Original Article
Osteoclasts and tumor cells dual targeting nanoparticle to treat bone metastases of lung cancer

https://doi.org/10.1016/j.nano.2019.102054Get rights and content

Abstract

Bone is one of the prone metastatic sites of lung cancer. Osteoclast plays an important role in bone resorption and the growth of bone metastases of lung cancer. In order to treat bone metastases of lung cancer, we reported a docetaxel (DTX)-loaded nanoparticle, DTX@AHP, which could target dually at osteoclasts and bone metastatic tumor cells. The in vitro drug release from DTX@AHP exhibited pH and redox responsive characteristics. DTX@AHP displayed high binding affinity with bone matrix. In addition, DTX@AHP significantly inhibited the differentiation of RAW264.7 into osteoclast and effectively inhibited the proliferation of osteoclasts and tumor cells in in-vitro 3D bone metastases model of lung cancer. DTX@AHP could accumulate in bone metastases sites in vivo. Consequently, DTX@AHP not only markedly inhibited the growth of bone metastases of lung cancer but also reduced osteolysis in tumor-bearing mice. DTX@AHP exhibited great potential in the treatment of bone metastases of lung cancer.

Graphical Abstract

Bone-targeted nanoparticles respectively deliver alendronate (ALN) and docetaxel (DTX) to osteoclasts and tumor cells of bone metastases, subsequently inhibiting the activation of osteoclasts and the growth of bone metastases of lung cancer. The osteolytic bone destruction is also attenuated.

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Section snippets

Methods

All materials are particularly described in supplementary information (SI).

Characterization of AHP

The chemical structure of AHP was identified by 1H NMR and FTIR. As showed in supplementary Figure 2, A, the peak at 2.97 ppm [-NH-CH2-CH2-CH2-C(OH)P2-] indicated the presence of ALN.47 The peak at 1.8 ppm [-COCH=C(COOH)-] implied the presence of CA.48 Besides, peaks at 1.91 ppm [-NH-CO-CH3] and 4.46 ppm [-CH(OH)-] signified to the protons of HA.49, 50 Additionally, peaks at 2.2 ppm [-HNCH2CH2CO-], 2.7 ppm [-CONHCH2CH2NH-], 3.2 ppm [-CONHCH2CH2NH2] and 3.3 ppm [-NHCH2CH2NHCO-] indicated the

Discussion

Bone resorption is a very serious complication of bone metastases of cancer. To treat bone metastases of cancer, it is crucial to reduce bone resorption and inhibit tumor growth at the same time. Osteoclast is the cell which is responsible for the resorption of bone. The osteoclast degrades the collagenous and noncollagenous proteins, subsequently forming bone lacunae.36, 37 Therefore, bone lacuna is an important index to evaluate bone resorption. At first, the in vitro anti-bone resorption

References (63)

  • S.G. Rotman et al.

    Drug delivery systems functionalized with bone mineral seeking agents for bone targeted therapeutics

    J Control Release

    (2018)
  • H. Vermeirsch et al.

    Bone cancer pain model in mice: evaluation of pain behavior, bone destruction and morphine sensitivity

    Pharmacol Biochem Behav

    (2004)
  • W.L. Ye et al.

    Actively targeted delivery of doxorubicin to bone metastases by a pH-sensitive conjugation

    J Pharm Sci

    (2015)
  • X.B. Fang et al.

    pH-sensitive micelles based on acid-labile pluronic F68-curcumin conjugates for improved tumor intracellular drug delivery

    Int J Pharm

    (2016)
  • W.N. Addison et al.

    Extracellular matrix mineralization in murine MC3T3-E1 osteoblast cultures: an ultrastructural, compositional and comparative analysis with mouse bone

    Bone

    (2015)
  • X. Xu et al.

    A novel doxorubicin loaded folic acid conjugated PAMAM modified with borneol, a nature dual-functional product of reducing PAMAM toxicity and boosting BBB penetration

    Eur J Pharm Sci

    (2016)
  • P. Kesharwani et al.

    Hyaluronic acid-conjugated polyamidoamine dendrimers for targeted delivery of 3,4-difluorobenzylidene curcumin to CD44 overexpressing pancreatic cancer cells

    Colloids Surf B Biointerfaces

    (2015)
  • F. Zhang et al.

    Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model

    J Control Release

    (2017)
  • W. Chen et al.

    Cancer statistics in China, 2015

    CA Cancer J Clin

    (2016)
  • J. Yang et al.

    The prognostic value of multiorgan metastases in patients with non-small cell lung cancer and its variants: a SEER-based study

    J Cancer Res Clin Oncol

    (2018)
  • H. Hsu et al.

    Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand

    Proc Natl Acad Sci U S A

    (1999)
  • G.A. Clines et al.

    Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

    Endocr Relat Cancer

    (2005)
  • T.A. Guise et al.

    Basic mechanisms responsible for osteolytic and osteoblastic bone metastases

    Clin Cancer Res

    (2006)
  • W.L. Ye et al.

    Doxorubicin-poly (ethylene glycol)-alendronate self-assembled micelles for targeted therapy of bone metastatic cancer

    Sci Rep

    (2015)
  • Y.P. Zhao et al.

    Redox and pH dual sensitive bone targeting nanoparticles to treat breast cancer bone metastases and inhibit bone resorption

    Nanoscale

    (2017)
  • Z. Luo et al.

    Tumor-targeted hybrid protein oxygen carrier to simultaneously enhance hypoxia-dampened chemotherapy and photodynamic therapy at a single dose

    Theranostics

    (2018)
  • S. Wilhelm et al.

    Analysis of nanoparticle delivery to tumours

    Nature Reviews Materials

    (2016)
  • H.J. Li et al.

    Smart superstructures with ultrahigh pH-sensitivity for targeting acidic tumor microenvironment: instantaneous size switching and improved tumor penetration

    ACS Nano

    (2016)
  • M. Dobosz et al.

    Multispectral fluorescence ultramicroscopy: three-dimensional visualization and automatic quantification of tumor morphology, drug penetration, and antiangiogenic treatment response

    Neoplasia

    (2014)
  • L. Pang et al.

    A novel strategy to achieve effective drug delivery: exploit cells as carrier combined with nanoparticles

    Drug Deliv

    (2017)
  • M.A. Traore et al.

    Construction of bacteria-based cargo carriers for targeted cancer therapy

    Methods Mol Biol

    (1831)

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    Declaration of interest: The authors declare that they have no conflicts of interest and state that the figures of the experiment are the first time to be disclosed.

    Statement of funding: This work was supported by the National Nature Science Foundation (No. 81872803).

    Note: The abstract is not presented at any meetings regarding the research.

    1

    The author contributed equally to this work.

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