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SCIENCE CHINA Materials, Volume 61, Issue 11: 1387-1403(2018) https://doi.org/10.1007/s40843-018-9271-4

Dendrimer-based strategies for cancer therapy: Recent advances and future perspectives

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  • ReceivedFeb 10, 2018
  • AcceptedApr 2, 2018
  • PublishedApr 28, 2018

Abstract

This review reports some recent advances on the use of dendrimer-based systems for cancer therapy. Dendrimers are emerging as promising carriers or stabilizers for drugs and nanoparticles (NPs) due to their highly branched 3-dimensional globular shape, internal hydrophobic cavity and multiple peripheral functional groups. The fabricated nanoplatforms loaded with therapeutic agents such as drugs, siRNAs or NPs can be further modified to have targeting specificity, antifouling properties and good biocompatibility. In particular, recent advances in the surface modifications of dendrimers and the application of dendrimers as versatile platforms for different therapeutic treatments to cancer including chemotherapy, radiotherapy, photothermal therapy, photodynamic therapy, gene therapy, and combination therapy will be introduced in detail.


Funded by

This research is financially supported by the Fundamental Research Funds for the Central Universities

the Science and Technology Commission of Shanghai Municipality(15520711400,17540712000)

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


Acknowledgment

This research is financially supported by the Fundamental Research Funds for the Central Universities (for Shi X, Xiong Z, and Shen M), the Science and Technology Commission of Shanghai Municipality (15520711400 and 17540712000), and the National Natural Science Foundation of China (81761148028 and 21773026).


Interest statement

The authors declare that they have no conflict of interest.


Contributions statement

Xiong Z wrote the manuscript; Shen M and Shi X designed the outlines and carefully revised the manuscript.


Author information

Zhijuan Xiong received her Bachelor’s degree in biological engineering from Donghua University in 2014. Now she is a PhD student at Donghua University under the supervision of Prof. Xiangyang Shi. Her current research interests include the design of dendrimer-based systems for cancer diagnosis and therapy.


Mingwu Shen received her PhD degree in 2001 from Tsinghua University. Afterwards, she went to the University of Michigan, Ann Arbor as a visiting scholar and a research area specialist intermediate. She joined Donghua University in 2008 as an associate professor, and was promoted to be a full professor of biomedical engineering in 2018. Her current research interests include nanoparticle-based platforms for medical imaging and therapy applications, and the development of nanofiber-based technology for biomedical and environmental applications.


Xiangyang Shi obtained his PhD degree in 1998 from the Chinese Academy of Sciences. From 2002 to 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. His current research interests are focused on the development of organic/inorganic hybrid nanoplatforms and microfluidic platforms for sensing, imaging, and theranostic applications, in particular for precision cancer imaging and therapy.


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  • Figure 1

    Synthesis of tetra-functional poly(amidoamine) (PAMAM) dendrimers: exhaustive Michael addition of amine groups with methyl acrylate, followed by amidation of the resulting esters with ethylenediamine. Reproduced with permission from Ref. [8], Copyright 2001, Elsevier.

  • Figure 2

    A dimensionally scaled comparison of a series of poly(amidoamine) (PAMAM) dendrimers (NH3 core; G=4–7) with a variety of proteins, a typical lipid-bilayer membrane and DNA, indicating the closely matched size and contours of important proteins and bioassemblies. Reproduced with permission from Ref. [8]. Copyright 2001, Elsevier.

  • Figure 3

    Synthesis of different generations (3.0G, 4.0G and 5.0G) of PPI dendrimers. Reproduced with permission from Ref. [21]. Copyright 2014, Elsevier.

  • Figure 4

    Dendrimer-based drug delivery systems of different types: (a) Drugs physically entrapped inside the dendrimers; (b) drugs adsorbed on the surface of the dendrimers through different intermolecular interaction forces; (c) drugs conjugated to the dendrimers. Reproduced with permission from Ref. [37]. Copyright 2013, the Royal Society of Chemistry.

  • Figure 5

    Schematic illustration of the synthesis of the Au-TOS-FA DENPs (a), growth of U87MG xenografted tumors after various treatments (b) and the body weight of U87MG tumor-bearing mice after various treatments (c). The relative tumor volumes and body weight were normalized according to their initial weights (Mean ± SD, n=6). Reproduced with permission from Ref. [89]. Copyright 2015, Elsevier.

