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Review ArticleReview Article

Target Site Delivery and Residence of Nanomedicines: Application of Quantitative Systems Pharmacology

Jessie L.-S. Au, Roberto A. Abbiati, M. Guillaume Wientjes and Ze Lu
Yoshihiro Ishikawa, ASSOCIATE EDITOR
Pharmacological Reviews April 2019, 71 (2) 157-169; DOI: https://doi.org/10.1124/pr.118.016816
Jessie L.-S. Au
Institute of Quantitative Systems Pharmacology, Carlsbad, California (J.L.-S.A., R.A.A., M.G.W., Z.L.); Department of Pharmaceutical Sciences, University of Oklahoma, Oklahoma City, Oklahoma (J.L.-S.A., R.A.A.); Optimum Therapeutics LLC, Carlsbad, California (J.L.-S.A., M.G.W., Z.L.); and College of Pharmacy, Taipei Medical University, Taipei, Taiwan, Republic of China (J.L.-S.A.)
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Roberto A. Abbiati
Institute of Quantitative Systems Pharmacology, Carlsbad, California (J.L.-S.A., R.A.A., M.G.W., Z.L.); Department of Pharmaceutical Sciences, University of Oklahoma, Oklahoma City, Oklahoma (J.L.-S.A., R.A.A.); Optimum Therapeutics LLC, Carlsbad, California (J.L.-S.A., M.G.W., Z.L.); and College of Pharmacy, Taipei Medical University, Taipei, Taiwan, Republic of China (J.L.-S.A.)
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M. Guillaume Wientjes
Institute of Quantitative Systems Pharmacology, Carlsbad, California (J.L.-S.A., R.A.A., M.G.W., Z.L.); Department of Pharmaceutical Sciences, University of Oklahoma, Oklahoma City, Oklahoma (J.L.-S.A., R.A.A.); Optimum Therapeutics LLC, Carlsbad, California (J.L.-S.A., M.G.W., Z.L.); and College of Pharmacy, Taipei Medical University, Taipei, Taiwan, Republic of China (J.L.-S.A.)
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Ze Lu
Institute of Quantitative Systems Pharmacology, Carlsbad, California (J.L.-S.A., R.A.A., M.G.W., Z.L.); Department of Pharmaceutical Sciences, University of Oklahoma, Oklahoma City, Oklahoma (J.L.-S.A., R.A.A.); Optimum Therapeutics LLC, Carlsbad, California (J.L.-S.A., M.G.W., Z.L.); and College of Pharmacy, Taipei Medical University, Taipei, Taiwan, Republic of China (J.L.-S.A.)
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Yoshihiro Ishikawa
Roles: ASSOCIATE EDITOR
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    Fig. 1.

    Transport of NP from the injection site to the target site. After an intravenous injection, NP are distributed in blood and undergo the following processes: 1) interaction with proteins in blood to form NP-PC, 2) removal by phagocytic/RES entrapment or elimination by metabolism and excretion, 3) transport to organs and tissues via blood circulation, 4) extravasation into the tissue interstitium via transvascular diffusion or convection, 5) interaction with ECM components, 6) transport by interstitial diffusion and convection to reach individual cells, 7) interaction with cells (binding, internalization, efflux), and 8) intracellular trafficking and interaction with endocytic organelles. The drawing of NP, ECM components, and subcellular organelles is not to scale. Note that the proteins on the PC formed in blood may exchange with proteins in ECM (not depicted in the figure). See the text for more details on individual processes. API, active pharmaceutical ingredient; ER, endoplasmic reticulum; ERC, endocytic recycling compartment; ESCRT, endosomal sorting complexes required for transport; ILV, intraluminal vesicle; LYSO, lysosome; MVB, multivesicular body; TGN, trans-Golgi network. This figure is adapted from Li et al. (2012) and reprinted with permission.

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    Fig. 2.

    A kinetic model of intracellular trafficking. This kinetic model is based on the intracellular trafficking scheme shown in the far-right panel of Fig. 1. kx denotes the inter-compartmental transfer rate constant, with x being the destination compartment. ERC, endocytic recycling compartment; ILV, intraluminal vesicle; MVB, multivesicular body. This figure is adapted from Abbiati and Au (2018) and reprinted with permission.

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    Fig. 3.

    NP-PC. (A) Schematic illustration of hard and soft PC. The rate of protein adsorption and desorption determines their exchange time and lifetime in PC. The hard or soft PC is composed of multiple proteins. (B) Kinetics of evolution of proteins on PC. Colors indicate the following: red, albumin; blue, transferrin; and green, fibrinogen. (C) Venn diagrams of the numbers of unique proteins adsorbed onto pegylated liposomes recovered from blood of the CD1 mouse at 10 minutes, 1 hour, and 3 hours postinjection (left), and proteins adsorbed onto liposomes with different surface modifications (bare or nonpegylated, pegylated, conjugated with cell surface associated mucin 1 transmembrane glycoprotein antibody) recovered at 10 minutes postinjection (right). (D) NP composition affects PC protein compositions and PC composition affects NP uptake into cells. Analysis of NP-PC with LC-MS shows different PC protein compositions for different PS-COOH NP. Coating of NP by ApoA4 or ApoC3 reduces cellular uptake, whereas coating by ApoH increases uptake. Apo, apolipoprotein; LC, liquid chromatography; MS, mass spectrometry; MUC-1, cell surface associated mucin 1; PS-COOH, carboxy-functionalized polystyrene. Images in this figure were adapted from the following sources and are reprinted with permission: Rahman et al. (2013) (legend also) (A), Vilanova et al. (2016) (B), Hadjidemetriou et al. (2015, 2016) (C), and Ritz et al. (2015) (D).

