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SCIENCE CHINA Materials, Volume 61, Issue 11: 1367-1386(2018) https://doi.org/10.1007/s40843-018-9244-5

Recent therapeutic applications of the theranostic principle with dendrimers in oncology

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  • ReceivedJan 19, 2018
  • AcceptedMar 6, 2018
  • PublishedApr 8, 2018

Abstract

At the intersection between treatment and diagnosis, nanoparticles technologies are strongly impacting the development of both therapeutic and diagnostic agents. Consequently, the development of novel modalities for concomitant noninvasive therapy and diagnostics known as theranostics as a single platform has gained significant interests. These multifunctional theranostic platforms include carbon-based nanomaterials (e.g., carbon nanotubes), drug conjugates, aliphatic polymers, micelles, vesicles, core-shell nanoparticles, microbubbles and dendrimers bearing different contrast agents and drugs, such as cytotoxic compounds in the oncology domain. Dendrimers emerged as a new class of highly tunable hyperbranched polymers, and have been developed as useful theranostic platforms. Magnetic resonance imaging, gamma scintigraphy, computed tomography and optical imaging are the main techniques developed with dendrimers in the theranostic domain in oncology. Different imaging agents have been used such as Gd(III), 19F, Fe2O3 (MRI), 76Br (PET), 111In, 88Y, 153Gd, 188Re, 131I (SPECT), 177Lu, gold (CT) and boronated groups, siliconnaphthalocyanines, dialkylcarbocyanines and QDs (optical imaging dyes).


Funded by

FCT-Fundação para a Ciência e a Tecnologia(project,PEst-OE/QUI/UI0674/2013,CQM,Portuguese,Government,funds)

ARDITI through the project M1420-01-0145-FEDER-000005 - Centro de Química da Madeira - CQM+(Madeira,14-20)

Centre National de la Recherche Scientifique(CNRS,France)

the National Natural Science Foundation of China(21773026,81761148028)

and the Sino-French Caiyuanpei Programme.


Acknowledgment

This review is the result of intense cooperation between France, China and Portugal in the domain of dendrimers and cannot be possible without the devotion of our coworkers, the work of the colleagues all over the world and the support of several funding agencies. Mignani S, Rodrigues J, and Tomas H acknowledge the support of FCT-Fundação para a Ciência e a Tecnologia (project PEst-OE/QUI/UI0674/2013, CQM, Portuguese Government funds), and ARDITI through the project M1420-01-0145-FEDER-000005 - Centro de Química da Madeira - CQM+ (Madeira 14-20), and Majoral J-P also acknowledges the funds from Centre National de la Recherche Scientifique (CNRS, France). Shi X acknowledges the support by the National Natural Science Foundation of China (21773026 and 81761148028), and (Mignani S, Majoral J-P and Shi X) by the Sino-French Caiyuanpei Programme.


Interest statement

The authors declare that they have no conflict of interest.


Contributions statement

Authors contributed equally.


Author information

Serge Mignani was Head of the Medicinal Chemistry Department and Scientific Director (Sanofi). In 2017, he was nominated as Professor in medicinal chemistry at the Centro de Quimica da Madeira, University of Madeira at Fungal, Portugal. He is member of scientific advisory board of Glycovax Pharma (Montreal, Canada), and Sai Phytoceuticals (New Delhi, India). He is consultant in medicinal chemistry at the Indian Institute of Integrative Medicine (Prof. R. Vishwakarma, IIIM, Jammu, India), the ‘Laboratoire Chimie de Coordination’ (Prof. J-P. Majoral, Toulouse, France), and the Donghua University (Prof. X. Shi, Shanghai, China).


João Rodrigues is a staff member of the University of Madeira since 1999 (Portugal) and Adjunct Professor at Northwestern Polytechnical University, Xi’an (China) since June 2017. In September 2017, he was nominated member of the Scientific Board of the Portuguese National Science Foundation (FCT) in the areas of Exact Sciences and Engineering. In the last three years, he authored 24 papers and 2 book chapters (h index 21, i10 index = 30). His main research interests are on the synthesis and characterization of molecular materials namely, nanoparticles, dendrimers and polymers for biomedical applications (e.g., emergent and infectious diseases, and oncology).


Xiangyang Shi obtained his PhD degree in 1998 from the Chinese Academy of Sciences. From 2002-2008, he was appointed as a research fellow, research associate II, research investigator, and research assistant professor in Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor. In September 2008, he joined Donghua University as a full professor. He has published more than 268 peer-reviewed SCI-indexed journal articles. His current research interests are focused on dendrimer-based nanomedicine, and electrospun polymer nanofiber-based technology for applications in regenerative medicine, sensing, and therapeutics.


Jean-Pierre Majoral is Emeritus Director of Research, Exceptional Class at the CNRS in Toulouse. His research interest is focused on the design and the properties of macromolecules such as phosphorus dendrimers and hyperbranched polymers. Main efforts are directed at the use of dendrimers in medicinal chemistry, material sciences and catalysis. He is co-founder and scientific director of the start-up Dendris. He is a member of several Academies of Sciences worldwide, got a dozen of international awards, and is an author of over 635 publications, 7 books, 35 book chapters, and 45 patents (h index 65, over 15,700 citations).


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  • Figure 1

    Schematic description of theranostic dendrimer strategy.

  • Figure 2

    2D chemical structure of G1-G5 PAMAM dendrimers.

  • Figure 3

    Schematic chemical structure of G5 FGF-dendrimer conjugate.