  • Figure 6

    The structure of chlorotoxin-conjugated multifunctional dendrimers labeled with radionuclide 131I (a), the SPECT images of ex vivo tumors (b) and the tumor volume (c) of C6 tumor-bearing mice after various treatments (mean ± SD, n=5). Reproduced with permission from Ref. [91]. Copyright 2015, American Chemical Society.

  • Figure 7

    Schematic illustration of pH-sensitive PEGylated PAMAM dendrimer-DOX conjugate-hybridized gold nanorod (PEG-DOX-PAMAM-AuNR) for combined photothermal-chemotherapy. Reproduced with permission from Ref. [95]. Copyright 2014, the Royal Society of Chemistry.

  • Figure 8

    (a) Synthesis of mono-(PcSi(OH)(mob), 2) and disubstituted (PcSi(mob)2, 3) derivatives of the silicon phthalocyanine (PcSi(OH)2, 1). (b) Schematic representation of tumor targeted theranostic platform based on phthalocyanine-loaded dendrimer (Pc−Luteinizing Hormone Releasing Hormone). Reproduced with permission from Ref. [100]. Copyright 2013, American Chemical Society.

  • Figure 9

    Schematic illustration of the formation of the RGD-Au DSNSs for CT/thermal imaging and combinational therapy of tumors. Reproduced with permission from Ref. [51]. Copyright 2016, WILEY-VCH.

  • Table 1   Examples of dendrimer surface decoration and functionalization

    Dendrimer type

    Surface modification agent

    Function

    Reference

    PAMAM

    PEG

    Reducing cytotoxicity

    [42]

    Phosphorylcholine

    [44]

    CBAA

    [45,46]

    Acetyl

    [42,4648]

    CBAA

    [45,46]

    RGD

    [4953]

    pAb antibody

    [54]

    Lactobionic acid

    [55]

    Fluorescein isothiocyanate

    Fluorescence imaging

    [55]

    Fluorochrome Cy5.5

    [50]

    PPI

    PEG

    Reducing cytotoxicity

    [43,56]

    Maltotriose

    [57--59]

    Anti-EGFRvlll scFV

    Targeting property

    [60]

    FA

    [61]

    Histidine, pyridine, piperazine

    Buffering capacity property

    [62]

    PLL

    PEG

    Reducing cytotoxicity

    [63]

    FA

    Targeting property

    [64]

    Phosphorous dendrimers

    Azabisphosphonate

    Targeting property

    [65]

    8-Anilino-1-naphthalenesulfonate

    Fluorescence imaging

    [66]

  • Table 2   Examples of dendrimer-based cancer therapy

    Cancer therapy type

    Dendrimer type

    Founctional agents

    Reference

    Chemotherapy

    PAMAM

    DOX

    [86]

    2-ME

    [87]

    GEM

    [88]

    α-TOS

    [53,89]

    PPI

    DOX

    [90]

    PLL

    MTX

    [43]

    Radiotherapy

    PAMAM

    131I

    [91,92]

    177Lu

    [93,94]

    PTT

    PAMAM

    GNRs

    [95]

    ICG

    [96]

    MoS2

    [97]

    CuS

    [98]

    Au NSs

    [51]

    PDT

    PAMAM

    Ce6

    [99]

    PPI

    Phthalocyanines

    [100]

    Phosphorus dendrimers

    Methylene blue

    [101]

    Rose bengal

    [101,102]

    Gene therapy

    PAMAM

    Luciferase-targeted siRNA or Bcl-2 siRNA

    [103]

    Bcl-2 siRNA

    [51,97,104107]

    siBcl-xl, siBcl-2, siMcl-1 siRNAs and a siScrambled sequence

    [108]

    PPI

    Bcl-2 siRNA

    [109]

    Luciferase-targeted siRNA

    [60]

    pDNA

    [56,62]

    Phosphorus dendrimers

    siBcl-xl, siBcl-2, siMcl-1 siRNAs and a siScrambled sequence

    [108]

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