A micelle-shedding thermosensitive hydrogel as sustained release formulation.

In this paper it is shown that when a thermosensitive hydrogel based on poly(N-isopropylacrylamide)-poly(ethylene glycol)-poly(N-isopropylacrylamide) (pNIPAm-PEG-pNIPAm) was transferred into water, flower-like micelles were continuously released as long as the medium was regularly refreshed. On the other hand, if the medium was not refreshed the concentration of micelles reached an equilibrium. When this gel was loaded with the cytostatic agent paclitaxel (PTX), the released micelles solubilized PTX, as evidenced by a PTX concentration in the release medium above its aqueous solubility. To test the applicability of these micelle-releasing gels for sustained and systemic delivery of PTX an in vivo experiment was performed in tumor-bearing mice. pNIPAm-PEG-pNIPAm gels (without and with 1.2% and 6.0% PTX loading) were administered i.p. in nude mice bearing 14C human squamous cell carcinoma tumor xenografts to obtain doses corresponding to one and five times the maximum tolerated dose of PTX (when given i.v. as the standard formulation in Cremophor EL/ethanol). All gel formulations were well tolerated and no signs of acute systemic toxicity were observed. After injection of the highest dose, PTX levels in serum could be determined for 48 h with a comparatively long elimination half-life of 7.4 h pointing to a sustained release of PTX. A bioavailability of 100% was calculated from the area under the curve of plasma concentration vs time. Furthermore, at the highest dose, PTX was shown to completely inhibit tumor growth for at least 3 weeks with a single hydrogel injection. This promising concept may find application as a depot formulation for sustained, metronomic dosing of chemotherapeutics.