Smart Superstructures with Ultrahigh pH-Sensitivity for Targeting Acidic Tumor Microenvironment: Instantaneous Size Switching and Improved Tumor Penetration
Abstract
The currently low delivery efficiency and limited tumor penetration of nanoparticles remain two major challenges of cancer nanomedicine. Here, we report a class of pH-responsive nanoparticle superstructures with ultrasensitive size switching in the acidic tumor microenvironment for improved tumor penetration and effective in vivo drug delivery. The superstructures were constructed from amphiphilic polymer directed assembly of platinum-prodrug conjugated polyamidoamine (PAMAM) dendrimers, in which the amphiphilic polymer contains ionizable tertiary amine groups for rapid pH-responsiveness. These superstructures had an initial size of ∼80 nm at neutral pH (e.g., in blood circulation), but once deposited in the slightly acidic tumor microenvironment (pH ∼6.5-7.0), they underwent a dramatic and sharp size transition within a very narrow range of acidity (less than 0.1-0.2 pH units) and dissociated instantaneously into the dendrimer building blocks (less than 10 nm in diameter). This rapid size-switching feature not only can facilitate nanoparticle extravasation and accumulation via the enhanced permeability and retention effect but also allows faster nanoparticle diffusion and more efficient tumor penetration. We have further carried out comparative studies of pH-sensitive and insensitive nanostructures with similar size, surface charge, and chemical composition in both multicellular spheroids and poorly permeable BxPC-3 pancreatic tumor models, whose results demonstrate that the pH-triggered size switching is a viable strategy for improving drug penetration and therapeutic efficacy.
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pH-sensitive nanoparticles composed of dendrimer building blocks showed better tumor penetration and dissociated into smaller sizes in the tumor environment.
“Li and coworkers showed the size effect of pH-sensitive nanoparticles composed of dendrimer building blocks with better tumor penetration and their dissociation into smaller sizes in the tumor environment.245”
From Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles (2019) · cites this paper as [245]
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Self-citation
- Authors
- Li, H.-J., Du, J.-Z., Liu, J., Du, X.-J., Shen, S., Zhu, Y.-H., Wang, X., Ye, X., Nie, S., & Wang, J.
- Affiliations
- Georgia Institute of Technology (US)
- University of Science and Technology of China (CN)
- Hefei National Laboratory for Physical Sciences at the Microscale, Hefei, Anhui 230027, China
- Corresponding author
- Du, Jin-Zhi
- Nie, Shuming
- Wang, Jun
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-06-03
- Volume
- 10
- Issue
- 7
- Pages
- 6753-6761
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- OpenAlex
- W2409932367
- Cited by
- 537
- References
- 46
- Citations by year
- 2026: 14 · 2025: 32 · 2024: 31 · 2023: 41 · 2022: 58 · 2021: 69 · 2020: 80 · 2019: 73 · 2018: 76 · 2017: 52 · 2016: 10
- FWCI
- 28.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Nano (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA163256)
- Ministry of Science and Technology of the People's Republic of China (2012CB932500, 2013CB933900, 2015CB932100)
- National Natural Science Foundation of China (51390482)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Keywords
- pH-responsive nanoparticles, tumor acidosis, tumor penetration, PAMAM dendrimers, platinum prodrug, tertiary amines, enhanced permeability and retention effect, nanoparticle extravasation, pancreatic cancer, tumor spheroids, drug delivery
- MeSH terms
- Humans, Hydrogen-Ion Concentration, Neoplasms, Drug Delivery Systems, Cell Line, Tumor, Dendrimers, Nanoparticles, Tumor Microenvironment
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