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Hyperthermia-Mediated Docetaxel Derivative Release from Temperature-Sensitive Nanomedicines

[ Vol. 5 , Issue. 2 ]


Sin-Yuin Yeo, Iris Verel, Erica Aussems-Custers, Monique Berben, Charles F. Sio, Sander Langereis and Holger Grull   Pages 132 - 139 ( 8 )


Background: Temperature-sensitive liposomes (TSLs) containing chemotherapeutic drugs offer the prospect of increased drug delivery and bioavailability at the diseased sites. This concept is applied to hydrophilic drugs, which can be encapsulated in the inner water-rich lumen of the liposomes. In order to extend the concept of TSL to a hydrophobic drug, such as docetaxel (DTX), this drug was modified at the hydroxyl group in the C-2’ position into an N-methyl-piperazinyl butanoic acid ester. This modification resulted in a more hydrophilic DTX derivative (MPB-DTX) and hence, enabled stable encapsulation of MPB-DTX in the interior of liposomes. Under hyperthermic conditions, MPB-DTX will be released from the interior of TSL and activated in situ by pH 7.4 and esterases in vivo. Herein, the development and characterization of TSLs containing MPB-DTX [TSL(MPB-DTX)] for hyperthermiamediated drug delivery were described. Methods: TSL(MPB-DTX) was formulated with DPPC, MSPC, DSPE-PEG2000 and DPPE-rhodamine at a molar ratio of 85:10:5:0.2. The hydrodynamic radii (rh) and melting phase transition temperature (Tm) of TSLs were characterized using dynamic light scattering (DLS) and differential scanning calorimetry (DSC), respectively. The in vitro release kinetics as well as the blood kinetics and biodistribution of TSL(MPB-DTX) were investigated in rats. Results: The rh and Tm of TSLs were 62±3 nm and 41±0.1 °C, respectively. At 37 °C, TSL(MPB-DTX) exhibited a maximum of 38±5% MPB-DTX release in HBS supplemented with 50% FBS at pH 7.4 within one hour. At 42°C, rapid drug release to 66% could be achieved within minutes while 34% of the MPB-DTX remained with the liposomes. In nude rats, TSL(MPB-DTX) was shown to have a circulation half-life of 40±8 min while free MPB-DTX was cleared from the circulation within the first 10 min after injection. Biodistribution results confirmed clearance of the MPB-DTX from the circulation and low accumulation of MPB-DTX at non-clearing organs for both the TSL and free formulation. Conclusions: The rapid but incomplete release of TSL(MPB-DTX) indicates potential for a two-step delivery approach: (i) hyperthermia-mediated intravascular MPB-DTX release and (ii) enhanced accumulation of TSL(MPB-DTX) in tumor tissue via enhanced permeability and retention mediated uptake.


Temperature-sensitive liposomes, TSL, docetaxel, hyperthermia, prodrug.


Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.

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