Free Doxorubicin Concentration Research Articles

Convection enhanced delivery of liposome encapsulated doxorubicin for brain tumour therapy

Convection enhanced delivery is promising to overcome the blood brain barrier. However, the treatment is less efficient in clinic due to the rapid elimination of small molecular drugs in brain tumours. In this study, numerical simulation is applied to investigate the convection enhanced delivery of liposome encapsulated doxorubicin under various conditions, based on a 3-D brain tumour model that is reconstructed from magnetic resonance images. Treatment efficacy is evaluated in terms of the tumour volume where the free doxorubicin concentration is above LD90. Simulation results denote that intracerebral infusion is effective in increasing the interstitial fluid velocity and inhibiting the fluid leakage from blood around the infusion site. Comparisons with direct doxorubicin infusion demonstrate the advantages of liposomes in enhancing the doxorubicin accumulation and penetration in the brain tumour. Delivery outcomes are determined by both the intratumoural environment and properties of therapeutic agents. The treatment efficacy can be improved by either increasing the liposome solution concentration and infusion rate, administrating liposomes in the tumour with normalised microvasculature density, or using liposomes with low vascular permeability. The delivery is less sensitive to liposome diffusivity in the examined range (E-11~E-7 cm2/s) as convective transport is dominative in determining the liposome migration. Drug release rate is able to be optimised by keeping a trade-off between enhancing the drug penetration and providing sufficient free doxorubicin for effective cell killing. Results from this study can be used to improve the regimen of CED treatments.

Rapid, Reversible Release from Thermosensitive Liposomes Triggered by Near-Infra-Red Light.

We present a novel drug carrier consisting of plasmonic hollow gold nanoshells (HGN) chemically tethered to liposomes made temperature sensitive with lysolipids (LTSL). Continuous-wave irradiation by physiologically friendly near infra-red light at 800 nm for 2.5 minutes at laser intensities an order of magnitude below that known to damage skin generates heating localized to the liposome membrane. The heating increases the liposome permeability in an irradiation dose-dependent, but reversible manner, resulting in rapid release of small molecules such as the self-quenching dye carboxyfluorescein or the chemotherapeutic doxorubicin, without raising the bulk temperature. The local rise in nanoshell temperature under laser irradiation was inferred by comparing dye release rates from the LTSL via bulk heating to that induced by irradiation. Laser-irradiation of LTSL enables precise control of contents release with low temperature gradients confined to areas irradiated by the laser focus. The combined effects of rapid local release and localized hyperthermia provide a synergistic effect as shown by a near doubling of androgen resistant PPC-1 prostate cancer cell toxicity compared to the same concentration of free doxorubicin.

Effects of gamma- and hydroxypropyl-gamma-cyclodextrins on the transport of doxorubicin across an in vitro model of blood-brain barrier.

Association between doxorubicin (DOX) and gamma-cyclodextrin (gamma-CD) or hydroxypropyl-gamma-CD (HP-gamma-CD) has been examined to increase the delivery of this antitumoral agent to the brain. The stoichiometry and the stability constant of gamma-CD or HP-gamma-CD and DOX complexes were determined in physiological medium by UV-visible spectroscopy. By using an in vitro model of the blood-brain barrier (BBB), endothelial permeability and toxicity toward the brain capillary endothelial cells of DOX, gamma-CD, and HP-gamma-CD were performed. For each CD, endothelial permeability was relatively low and a disruption of the BBB occurred at 20 microM, 20 mM, and 50 mM DOX, gamma-CD, and HP-gamma-CD, respectively. Increasing amounts of CDs were added to a fixed DOX concentration. Addition of gamma-CD or HP-gamma-CD, up to 15 and 35 mM, respectively, decreased the DOX delivery, probably due to the low complex penetration across the BBB and the decrease in free DOX concentration. Higher CD concentrations increased the DOX delivery to the brain, but this effect is due to a loss of BBB integrity. In contrast to what was observed on Caco-2 cell model with various drugs, CDs are not able to increase the delivery of DOX across our in vitro model of BBB.