One of the unique features of CDP is that the CD blocks form inclusion complexes with hydrophobic small-molecule drugs through both intra- and intermolecular interactions. Such interactions between adjacent polymer strands are essential for catalyzing the self-assembly of several CD-PEG polymer strands into highly reproducible nanoparticles (Figure 2). Parameters affecting the particle size are the type of drug, the polymer molecular weight, and the drug loading.

Covalent attachment of a hydrophobic drug is required to initiate self-assembly, and release of drug from Inhibitors,research,lifescience,medical the polymer results in the disassembly into individual polymer strands Inhibitors,research,lifescience,medical of 8-9nm, which have the potential to be cleared

through the kidney [5–7]. Figure 2 Transmission electron micrograph (TEM) of CRLX101 (from [8]). Table 2 Linkers and drugs evaluated with the CDP nanoparticle system. The cleavage position is indicated with an arrow. CDP-based nanoparticles are highly water soluble at concentrations >100mg/mL, limited by the high viscosity of resulting solutions, increasing Inhibitors,research,lifescience,medical the solubility of hydrophobic drugs by more than 100-fold (Table 2). One attractive feature of nanoparticle prodrugs is their ability to protect small-molecule therapeutics from enzymatic and chemical degradation. This was PS-341 molecular weight impressively shown in the case of the camptothecin (CPT) drug, CRLX101 (formerly IT-101). The chemical structure

Inhibitors,research,lifescience,medical of CPT includes an unstable lactone ring that is highly susceptible to spontaneous and reversible hydrolysis, which yields an inactive, but more water-soluble, carboxylate form that predominates at physiologic pH. To form CRLX101, CPT is derivatized at the 20-OH position with the natural amino acid glycine to form an ester linkage for covalent attachment to CD-PEG (Table 2). In vitro studies confirmed that this linker strategy successfully stabilizes the labile lactone ring of Inhibitors,research,lifescience,medical CPT in its closed, active form. Release of CPT from the nanoparticles was found to be mediated through both enzymatic and base-catalyzed hydrolyses of the ester bond, with observed half-lives of 59 and 41 hours in PBS and human plasma, respectively [3]. Release of methylprednisolone showed similar kinetics, with observed half-lives of 50 why and 19 hours in PBS and human plasma, respectively [6]. These release kinetics are substantially slower than what is typically observed with nonnanoparticle ester prodrugs [9, 10] and this is most likely due to the displacement of water from within and reduced access of enzymes to the hydrophobic core of CDP nanoparticles. The disulfide linked ester conjugate was significantly more stable, with minimal release observed in PBS or human plasma over 72 hours [5].