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. 2015 Sep;43(9):2291-300.
doi: 10.1007/s10439-015-1276-9. Epub 2015 Feb 11.

Towards Optimal Design of Cancer Nanomedicines: Multi-stage Nanoparticles for the Treatment of Solid Tumors

Triantafyllos Stylianopoulos  1 , Eva-Athena Economides, James W Baish, Dai Fukumura, Rakesh K Jain
Affiliations

Towards Optimal Design of Cancer Nanomedicines: Multi-stage Nanoparticles for the Treatment of Solid Tumors

Triantafyllos Stylianopoulos et al. Ann Biomed Eng. 2015 Sep.

Abstract

Conventional drug delivery systems for solid tumors are composed of a nano-carrier that releases its therapeutic load. These two-stage nanoparticles utilize the enhanced permeability and retention (EPR) effect to enable preferential delivery to tumor tissue. However, the size-dependency of the EPR, the limited penetration of nanoparticles into the tumor as well as the rapid binding of the particles or the released cytotoxic agents to cancer cells and stromal components inhibit the uniform distribution of the drug and the efficacy of the treatment. Here, we employ mathematical modeling to study the effect of particle size, drug release rate and binding affinity on the distribution and efficacy of nanoparticles to derive optimal design rules. Furthermore, we introduce a new multi-stage delivery system. The system consists of a 20-nm primary nanoparticle, which releases 5-nm secondary particles, which in turn release the chemotherapeutic drug. We found that tuning the drug release kinetics and binding affinities leads to improved delivery of the drug. Our results also indicate that multi-stage nanoparticles are superior over two-stage nano-carriers provided they have a faster drug release rate and for high binding affinity drugs. Furthermore, our results suggest that smaller nanoparticles achieve better treatment outcome.

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Conflict of interest statement

Conflict of interest: R.K.J. received research grants from Dyax, MedImmune and Roche; consultant fees from Enlight, Ophthotech, SynDevRx and Zyngenia; owns equity in Enlight, Ophthotech, SynDevRx and XTuit, serves on the Board of Directors of XTuit and Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors and Tekla Healthcare Opportunities Fund. No reagents or funding from these companies was used in these studies. Therefore, there is no significant financial or other competing interest in the work.

Figures

Figure 1
Figure 1
Schematic shows the three different delivery strategies considered in the study: chemotherapy alone (one-stage), conventional two-stage nanoparticle delivery system consisting of the nano-carrier and the drug and the new multi-stage nanoparticle delivery system consisting of the primary nano-carrier, the secondary nanoparticle and the drug.
Figure 2
Figure 2
Optimization contour plots of the fraction of cells killed as a function of binding rate constant (Kon) and rate constant of release (Kel) for the two-stage (A) and multi-stage (B) 100 nm drug delivery systems. The blood half-life, Kd, was set to 10 h.
Figure 3
Figure 3
Comparison of the three delivery strategies. (A) intracellular (internalized) chemotherapy concentration as a function of time for chemotherapy alone (1 stage), the 100 nm two-stage delivery system (2 stage) and for the 100 nm multi-stage system (3 stage). (B) Intratumoral distribution of chemotherapy as a function of time, and (C) fraction of killed cells as a function of time. Three values of the binding rate constant Kon (M-1 s-1) were employed, whereas the rate constant of release, Kel was set to the physiologically relevant value of 1×10-3 s-1 based on experimental data. Concentration became dimensionless with division with the initial concentration at the entrance of the vascular network. Intratumoral distribution is the area fraction of the tumor where the drug has reached in concentrations above 5% of the concentration at the inlet of the vascular network.
Figure 4
Figure 4
Effect of vessel wall pore size (vascular permeability) on the efficacy of the 100 nm two-stage (A) and multi-stage (B) delivery systems.
Figure 5
Figure 5
Optimization contour plots of the fraction of killed cells as a function of binding rate constant (Kon) and rate constant of release (Kel) for the 20 nm two-stage (A) and multi-stage (B) nanoparticles for blood half-life Kd=10 h. Results of the two-stage (C) and multi-stage (D) delivery systems for Kd=22h.
Figure 6
Figure 6
Effect of vessel wall pore size (vascular permeability) on the efficacy of the 20 nm multi-stage nanoparticles.
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References

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