Tables

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    TABLE 1

    FDA-approved parenteral NP products containing active pharmaceutical ingredients on the U.S. market as of October 2018

    Trade NameActive Pharmaceutical IngredientFormulationAverage Diameter, nmRoute of AdministrationApproval Year
    DoxilDoxorubicinLiposome85Intravenous1995
    DaunoXomeDaunorubicinLiposome45Intravenous1996
    AmBisomeAmphotericin BLiposome60–70Intravenous1997
    VisudyneVerteporfinLiposome18–104Intravenous2000
    MarqiboVincristine sulfateLiposome100Intravenous2012
    OnivydeIrinotecan HCLLiposome110Intravenous2015
    VyxeosDaunorubicin/cytarabineLiposome100Intravenous2017
    AbraxanePaclitaxelNanoparticle130Intravenous2005
    SomatulineLanreotide acetateNanotube24Subcutaneous2007
    AbelcetAmphotericin BLipid complex1600–11,100Intravenous1995
    AmphotecAmphotericin BLipid complex150Intravenous1996
    OnpattroPatisiranLipid complex<100Intravenous2018
    • Note that Abelcet is included in an FDA NP product list (Bobo et al., 2016; Zheng et al., 2017) but has been reported to have an average diameter of >1000 nm (Clark et al., 1991; Johnson et al., 1998).

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    TABLE 2

    Effect of NP properties

    NP PropertyOutcome/Effect (Example)
    SizeReduced opsonization and RES uptake at <200 nm
    Affects transport (transvascular and interstitial) and retention (enhanced in tumors for 50–200 nm NP)
    Internalization of inorganic NP and liposomes (maximum at 30–50 nm)
    Intracellular trafficking/processing
    Surface chargeAffects opsonization (rapid RES clearance of cationic liposomes)
    Affects electrostatic interaction with vessel pore
    Promotes interactions with ECM components, reduces interstitial transport
    Increases binding to cell membrane and internalization (positively charged NP shows higher binding and internalization compared with neutral or negatively charged NP)
    Biomaterial and surface modificationCoating with hyaluronic acid reduces immunogenicity
    Cationic cell-penetrating peptide promotes NP internalization and perinuclear localization
    Collagenase and hyaluronidase alter ECM, promote interstitial transport
    Ligands for targeting (e.g., folate, transferrin, CD19, CD20, uPAR, HER2) enhances uptake and accumulation
    pH-sensitive fusogenic polymers, peptides, or lipids enhance cargo release in endosomes
    Shape and geometryHigher curvature leads to a larger degree of membrane wrapping
    Higher uptake of spherical NP vs. rod-shaped NP in murine macrophages and human HeLa cells
    Higher uptake of nanorods with shorter aspect ratio (length-to-width) in HeLa and human breast MCF7 cells vs. longer ratio, whereas the opposite was found for cationic crosslinked pegylated hydrogel NP in HeLa cells
    Lower uptake for smaller NP (100 and 300 nm) vs. larger NP with the same aspect ratio
    For mesoporous silica NP, spherical NP uses clathrin-mediated endocytosis, whereas the rod- or worm-shaped analogs prefer macropinocytosis
    Gold nanorods align to cell membrane in a near-parallel manner followed by rotating by ∼90° to enter the cell via a caveolae-mediated pathway
    Molecular dynamic simulations suggest slow membrane wrapping of NP with sharp edges or high curvature (e.g., cubes)
    Shape of NP affects biodistribution; for example, 1) longer circulation for higher aspect ratio NP (e.g., filomicelles, rods) vs. spherical NP; 2) discoidal/plate-like NP accumulate in the heart and lungs, presumably due to the margination under flow leading to the accumulation on vascular walls; and 3) spheres and short rods tend to accumulate more in the liver than longer rods, whereas NP with a higher aspect ratio concentrate more in the spleen and lungs
    • Readers are referred to earlier reviews (Wang et al., 2010; Li et al., 2012; Andar et al., 2014; Shang et al., 2014; Paliwal et al., 2015; Treuel et al., 2015; Au et al., 2016; Yang et al., 2016; Behzadi et al., 2017; Kinnear et al., 2017) for more details and the original citations. HER, human epidermal growth factor receptor; uPAR, urokinase-type plasminogen activator receptor.

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Pharmacological Reviews: 71 (2)
Pharmacological Reviews
Vol. 71, Issue 2
1 Apr 2019
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Review ArticleReview Article

QSP to Evaluate Target Site Delivery of Nanomedicines

Jessie L.-S. Au, Roberto A. Abbiati, M. Guillaume Wientjes and Ze Lu
Pharmacological Reviews April 1, 2019, 71 (2) 157-169; DOI: https://doi.org/10.1124/pr.118.016816

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Review ArticleReview Article

QSP to Evaluate Target Site Delivery of Nanomedicines

Jessie L.-S. Au, Roberto A. Abbiati, M. Guillaume Wientjes and Ze Lu
Pharmacological Reviews April 1, 2019, 71 (2) 157-169; DOI: https://doi.org/10.1124/pr.118.016816
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  • Article
    • Abstract
    • I. Introduction
    • II. Transport from Blood to the Tissue Interstitium
    • III. Interactions with the Extracellular Matrix and Cells
    • IV. Intracellular Trafficking
    • V. Examples of Applying Quantitative Systems Pharmacology to Estimate the Target Site Delivery and Residence of Small Molecule Drugs and Nanosized Medicines
    • VI. Interaction of Nanosized Medicine and Proteins to Form Protein Corona
    • VII. Unique Regulatory Issues Regarding Nanosized Medicine Products
    • VIII. Conclusions and Perspectives
    • Authorship Contributions
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