Drug Delivery Systems:  Water Soluble Taxol 2‘-Poly(ethylene glycol) Ester ProdrugsDesign and in Vivo Effectiveness

Abstract

Water soluble 2'-taxol poly(ethylene glycol) (PEG) esters have been synthesized and shown to function in vitro as prodrugs. However, in vivo experiments clearly establish that in order for these prodrugs to behave in a predictable fashion, the molecular weight of PEG must be of such magnitude so as to maintain a t1/2(circulation) > t1/2(hydrolysis). When PEG derivatives of molecular weight approximately 40 kDa were employed with paclitaxel, ca. 4% by weight of paclitaxel was carried by the water soluble prodrug form, and equivalent in vivo toxicity and increased life expectancy in the P388-treated mouse was observed. An effective method for prescreening prodrugs was found to be the acute murine lethality, which reflects the equivalency of the solubilized transport form and the native drug.

Preparation and characterization of novel poly(ethylene glycol) paclitaxel derivatives

“…335 The in vitro stability of the different PEG-PTX conjugates was studied evaluating by HPLC the release of PTX, after incubation at 37°C in buffer at various pH values (5.6, 7.4 and 9) or in serum; the results are shown in Table 1. As previously reported by Greenwald (Greenwald et al, 1996), we also observed that the half-life of the conjugates did not depend on the PEG's molecular weight.…”

“…The 20 kDa PEG-PTX conjugates showed a decrease in solubility values (150 and 180 mg/mL for mono-and di-substituted, respectively). A similar behavior was also observed for a reported series of PEG-PTX prodrugs, in which the water solubility decreased with the increasing of the polymer's molecular weight (Greenwald et al, 1996). 335 The in vitro stability of the different PEG-PTX conjugates was studied evaluating by HPLC the release of PTX, after incubation at 37°C in buffer at various pH values (5.6, 7.4 and 9) or in serum; the results are shown in Table 1.…”

“…The results, reported in Table 2, show that PTX was very active and that the prodrugs 3 and 4 display a quite similar toxicity; these data are in accordance with the stability experiments that indicated that PTX was rapidly released from the conjugates 3 and 4. On the contrary, an important decrease in the 360 cytoxicity (from two to four orders) was observed in the PEG-carbamate prodrugs, in particular for the compounds obtained reacting the C7 position of PTX (14 and 15); a reduction in cytotoxic activity of C7 ester or carbamate derivatives was yet reported by other research groups (Greenwald et al, 1996;Greenwald et al, 1995).…”

“…Some papers describe the different synthetic approaches adopted to covalently attach PEG to PTX: PEG of various molecular weights was linked to the C2' and/or C7 positions of PTX through different bonds either directly or through suitable spacers (i.e. amino acids) or linkers (Feng et al,75 2002; Greenwald et al, 1996;Greenwald et al, 1994;Li et al, 1996;Schoenmakers et al, 2004).…”

Haloperidol-associated Stealth Liposomes

“…After 0.5 h, dicyclohexylcarbodiimide (DCC, 5 mg, 0.023 mmol) was added to the reaction, with continued stirring at room temperature for 12 h. The solvent was evaporated, and the crude product was purified three times by recrystallization using methanol/ ether ( The integration of the protons in the aromatic moiety when attached to the high molecular weight PEG does not give accurate peak heights in contrast to other protons in NMR, as reported elsewhere (23). Electrospray mass spectra of the product revealed an inverted U shape mass spectral pattern with an increment of 44 (a characteristic of PEG-based molecules) spanning between molecular weights 2922 and 3450.…”