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Quantitative model for efficient temporal targeting of tumor cells and neovasculature.

Kohandel M, Haselwandter CA, Kardar M, Sengupta S, Sivaloganathan S - Comput Math Methods Med (2011)

Bottom Line: However, the timing and sequencing of these treatments seem to play essential roles in achieving a synergic outcome.Our model suggests that the experimental success of the nanoscale delivery system depends crucially on the trapping of chemotherapeutic agents within the tumor tissue.The numerical results also indicate that substantial further improvements in the efficiency of the nanoscale delivery system can be achieved through an adjustment of the temporal targeting mechanism.

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Mathematics, University of Waterloo, Waterloo, ON, Canada. kohandel@math.uwaterloo.ca

ABSTRACT
The combination of cytotoxic therapies and antiangiogenic agents is emerging as a most promising strategy in the treatment of malignant tumors. However, the timing and sequencing of these treatments seem to play essential roles in achieving a synergic outcome. Using a mathematical modeling approach that is grounded on available experimental data, we investigate the spatial and temporal targeting of tumor cells and neovasculature with a nanoscale delivery system. Our model suggests that the experimental success of the nanoscale delivery system depends crucially on the trapping of chemotherapeutic agents within the tumor tissue. The numerical results also indicate that substantial further improvements in the efficiency of the nanoscale delivery system can be achieved through an adjustment of the temporal targeting mechanism.

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Related in: MedlinePlus

Curves for the tumor volume of (a) lung cancer and (b) melanoma obtained with no treatment (V), nanocells containing only doxorubicin (NC[D]), liposomes containing only combretastatin (L[C]), liposomes with combretastatin and doxorubicin (L[CD]), nanocells with combretastatin and doxorubicin (NC[CD]) and nanocells with combretastatin and doxorubicin but with a delayed release of doxorubicin (NC[CD] and pNC = 0.8). The solid curves are obtained by integrating (1)–(6) in Section 2, and the data points are taken from the experiments by Sengupta et al. [19]. The same total amount of drugs is released by liposomes and nanocells for the combined therapeutic strategies, which corresponds to double the amount released for NC[D] and L[C] individually.
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fig2: Curves for the tumor volume of (a) lung cancer and (b) melanoma obtained with no treatment (V), nanocells containing only doxorubicin (NC[D]), liposomes containing only combretastatin (L[C]), liposomes with combretastatin and doxorubicin (L[CD]), nanocells with combretastatin and doxorubicin (NC[CD]) and nanocells with combretastatin and doxorubicin but with a delayed release of doxorubicin (NC[CD] and pNC = 0.8). The solid curves are obtained by integrating (1)–(6) in Section 2, and the data points are taken from the experiments by Sengupta et al. [19]. The same total amount of drugs is released by liposomes and nanocells for the combined therapeutic strategies, which corresponds to double the amount released for NC[D] and L[C] individually.

Mentions: To confirm our model, numerical simulations are performed according to the experimental protocol of Sengupta et al. [19] on lung cancer and melanoma (see Figure 2). In these experiments, 2.5 × 105 Lewis lung carcinoma cells or 3 × 105 GFP-positive BL6/F10 melanoma cells were implanted in male C57/BL6 mice, and treatments started when tumors reached 50 mm3 in volume (after about 8 days). The kinetics of tumor growth and blood vessel formation, as well as the data points for the control group (V, red), are used to estimate the related model parameters for the case of lung cancer (see Table 1). The experimental treatment schedules, as well as pharmacokinetics and pharmacodynamics of agents, are used in the simulations to fit the data for single administration of antiangiogenic therapy (combretastatin-encapsulated liposomes, L[C], brown) and chemotherapy (nanocells containing doxorubicin but lacking combretastatin, NC[D], blue). The corresponding curves for melanoma are obtained by modifying three model parameters describing the diffusion of cancer cells and the effect of therapeutic agents on the vascular network and cancer cells (see Section 2). We then perform numerical simulations with the estimated parameters to predict the results for the conventional (a liposome encapsulating both doxorubicin and combretastatin, L[CD], green) and nanocell (NC[CD], purple) approaches for the combination of antiangiogenic and cytotoxic treatments.


