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

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 multistage 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.

Role of vascular normalization in benefit from metronomic chemotherapy

“…Our model takes into consideration the growth/death rate of the cells, their inactivation by cancer cells, and their activation by oxygen, which increases their killing potential. Transport of oxygen and chemotherapy was modeled based on previous work (50,54). Fluid transport across the tumor vessel wall is described using Starling's approximation.…”

“…These model predictions are in agreement with previously reported experimental data (38, 39). (54). Increases in drug levels result in more efficient killing of CCs, CSCs, and ICCs (57,58).…”

Emerging therapies for pancreatic ductal carcinoma

“…Stylianopoulos et al discussed whether a multi-stage delivery system with slower drug release would be more effective at targeting the entire tumor; also the optimal size and pharmacokinetics were assessed. [43] In solid tumors even nanoparticles 100 nanometers in size may be too big. While nanotechnology offers an opportunity to improve chemotherapy, the authors discovered that in solid tumors 100 nanometer nanoparticles were less compartmentalized inside the tumor than normal chemotherapy.…”

“…Mildly timed release kinetics were also suggested to find a balance between effective concentrations and penetrating the tumor in its entirety. [43] This is a novel idea-to this point methods have been mainly focused on altering the fibrotic structure to help internalization of chemotherapy.…”

Intelligent drug delivery systems for the treatment of solid tumors

“…Multistage drug delivery systems are initially large nanoparticles so that they can ensure long circulation times, high load capacity and selective delivery to the tumor site through the EPR effect (29)(30)(31). When the nano particles enter the tumor interstitial space, they decrease in size to enable rapid diffusion and uniform distribution in the interior of the tumor.…”