Calorimetric investigation of the phase behaviour of the binary system 7-mPEG 5000-succinyloxymethyloxycarbonyl- Paclitaxel (PP7)/water

Abstract

Paclitaxel is an antineoplastic agent derived from the bark of the Pacific Yew Tree (Taxus brevifolia). Oral administration of the pure drug is problematic as it has a poor absorption due to its poor solubility in aqueous media. A specific water-soluble prodrug - PP7 - has been introduced by coupling the drug with a water-soluble polymer. For any kind of medical application and administration, knowledge of the binary isobaric phase-diagram is important since it gives information about solubility, phase transitions and the corresponding compositions. The system PP7 + H2O was studied calorimetrically from -20°C and shows the typical behaviour of an eutectic system. The properties of the phase diagram are discussed in view of other solution properties of the system presented earlier.

Polymer prodrug approaches applied to paclitaxel

“…It was also shown by Trynda-Lemiesz 158 that paclitaxel changes the conformation of albumin such that the CD-curve with the typical double-peak signature at 209 nm and 220 nm (n / p*-transition in an a-helical structure) becomes smaller with increasing paclitaxel content. It was recently shown by Hess et al [71][72][73][74][75][76][151][152][153][154][155] that this effect occurs even more strongly with PP7 and that pure mPEG 5000 does not cause this effect. It leaves the albumin conformation unchanged.…”

“…Our group recently developed a new series of poly-(ethyleneglycol)(PEG)-paclitaxel conjugates, namely PP7, [68][69][70][71][72][73][74][75][76][77] which introduces a hydrophilic PEG, succinic acid mono-ester of poly(ethyleneglycol) monomethylether, with a self-immolating linker (L) at the carbon 7 position (Scheme 3). 78 One possible way of overcoming poor water-solubility is the incorporation of a highly water-soluble nontoxic polymer, such as poly-(ethyleneglycol) (PEG), at the C2 0 or C7 position.…”

“…As a result any conformational changes that might be caused by nucleotide hydrolysis are hampered, and the protofilament remains in a straight and stable conformation unable to dissociate. [71][72][73][74][75][76][151][152][153][154][155] The interaction of paclitaxel and mPEG can change when both are combined to a prodrug where steric effects might prevent mutual interaction of the terpenoid taxane structure element or interaction with binding sites in albumin or other proteins. For interaction with tubulin the polymer chain has to be removed from the drug.…”

“…From our studies of the behaviour of PP7 in aqueous solution [71][72][73][74][75] and in particular from the phase diagram 76 it was concluded that the PEG-chain coils around the paclitaxel moiety of the prodrug, thus preventing the drug from interacting with other paclitaxel molecules since neither a crystalline nor a glassy phase of paclitaxel (Tm ¼ 220 C, Tg ¼ 160 C) 152 is observed in the prodrug where paclitaxel is bound to PEG with a degree of polymerization around 114 (equivalent to an average molar mass of 5,000 g mol À1 , polydispersity index ä ¼ 1.05).…”

Monitoring the Interaction of Albumin with a Paclitaxel‐Polymer Conjugate: Complex with Warfarin as Local Probe

“…[2][3][4][5][6][7][8][9][10] Although there is no evidence for self-assembly of PP7 it was shown that there are significant interactions with blood constituents like albumin -human serum albumin (HSA) and bovine serum albumin (BSA). There is interaction with the polymer conjugate as well as with just the lipophilic paclitaxel molecule.…”