Paclitaxel shows great promise as an anti-neoplastic agent for a variety of human cancers, including ovarian, breast, and non-small cell lung cancer and acquired immune deficiency syndrome (AIDS)-related Kaposi's sarcoma.1-6) Docetaxel and paclitaxel together form the drug category of taxanes. However, its low solubility in water is a major problem associated with the administration of paclitaxel. Side effects including nausea, vomiting, diarrhea, mucositis, myelosuppression, cardiotoxicity and neurotoxicity were reported. 7,8) Various alternative dosage forms for paclitaxel delivery have been developed to increase efficacy, decrease toxicity, and improve solubility of paclitaxel without using Cremophor ® EL, and many have entered phase I-III trials as intravenously injectable anticancer agents. For example, there are many on going phase II-III studies for polyglutamatepaclitaxel (CT-2103, XYOTAX) as well as phase I studies for polymeric micelle-formulated paclitaxel (Genexol-PM) and paclitaxel-incorporating micellar nanoparticle formulation (NK105). 9) Recently, an albumin-stabilized nanoparticle formulation of paclitaxel (Abraxane, ABI-007), 10) which was designed to overcome insolubility problems encountered with paclitaxel, has gained approval from the Food and Drug Administration (FDA) for treatment of metastatic breast cancer.These macromolecular prodrugs are thought to accumulate in tumors as a result of the enhanced permeability and retention (EPR) effect.11) This effect relies on the fact that tumors usually have hyperpermeable vasculatures, allowing longer circulating macromolecules to pass out through the leaky vessels into tumor tissue, from which there is no readily available returning lymphatic route.12) Long-circulating macromolecules-including albumin, polymer conjugates, polymeric micelles, and liposome-are well known to accumulate passively in solid tumors by the EPR effect. Therefore, intravenously administered drug-delivery systems would increase the concentration of antitumor drugs in tumor. For example, the polymer-protein conjugate styrene maleic anhydride-neocarzinostatin (SMANCS) was originally synthesized by Maeda H. and was subsequently approved in Japan as a treatment for hepatocellular carcinoma.
13)Molecular weight (MW) and electric charges of conjugates are critical to achieve effective tumor targeting.14) Macromolecules with MWs greater than roughly 70 kDa and weak anionic charges are known to circulate in blood for a long time due to small hepatic uptake and urinary excretion clearance.15) Such macromolecules are expected to accumulate in tumors effectively after intravenous administration. AZ10992 was thus designed to have the MW of approximately 150 kDa, weak anionic charges, and a peptidyl linker (GlyGlyPheGly) to provide an appropriate release rate of paclitaxel with time-dependent cytocidal activity. Our previous study demonstrated the proof of our design in terms of therapeutic efficacy.
16)However, further studies are required to provide crucial information about safety pr...