Nk911

NK911 is a doxorubicin-loaded PEG-b-PAsp copolymer micelle formulation developed by Kataoka and co-workers. Doxorubicin is both physically entrapped in the micelle core and chemically conjugated to the aspartic acid side chains of the core-forming block via amide linkages. NK911 is currently undergoing phase II clinical trial evaluation for efficacy and toxicity profiles. The formulation entered phase I in 2001, and the results from this trial revealed that NK911 exhibits a longer circulation half-life, a larger area under the curve (AUC), and reduced toxicities in comparison to the conventional formulation of doxorubicin.82 The prolonged circulation lifetime of NK911 is attributed to its composition and the monomodal size distribution of the micelles with a mean diameter of approximately 50 nm.16,82

The amphiphilic or polar nature of doxorubicin (log P value of 0.52) facilitates the partitioning of this drug from the micelle core into the external medium.84 Therefore, chemical conjugation of doxorubicin to the core-forming block can enhance drug retention and retard drug release from the micelles. The initial development of the PEG-b-Asp micelles for drug delivery consisted of only conjugated doxorubicin to the PAsp core. Specifically, PEG-b-PAsp copolymers were synthesized from PEG-b-PBLA with the subsequent addition of doxorubicin to the carboxyl groups on the side chains of the core-forming block. As a result of the conjugation, a 37 mol% substitution of doxorubicin was achieved that is equivalent to 20 mg/mL doxorubicin.85 The doxorubicin residues of the conjugates stabilize the micelle core through pi-pi stacking and hydrophobic interactions, providing the micelles with excellent kinetic stability in vivo.76

Subsequent studies revealed that the chemically conjugated doxorubicin exerts negligible antitumor activity in vitro and in vivo as a result of the lack of a cleavable linkage between the drug and the copolymer. Therefore, the next generation of the PEG-b-PAsp micelles was prepared to include physically encapsulated doxorubicin within the micelle core as well as the chemically conjugated drug. The amount of doxorubicin that could be physically entrapped within the core was found to be proportional to the amount of conjugated doxorubicin present. The enhanced compatibility between the physically entrapped drug and the micelle core is attributed to the presence of the chemically conjugated drug. In vivo studies confirmed that micelles with the highest amount of physically entrapped doxorubicin had the most potent anti-cancer activity.32

The formation of a dimerized form of the physically entrapped doxorubicin was detected within the micelles. Despite the fact that the dimer was found to have insignificant anti-tumor activity in vitro and in vivo, it plays a supplementary role to stabilize the entrapped doxorubicin. The addition of dimers to the micelles as part of the physically entrapped components can further prolong the circulation lifetime of the micelles in vivo.86 However, the addition of doxorubicin dimers was also found to decrease the aqueous solubility of the drug-loaded micelles that compromised the stability of the micelles following lyophilization and long-term storage. Therefore, the fully optimized NK911 formulation was prepared such that it only contained doxorubicin

monomer.82

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