Related Experiment Video
Updated: Jun 5, 2026
Magnetic-, Acoustic-, and Optical-Triple-Responsive Microbubbles for Magnetic Hyperthermia and Pothotothermal Combination Cancer Therapy
Published on: May 22, 2020
Multistage nanoparticle delivery system for deep penetration into tumor tissue
Cliff Wong1, Triantafyllos Stylianopoulos, Jian Cui
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract:
Current Food and Drug Administration-approved cancer nanotherapeutics, which passively accumulate around leaky regions of the tumor vasculature because of an enhanced permeation and retention (EPR) effect, have provided only modest survival benefits. This suboptimal outcome is likely due to physiological barriers that hinder delivery of the nanotherapeutics throughout the tumor. Many of these nanotherapeutics are ≈ 100 nm in diameter and exhibit enhanced accumulation around the leaky regions of the tumor vasculature, but their large size hinders penetration into the dense collagen matrix. Therefore, we propose a multistage system in which 100-nm nanoparticles "shrink" to 10-nm nanoparticles after they extravasate from leaky regions of the tumor vasculature and are exposed to the tumor microenvironment. The shrunken nanoparticles can more readily diffuse throughout the tumor's interstitial space. This size change is triggered by proteases that are highly expressed in the tumor microenvironment such as MMP-2, which degrade the cores of 100-nm gelatin nanoparticles, releasing smaller 10-nm nanoparticles from their surface. We used quantum dots (QD) as a model system for the 10-nm particles because their fluorescence can be used to demonstrate the validity of our approach. In vitro MMP-2 activation of the multistage nanoparticles revealed that the size change was efficient and effective in the enhancement of diffusive transport. In vivo circulation half-life and intratumoral diffusion measurements indicate that our multistage nanoparticles exhibited both the long circulation half-life necessary for the EPR effect and the deep tumor penetration required for delivery into the tumor's dense collagen matrix.
Insights
This study introduces a novel multistage nanotherapeutic system that shrinks from 100 nm to 10 nm within the tumor microenvironment. This size change enhances drug delivery and penetration into dense tumor tissues, improving cancer treatment efficacy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapeutics
Background:
- Current FDA-approved cancer nanotherapeutics rely on the enhanced permeation and retention (EPR) effect for passive tumor accumulation.
- Nanotherapeutics of ≈100 nm often fail to penetrate dense tumor matrices due to physiological barriers, limiting their efficacy.
- Modest survival benefits from existing nanotherapeutics highlight the need for improved tumor penetration.
Purpose of the Study:
- To develop a multistage nanotherapeutic system capable of size reduction within the tumor microenvironment.
- To overcome the limitations of large nanoparticle size hindering intratumoral diffusion.
- To enhance the delivery and penetration of nanotherapeutics into dense tumor collagen matrices.
Main Methods:
- A multistage system was designed where 100-nm nanoparticles degrade to 10-nm nanoparticles upon exposure to tumor-specific proteases (e.g., MMP-2).
- Gelatin nanoparticles encapsulating quantum dots (QDs) were used as a model system to track size changes and diffusion.
- In vitro studies assessed MMP-2 activation and enhanced diffusive transport, while in vivo studies measured circulation half-life and intratumoral diffusion.
Main Results:
- In vitro studies demonstrated efficient and effective size reduction of nanoparticles triggered by MMP-2.
- The shrunken 10-nm nanoparticles exhibited enhanced diffusive transport within the tumor microenvironment.
- In vivo measurements confirmed a long circulation half-life for EPR effect and deep tumor penetration into dense collagen matrices.
Conclusions:
- The proposed multistage nanotherapeutic system effectively shrinks in response to the tumor microenvironment, improving intratumoral diffusion.
- This approach overcomes size-related barriers, enabling deeper penetration into dense tumor tissues.
- The system holds promise for enhancing the efficacy of cancer nanotherapeutics by improving drug delivery throughout the tumor.
Related Concept Videos
01:24Modified-Release Drug Delivery Systems: Site-Targeted
01:24Site-Targeted Drug Delivery Systems: Polymeric Carriers