Quantitative model for efficient temporal targeting of tumor cells and neovasculature.

Kohandel M, Haselwandter CA, Kardar M, Sengupta S, Sivaloganathan S - Comput Math Methods Med (2011)

Curves for the tumor volume of (a) lung cancer and (b) melanoma obtained with no treatment (V), nanocells containing only doxorubicin (NC[D]), liposomes containing only combretastatin (L[C]), liposomes with combretastatin and doxorubicin (L[CD]), nanocells with combretastatin and doxorubicin (NC[CD]) and nanocells with combretastatin and doxorubicin but with a delayed release of doxorubicin (NC[CD] and pNC = 0.8). The solid curves are obtained by integrating (1)–(6) in Section 2, and the data points are taken from the experiments by Sengupta et al. [19]. The same total amount of drugs is released by liposomes and nanocells for the combined therapeutic strategies, which corresponds to double the amount released for NC[D] and L[C] individually.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3065043&req=5

fig2: Curves for the tumor volume of (a) lung cancer and (b) melanoma obtained with no treatment (V), nanocells containing only doxorubicin (NC[D]), liposomes containing only combretastatin (L[C]), liposomes with combretastatin and doxorubicin (L[CD]), nanocells with combretastatin and doxorubicin (NC[CD]) and nanocells with combretastatin and doxorubicin but with a delayed release of doxorubicin (NC[CD] and pNC = 0.8). The solid curves are obtained by integrating (1)–(6) in Section 2, and the data points are taken from the experiments by Sengupta et al. [19]. The same total amount of drugs is released by liposomes and nanocells for the combined therapeutic strategies, which corresponds to double the amount released for NC[D] and L[C] individually.
Mentions: To confirm our model, numerical simulations are performed according to the experimental protocol of Sengupta et al. [19] on lung cancer and melanoma (see Figure 2). In these experiments, 2.5 × 105 Lewis lung carcinoma cells or 3 × 105 GFP-positive BL6/F10 melanoma cells were implanted in male C57/BL6 mice, and treatments started when tumors reached 50 mm3 in volume (after about 8 days). The kinetics of tumor growth and blood vessel formation, as well as the data points for the control group (V, red), are used to estimate the related model parameters for the case of lung cancer (see Table 1). The experimental treatment schedules, as well as pharmacokinetics and pharmacodynamics of agents, are used in the simulations to fit the data for single administration of antiangiogenic therapy (combretastatin-encapsulated liposomes, L[C], brown) and chemotherapy (nanocells containing doxorubicin but lacking combretastatin, NC[D], blue). The corresponding curves for melanoma are obtained by modifying three model parameters describing the diffusion of cancer cells and the effect of therapeutic agents on the vascular network and cancer cells (see Section 2). We then perform numerical simulations with the estimated parameters to predict the results for the conventional (a liposome encapsulating both doxorubicin and combretastatin, L[CD], green) and nanocell (NC[CD], purple) approaches for the combination of antiangiogenic and cytotoxic treatments.

Bottom Line: However, the timing and sequencing of these treatments seem to play essential roles in achieving a synergic outcome.Our model suggests that the experimental success of the nanoscale delivery system depends crucially on the trapping of chemotherapeutic agents within the tumor tissue.The numerical results also indicate that substantial further improvements in the efficiency of the nanoscale delivery system can be achieved through an adjustment of the temporal targeting mechanism.

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Mathematics, University of Waterloo, Waterloo, ON, Canada. kohandel@math.uwaterloo.ca

ABSTRACT
The combination of cytotoxic therapies and antiangiogenic agents is emerging as a most promising strategy in the treatment of malignant tumors. However, the timing and sequencing of these treatments seem to play essential roles in achieving a synergic outcome. Using a mathematical modeling approach that is grounded on available experimental data, we investigate the spatial and temporal targeting of tumor cells and neovasculature with a nanoscale delivery system. Our model suggests that the experimental success of the nanoscale delivery system depends crucially on the trapping of chemotherapeutic agents within the tumor tissue. The numerical results also indicate that substantial further improvements in the efficiency of the nanoscale delivery system can be achieved through an adjustment of the temporal targeting mechanism.

Show MeSH
Related in: MedlinePlus