Various liposomal drug carriers have been designed to overcome short plasma half-life and toxicity related side effects of chemotherapeutic agents. optimization of drug delivery systems to achieve a better therapeutic index. Introduction Current chemotherapy may be improved if sufficient levels of drug were obtained in the tumor while at the same time limiting system toxicity. Doxorubicin (DOX) is usually a clinically used chemotherapy agent with dose limiting toxicities 66-97-7 manufacture  and a short plasma half life of five to ten minutes . To overcome short plasma half-life of DOX and to reduce systemic toxicity, pegylated Stealth liposomal drug carriers for DOX (e.g., Doxil?) have been developed , allowing for long circulation occasions, up to several days , . 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 , , . A different liposomal approach was first proposed in the late 1970s by Yatvin and colleagues  called H3/l heat sensitive liposomes (TSL). TSL rapidly release their content upon heating (within seconds to minutes) , , , while at body temperature the drug is somewhat stably encapsulated (Figure 1). Therefore, TSL in combination with heating of the target region can selectively enhance bioavailability of the drug locally while 66-97-7 manufacture minimizing systemic exposure. Figure 1 Release of DOX from different TSL at normal body temperature of 37C and at 42C. In the last decade there has been increased interest in 66-97-7 manufacture the TSL-based delivery, in part due to advances in image-guided hyperthermia applicators. The TSL approach requires the perfect marriage of liposomal properties, in terms of plasma pharmacokinetics and temperature dependent release, with a hyperthermia applicator that generates accurate and homogeneous spatial temperature distributions. TSL have been successfully combined in both preclinical and clinical studies with heat-based thermal therapies including radiofrequency ablation , , ultrasound hyperthermia , , , and microwave hyperthermia . Although many reports suggest potential of a TSL based approach, the optimal combination of TSL and hyperthermia applicator properties for a given tumor type remains unknown. For example, TSL were formulated to provide ultrafast release within seconds ,  while other approaches use a longer 66-97-7 manufacture circulating liposome with longer release times within minutes to hours , , . Ultrafast release TSL may facilitate an intravascular triggered tumor delivery paradigm, but more stable long circulating liposomes may first accumulate in the tumor region prior to substantial temperature activated drug release. One difficulty in uncovering an optimal combination of TSL and hyperthermia applicators is that drug delivery is determined by 66-97-7 manufacture the interplay of several transport mechanisms affected by a large number of parameters, e.g. vascular density, permeability, perfusion, and rate of cellular uptake to name a few. While it is not possible to systematically examine (or in many cases even measure) the influence of these parameters with in vivo studies, computational models offer the unique ability to efficiently perform such a multi-parameter analysis. In prior studies, mathematical models have described the pharmacokinetics of DOX resulting from different drug delivery methods , , , including intravascular and extravascular triggered release from TSL , , . Mathematical analysis of drug delivery kinetics can thus identify the key parameters that affect drug distribution. Furthermore, these models may facilitate optimization of parameters, such as drug release rate and plasma half-life. The objective of this study was to mathematically model and compare standard chemotherapy to Stealth liposomes and TSL with different release time constants triggered intra- or extra-vascularly, and to determine plasma- and tumor concentrations of bioavailable drug. Further we examined importance of liposome extravasation and changes in cellular uptake rate. These findings are significant in that they provide a basic foundation for current activate-able drug delivery approaches and essential guidance for future drug delivery system development. Materials and Methods A mathematical model to simulate and compare drug delivery after administration of either liposomal encapsulated DOX or DOX alone was developed. Specifically, the following cases.