  • Figure 4

    Schematic chemical structure of G5 DOX-FA-dendrimer conjugate.

  • Figure 5

    Schematic illustrations of the synthesis of TSPDS based on self-assembly, polymerization and coordination steps. Reprinted with permission from Ref. [26], Copyright 2016, Ivyspring International Publisher.

  • Figure 6

    Schematic chemical structure of Gd(III) complexed with DTPA and DOTA.

  • Figure 7

    Schematic chemical structure of G2, G6 PAMAM-DTPA dendrimers.

  • Figure 8

    Schematic chemical structure of G6 PAMAM-(GdDO3A) and G6 PAMAM-cystamine-(GdDO3A).

  • Figure 9

    Schematic chemical structure of polyethylene glycol (PEG)-core-(Gd-DOTA) dendrimers.

  • Figure 10

    Chemical structure of dendrimersome based on 3,5-C12-EG-(OH)4, Gd(III)DTAGA(C18)2 and prednisolone phosphate.

  • Figure 11

    Pictorial representation of the folate receptor-mediated endocytosis followed by drug release of the targeted theranostic formulation SPIONs@FA-PAMAM-CDF in cancer cells overexpressing folate receptors. Reprinted with permission from [45]. Copyright 2018, American Chemical Society.

  • Figure 12

    Chemical structure of PET 76Br-cRGD nanoprobe targeting αvβ3-integrin. Modified from Ref. [46]. Copyright 2009, The National Academy of Sciences of the USA.

  • Figure 13

    Schematic structure of CH12-HSPA-188Re. The links between the Ab and the chelate with the hyper branched polysulfonamine-based dendrimers are arbitrarily attributed.

  • Figure 14

    Schematic chemical structure of G4-PAMAM (DMAA-IPA)37.

  • Figure 15

    Schematic chemical structure of 177Lu-DenAuNP-folate-bombesin.

  • Figure 16

    Schematic chemical structure of 50Au-5FA-G5 PAMAM.

  • Figure 17

    Schematic structure of VEGF-DB/Cy5.

  • Figure 18

    Schematic chemical structure of PEG-G4 PPI-LHRH-PcSi(OH)(mob).

  • Figure 19

    Fluorescently-labeled first generation phosphorhydrazone dendrimer able to trigger the human immune system towards either anti-inflammatory properties or anti-cancer properties.

  • Figure 20

    Phosphorhydrazone anti-cancer dendrimer having 12 fluorophore inside the structure, and 12 pyridine imine and PEG as terminal functions.

  • Table 1   Imaging modality, type of imaging agents and their respective advantages and disadvantages

    Imaging modality

    Type of imaging agent

    Advantages

    Disadvantages

    Optical imaging dye

    Fluorescent dyes, photoproteins, quantum dots

    High sensibility

    No radiation

    Multi-channel imaging

    Not for clinical imaging

    Low resolution

    Limited tissue penetration (<1 cm)

    Computed tomography (CT)

    Heavy elements, e.g. iodine, gold

    High spatial resolution

    Low radiation exposure

    Tissue differentiation

    No depth limit

    Relatively low cost

    Radiation

    Nontissue-specificity

    Need contrast agent for tissue differentiation

    Mainly used for lung and bone

    Magnetic resonance imaging (MRI)

    Para- or supramagnetic metals (e.g., Gd(III), manganese oxide, Fe2O3, or Fe3O4)

    19Fluorine labeled compounds

    High resolution

    No ionizing radiation

    Physiological and anatomical images

    No depth limit

    Quantitative results

    Limited to patients without metallic devices (e.g., pacemakers)

    High cost

    Gamma scintigraphy (PET)

    Radionuclides

    (e.g., 18F, 11C, 64Cu, 15O, 76Br),

    Image biochemical process

    High sensitivity

    No depth limit

    Quantitative results

    Low cost

    Radiation

    Low resolution

    Limited imaging depth (cm)

    Gamma scintigraphy (SPECT)

    111In chelates, 99mTc

    Ultrasound

    Gas-filled microbubbles

    High resolution

    Non invasive

    Simple procedure to operate

    No radiation exposure

    Low cost

    Low resolution

  • Table 2   Selected examples of TNPs in oncology (except dendrimers)

    TNPs type

    Material involved

    Anticancer drugs

    Contrast agents

    Targeting moieties

    Carbon nanotubes

    Carbon

    Cisplatin

    Quantum dots

    EGFi [15]

    Drug conjugates

    HPMAa

    DY-615

    RGDj [16]

    Aliphatic polyesters

    PLGAb + poly(allylamine)/PEG

    Docetaxel

    SPIOf

    SCAb antibody [17]

    Micelles

    PEG-PLAc

    Doxorubicin

    SPIOf

    RGDj [18]

    Vesicles

    PBGBHd

    Docetaxel

    Tc-99m

    Passive diffusion [19]

    Core-shell nanoparticles

    PAAe/SPIOf

    Paclitaxel

    SPIOf/Dilh

    Folic acid [20]

    Microbubbles

    PEG-PLAc/PFPg

    Doxorubicin

    PFPg

    Passive diffusion [21]

  • Table 3   Imaging agents used with dendrimers

    MRI

    PET

    SPECT

    CT

    Optical imaging dye

    Gd(III), 19F, Fe2O3

    76Br

    111In, 88Y, 153Gd, 188Re, 131I

    111In, 177Lu, gold

    Boronated groups

    Siliconnaphthalocyanine

    Dialkylcarbocyanine

    QDs

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