Multi-objective optimization of tumor response to drug release from vasculature-bound nanoparticles

Abstract

the pharmacokinetics of nanoparticle-borne drugs targeting tumors depends critically on nanoparticle design. Empirical approaches to evaluate such designs in order to maximize treatment efficacy are timeand cost-intensive. We have recently proposed the use of computational modeling of nanoparticlemediated drug delivery targeting tumor vasculature coupled with numerical optimization to pursue optimal nanoparticle targeting and tumor uptake. Here, we build upon these studies to evaluate the effect of tumor size on optimal nanoparticle design by considering a cohort of heterogeneously-sized tumor lesions, as would be clinically expected. the results indicate that smaller nanoparticles yield higher tumor targeting and lesion regression for larger-sized tumors. We then augment the nanoparticle design optimization problem by considering drug diffusivity, which yields a twofold tumor size decrease compared to optimizing nanoparticles without this consideration. We quantify the tradeoff between tumor targeting and size decrease using bi-objective optimization, and generate five Paretooptimal nanoparticle designs. the results provide a spectrum of treatment outcomes-considering tumor targeting vs. antitumor effect-with the goal to enable therapy customization based on clinical need. this approach could be extended to other nanoparticle-based cancer therapies, and support the development of personalized nanomedicine in the longer term. Chemotherapy is the treatment of choice to control metastatic cancer-a stage often reported in patients at the time of clinical presentation. Unfortunately, patients undergoing chemotherapy may have low median survival, especially for pancreatic, lung, and liver cancer 1. Negative response to treatment is attributed to a number of factors, including tumor microenvironmental barriers, evolution of resistance to drug, and chemotherapeutic toxicity. It has been shown that nanoparticle-mediated drug delivery may substantially enhance the pharmacokinetics of anticancer drugs while addressing some of these factors 2. However, while many nano-based formulations have undergone pre-clinical and clinical evaluation, few have been translated to the clinic 3. The targeting potential of nanotherapy is strongly associated with nanoparticle biophysical and biochemical properties 4-6. These properties include size 7 , shape (e.g., sphere or ellipsoid) 5 , stiffness 4,8 , and binding affinity of nanoparticle surface ligands to receptors upregulated in cells in tumors 5. Computational studies have investigated the effect of these properties on treatment efficacy in an attempt to find nanoparticles optimized for maximal anti-tumor activity. Nanoparticle margination 6 and adhesion to tumor vasculature 5 have been modeled as a function of nanoparticle properties (size, aspect ratio, ligand surface density, and ligand-receptor binding affinity). Uncertainties in ligand surface density and ligand-receptor affinity have been quantified and incorporated in a nanoparticle-tumor adhesion model using a Bayesian hierarc...

Modeling of Nanotherapy Response as a Function of the Tumor Microenvironment: Focus on Liver Metastasis

“…Biodistribution/physiological pharmacokinetics Li et al, 2010Li et al, , 2012Li and Reineke, 2011;Dogra et al, 2020a Transport in avascular tumors Gao et al, 2013;Curtis et al, 2016a Transport in irregularly vascularized tumors van de Ven et al, 2013;Wu et al, 2014;Curtis et al, 2016a;Miller and Frieboes, 2019a,b Transport based on nanoparticle physical characteristics Decuzzi and Ferrari, 2006;Decuzzi et al, 2009;Godin et al, 2010b Binding to tumor vasculature Frieboes et al, 2013;Curtis et al, 2015;Chamseddine et al, 2018Chamseddine et al, , 2020 Interactions with macrophages Leonard et al, , 2017Leonard et al, , 2020Mahlbacher et al, 2018 Intracellular pharmacokinetics Li et al, 2013;Miller and Frieboes, 2019b For tumor detection Reichel et al, 2015 For hyperthermia applications Kaddi et al, 2013 For drug delivery van de Ven et al, 2012;Li et al, 2013;Curtis et al, 2015Curtis et al, , 2016aLeonard et al, , 2017Leonard et al, , 2020Chamseddine et al, 2018Chamseddine et al, , 2020Miller and Frieboes, 2019a,b; FIGURE 4 | Effect of repeated therapy on simulated breast cancer liver metastsis lesions over 9 day, showing (A) drug (as% of maximum blood levels) and (B) tumor effect (as% of initial lesion diameter) after nAb-PTX and MSV-nAb-PTX injection. In all cases, therapy is initiated at 0, 3, and 6 day.…”

“…The effect of irregular vascularization on nanoparticle transport and drug release in tumor tissue has been evaluated in several studies ( van de Ven et al, 2012 ; Li et al, 2013 ; Curtis et al, 2015 , 2016a , b ; Leonard et al, 2016 , 2017 , 2020 ; Chamseddine et al, 2018 , 2020 ; Miller and Frieboes, 2019a , b ). The role of macrophages in nanotherapeutic transport and effect on hypo-vascularized tumor lesions such as breast cancer liver metastases was evaluated in Leonard et al (2016 , 2017) .…”

Drug-loaded nanoparticles for cancer therapy: a high-throughput multicellular agent-based modeling study

“…Beyond ODE approaches, PDEs and/or hybrid PDE/ABM approaches have also been employed in cancer nanotherapy research. For example, Frieboes and co-workers evaluated cancer nanotherapy that included multiscale effects in a continuum tumor tissue representation, including NP transport, drug release and effects on vascularized tumor growth dynamics [25, 26, 27, 28, 29, 30]. These PDE and hybrid ABM/PDE models have advanced the modeling of tumor cell heterogeneity and spatial interactions (e.g., NPs and released-drug distribution within tumor tissue as well as tumor cell response to the microenvironments).…”

Single-Step Synthesis of Highly Tunable Multifunctional Nanoliposomes for Synergistic Cancer Therapy

“…Malignant tumors seriously affect human health, and the fatality rate remains high . With the development of nanomedicine and materials engineering, − a variety of nanoparticles, such as hydrogels, polypeptides, mesoporous particles, dendrimers, micelles, liposomes, and microneedles, have been applied for effective cancer therapy. − In recent years, drug-loaded nanoliposomes have often been used in anti-tumor therapy due to their controllable particle size, high encapsulation efficiency, and good biocompatibility. − …”