Poly(ethylene glycol)-human serum albumin-paclitaxel conjugates: preparation, characterization and pharmacokinetics

Paclitaxel has been found to be very effective against several human cancer s, such as ovarian, breast and non-small cell lung cancer and has received marketing approval for metastatic cancers. One of main problems with its us e is its poor solubility, which makes irritant solubilitazion agents necess ary. In previous research we demonstrated that linkage to human serum album in (HSA) was useful to increase the in vivo performance of paclitaxel. In t his article, in order to improve stability and solubility of paclitaxel con jugate, we linked covalently a monomethoxy poly(ethylene glycol) (mPEG) cha in to HSA. New thioimidate mPEG derivatives, highly reactive and stable, we re used and two different conjugates (with PEG of molecular mass 2 or 5 kDa ) were prepared, purified and characterized. The antitumor activity of the free drug and conjugates was tested on three different tumor cell lines. Th e PEG grafted conjugates maintained high cytotoxicity, similar to that of u ngrafted conjugates, with efficient cell binding and internalization follow ed by release of the drug inside the cell. The changes in pharmacokinetics and distribution of radio-labelled conjugates were evaluated by i.v. admini stration to mice and compared with those of the free drug and ungrafted con jugates. The total clearance was reduced (from 3.6 ml/h for free drug to 2. 9, 1.97 and 1.41 for ungrafted, 2 and 5 kDa PEG conjugates, respectively). Organ uptake was reduced, in particular by liver and spleen. (C) 2001 Elsev ier Science B.V. All rights reserved.