal-acetate bonds . Inhibitors,research,lifescience,medical It is also understood that these ligation events form rapidly when the carboxylic acid is in the carboxylate form (e.g., high pH, pH ~ 7-8) yet only weakly interact when the carboxylic acids are fully protonated (e.g., low pH, pH 4-5), therefore Inhibitors,research,lifescience,medical allowing release of the drug in low-pH environments, such as regions surrounding the tumor, and the endosomes of tumor cells following endocytosis of micelles. The poly(ethylene glycol) block (Figure 1, shown in gray) allows for water solubility and provides “stealth” properties to the micelle in order to avoid protein opsonization and the reticuloendothelial system . Figure 1 The IVECT polymer micelle. Drugs are loaded into the core hydrophobic block (yellow). The crosslinking
Inhibitors,research,lifescience,medical block (green) provides stability to the Inhibitors,research,lifescience,medical micelle by forming pH-reversible metal-acetate bonds that allow for triggered drug release near the tumor. The … Figure 2 Metal-acetate crosslinking chemistry for stabilization of polymer micelles. While the drug is localized in the core block, the poly(aspartic acid) block of the middle block reacts with metals to form metal acetate bonds. Bonds are Inhibitors,research,lifescience,medical formed at high pH and … As an initial study, the triblock copolymer was used to encapsulate several different small molecule drugs with varying hydrophobicities. A trend was discovered such that the ability of the triblock to encapsulate a drug was dependent on the drug’s
LogP value. Effective encapsulation was achieved with molecules having a Log P > 1.4 (Figure 3). The weight loadings of the formulations ranged see more between 1 and 20%. Molecules that were encapsulated were subsequently crosslinked by the addition of iron chloride. The addition of iron chloride to the micelle did not affect the drug and many did not result in generation of polymer-drug conjugates. To test stability of the crosslinked micelle, the in vitro stability of the micelle below the CMC was determined using a dialysis assay. In contrast to the encapsulation retention, there was no clear correlation between the LogP value and crosslinking retention (Table 1). The particle sizes of crosslinked micelles, as determined by dynamic light scattering, also did not seem related to the LogP value.