Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Jan 7;7(3):538-558.
doi: 10.7150/thno.16684. eCollection 2017.

Current Multistage Drug Delivery Systems Based on the Tumor Microenvironment

Binlong Chen  1 , Wenbing Dai  2 , Bing He  1 , Hua Zhang  2 , Xueqing Wang  2 , Yiguang Wang  1 , Qiang Zhang  1
Affiliations
Review

Current Multistage Drug Delivery Systems Based on the Tumor Microenvironment

Binlong Chen et al. Theranostics. .

Abstract

The development of traditional tumor-targeted drug delivery systems based on EPR effect and receptor-mediated endocytosis is very challenging probably because of the biological complexity of tumors as well as the limitations in the design of the functional nano-sized delivery systems. Recently, multistage drug delivery systems (Ms-DDS) triggered by various specific tumor microenvironment stimuli have emerged for tumor therapy and imaging. In response to the differences in the physiological blood circulation, tumor microenvironment, and intracellular environment, Ms-DDS can change their physicochemical properties (such as size, hydrophobicity, or zeta potential) to achieve deeper tumor penetration, enhanced cellular uptake, timely drug release, as well as effective endosomal escape. Based on these mechanisms, Ms-DDS could deliver maximum quantity of drugs to the therapeutic targets including tumor tissues, cells, and subcellular organelles and eventually exhibit the highest therapeutic efficacy. In this review, we expatiate on various responsive modes triggered by the tumor microenvironment stimuli, introduce recent advances in multistage nanoparticle systems, especially the multi-stimuli responsive delivery systems, and discuss their functions, effects, and prospects.

Keywords: activatable nanoparticles; drug delivery systems; multistage; stimuli-responsive; tumor microenvironment.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Fig 1
Fig 1
Various tumor microenvironment-activatable responsive modes. (A) PEG detachment; (B) Ligand re-emergence; (C) Charge reversal; (D) Size shrinkage; (E) Triggered drug release; (F) Signal Turn-OFF/ON.
Fig 2
Fig 2
Clustered nanoparticles with extracellular pH-triggered size shrinkage and intracellular-activatable drug release. (A) Chemical structure and schematic of the iCluster/Pt. (B) TEM images of acid-triggered dendrimers released from iCluster. (C) pH- and redox-induced dendrimers liberation and Pt release. (D) Confocal images of liberated dendrimers penetration into tumors. Adapted from Ref with permission from National Academy of Sciences.
Fig 3
Fig 3
Extracellular- and intracellular-responsive stepwise size reduction and charge reversal for nuclear targeted delivery. Adapted from Ref with permission from Wiley-VCH.
Fig 4
Fig 4
Cellular acid-induced, swelling-shrinking reversible nanoparticle for sequential intra-intercellular delivery. Adapted from Ref with permission from Wiley-VCH.
Fig 5
Fig 5
Four-stage drug delivery system applicable for various tumors.
See this image and copyright information in PMC

References

    1. Yasuhiro Matsumura HM. A New Concept for Macromolecular Therapeutics in Cancer Chemotherapy: Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs. Cancer Res. 1986;46:6387–92. - PubMed
    1. Wagner V, Dullaart A, Bock AK. et al. The emerging nanomedicine landscape. Nat Biotechnol. 2006;24:1211–7. - PubMed
    1. Fang J, Nakamura H, Maeda H. The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev. 2011;63(3):136–151. - PubMed
    1. Durymanov MO, Rosenkranz AA, Sobolev AS. Current Approaches for Improving Intratumoral Accumulation and Distribution of Nanomedicines. Theranostics. 2015;5:1007–20. - PMC - PubMed
    1. Chauhan VP, Jain RK. Strategies for advancing cancer nanomedicine. Nat Mater. 2013;12:958–62. - PMC - PubMed

Publication types

MeSH terms

Substances