Abstract
Various liposomal drug carriers have been developed to overcome short plasma half-life and toxicity related side effects of chemotherapeutic agents. We developed a mathematical model to compare different liposome formulations of doxorubicin (DOX): conventional chemotherapy (Free-DOX), Stealth liposomes (Stealth-DOX), temperature sensitive liposomes (TSL) with intra-vascular triggered release (TSL-i), and TSL with extra-vascular triggered release (TSL-e). All formulations were administered as bolus at a dose of 9 mg/kg. For TSL, we assumed locally triggered release due to hyperthermia for 30 min. Drug concentrations were determined in systemic plasma, aggregate body tissue, cardiac tissue, tumor plasma, tumor interstitial space, and tumor cells. All compartments were assumed perfectly mixed, and represented by ordinary differential equations. Contribution of liposomal extravasation was negligible in the case of TSL-i, but was the major delivery mechanism for Stealth-DOX and for TSL-e. The dominant delivery mechanism for TSL-i was release within the tumor plasma compartment with subsequent tissue- and cell uptake of released DOX. Maximum intracellular tumor drug concentrations for Free-DOX, Stealth-DOX, TSL-i, and TSL-e were 3.4, 0.4, 100.6, and 15.9 µg/g, respectively. TSL-i and TSL-e allowed for high local tumor drug concentrations with reduced systemic exposure compared to Free-DOX. While Stealth-DOX resulted in high tumor tissue concentrations compared to Free-DOX, only a small fraction was bioavailable, resulting in little cellular uptake. Consistent with clinical data, Stealth-DOX resulted in similar tumor intracellular concentrations as Free-DOX, but with reduced systemic exposure. Optimal release time constants for maximum cellular uptake for Stealth-DOX, TSL-e, and TSL-i were 45 min, 11 min, and <3 s, respectively. Optimal release time constants were shorter for MDR cells, with ∼4 min for Stealth-DOX and for TSL-e. Tissue concentrations correlated well quantitatively with a prior in-vivo study. Mathematical models may thus allow optimization of drug delivery systems to achieve a better therapeutic index.
Highlights
Current chemotherapy may be improved if sufficient levels of drug were obtained in the tumor while at the same time limiting system toxicity
The objective of this study was to mathematically model and compare standard chemotherapy to Stealth liposomes and temperature sensitive liposomes (TSL) with different release time constants triggered intra- or extra-vascularly, and to determine plasma- and tumor concentrations of bioavailable drug
We modeled Free-DOX and Stealth-DOX without hyperthermia, and the two TSL-formulations with hyperthermia
Summary
Current chemotherapy may be improved if sufficient levels of drug were obtained in the tumor while at the same time limiting system toxicity. To overcome short plasma half-life of DOX and to reduce systemic toxicity, pegylated Stealth liposomal drug carriers for DOX (e.g., DoxilH) have been developed [3], allowing for long circulation times, up to several days [4,5]. Stealth liposomes, such as Doxil, remain an excellent example of a drug delivery system with reduced toxicity, but there have been limited benefits in terms of clinical efficacy [6,7,8]. TSL in combination with heating of the target region can selectively enhance bioavailability of the drug locally while minimizing systemic exposure
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