A mathematical model to predict nanomedicine pharmacokinetics and tumor delivery

Dogra, Prashant; Butner, Joseph D.; Ruiz-Ramírez, Javier; Chuang, Yao-Li; Noureddine, Achraf; Brinker, C. Jeffrey; Cristini, Vittorio; Wang, Zhihui

doi:10.1016/j.csbj.2020.02.014

Cited by 74 publications

(70 citation statements)

References 76 publications

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“…A tumor-compartment bearing PB-PK model has recently been developed to investigate the effects of nanoparticle properties, tumour variables and individual physiological differences on the plasma circulation time, MPS sequestration, tumor delivery, and excretion of nanoparticles. This model provides important mechanistic information and evaluates the impact of both physiological and pathophysiological conditions that could affect tumour delivery and inform patient selection, however it does not address drug release 33 . Using non‐invasive in vivo imaging enables the visualization and quantification of the whole‐body disposition behavior of nanoparticles and other advanced therapeutics which is essential for a comprehensive understanding of their distribution.…”

Section: Discussionmentioning

confidence: 99%

Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy

et al. 2021

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Dual Bcl-2/Bcl-xL inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual Bcl-2/Bcl-xL inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer. Mathematical modelling was employed to determine the optimal release rate of the drug from the dendrimer for maximal therapeutic index in terms of preclinical anti-tumour efficacy and cardiovascular tolerability. The optimised candidate is shown to be efficacious and better tolerated in preclinical models compared with AZD4320 alone. The AZD4320-dendrimer conjugate (AZD0466) identified, through mathematical modelling, has resulted in an improved therapeutic index and thus enabled progression of this promising dual Bcl-2/Bcl-xL inhibitor into clinical development.

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Section: Discussionmentioning

confidence: 99%

Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy

et al. 2021

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“…The higher the SI, the more significance a parameter holds. A detailed description of the GSA workflow can be found in 38, 60, 61 . All analyses were performed in MATLAB R2018a.…”

Section: Methodsmentioning

confidence: 99%

Innate immunity plays a key role in controlling viral load in COVID-19: mechanistic insights from a whole-body infection dynamics model

Dogra

Ruiz-Ramírez

Sinha

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen of immense public health concern. Efforts to control the disease have only proven mildly successful, and the disease will likely continue to cause excessive fatalities until effective preventative measures (such as a vaccine) are developed. It is important to better understand SARS-CoV-2 pathogenesis and population susceptibility to infection in order to develop effective disease management strategies. To this end, physiologically relevant mathematical modeling can provide a robust in silico tool to understand COVID-19 pathophysiology and the in vivo dynamics of SARS-CoV-2. Guided by ACE2-tropism (ACE2 receptor dependency of the virus for infection) of the virus, and by incorporating cellular-scale viral dynamics and innate and adaptive immune response, we have developed a multiscale mechanistic model for simulating the time-dependent evolution of viral load distribution in susceptible organs of the body. Following calibration with in vivo and clinical data, we used the model to simulate viral load progression in a virtual patient with varying degrees of compromised immune status. Further, to understand the effects of physiological factors and underlying conditions on viral load dynamics, we conducted global sensitivity analysis of model parameters and ranked them for their significance in governing clearance of viral load from the body. Antiviral drug therapy, interferon therapy, and their combination was simulated to study the effects on viral load kinetics of SARS-CoV-2. The model highlights the importance of innate immunity (interferons and resident macrophages) in controlling viral load, and the significance of timing when initiating therapy following infection.

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“…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.…”

Section: Nanotherapy Focus Referencesmentioning

confidence: 99%

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

Frieboes

Raghavan

Godin

2020

Front. Bioeng. Biotechnol.

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The tumor microenvironment (TME) presents a challenging barrier for effective nanotherapy-mediated drug delivery to solid tumors. In particular for tumors less vascularized than the surrounding normal tissue, as in liver metastases, the structure of the organ itself conjures with cancer-specific behavior to impair drug transport and uptake by cancer cells. Cells and elements in the TME of hypovascularized tumors play a key role in the process of delivery and retention of anti-cancer therapeutics by nanocarriers. This brief review describes the drug transport challenges and how they are being addressed with advanced in vitro 3D tissue models as well as with in silico mathematical modeling. This modeling complements network-oriented techniques, which seek to interpret intra-cellular relevant pathways and signal transduction within cells and with their surrounding microenvironment. With a concerted effort integrating experimental observations with computational analyses spanning from the molecular-to the tissue-scale, the goal of effective nanotherapy customized to patient tumor-specific conditions may be finally realized.

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A mathematical model to predict nanomedicine pharmacokinetics and tumor delivery

Cited by 74 publications

References 76 publications

Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy

Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy

Innate immunity plays a key role in controlling viral load in COVID-19: mechanistic insights from a whole-body infection dynamics model

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

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