Multistage nanoparticle delivery system for deep penetration into tumor tissue

By Cliff R. Wong, Triantafyllos Stylianopoulos, Jian Cui, John D. Martin, Vikash P Chauhan, Wen Jiang, Zoran Popović, Rakesh K. Jain, Moungi G. Bawendi, Dai Fukumura. Proceedings of the National Academy of Sciences of the United States of America, 2011

1,002 citations recorded by the source corpus.

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.

Subfields: Biomaterials, Biomedical Engineering, Cancer Research

View Paper: https://www.semanticscholar.org/paper/ca940d780fbb75fd9de9cb291f322028c8f9cf2c

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In Biomaterials

1. O. Farokhzad
2. N. Bertrand
3. N. Kamaly
4. Xiaoyang Xu
5. Jun Wu
6. Alexandre Albanese
7. T. Vandamme
8. W. Chan

In Biomedical Engineering

1. N. Bertrand
2. Xiaoyang Xu
3. N. Kamaly
4. Jun Wu
5. O. Farokhzad
6. Fabian Kiessling
7. W. Chan
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In Cancer Research

1. O. Farokhzad
2. N. Bertrand
3. Jun Wu
4. Xiaoyang Xu
5. T. Lammers
6. N. Kamaly

Citations in the corpus

• Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. (2014, background): “who developed 90-nm NPs that disintegrated into 10-nm quantum dots when degraded by tumor proteinases [84].”
• In vivo delivery of miRNAs for cancer therapy: Challenges and strategies (2014, background): “A linker susceptible to proteases cleavage such as MMP-2 cleavage can be conjugated to the well PEGylated nanoparticles to achieve the efficient tumor penetration of the modified nanoparticles [140].”
• Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy (2016, background): “Such a requirement has promoted the recent development of stimuli-responsive nanoparticles that are able to shrink their sizes by responding to enzymes or UV light (15, 34).”
• Size-Dependent Localization and Penetration of Ultrasmall Gold Nanoparticles in Cancer Cells, Multicellular Spheroids, and Tumors in Vivo (2012, positive): “developed to realize deep tumor penetration and high accumulation in tumor in vivo.(43) In addition, the delivery of small nanoparticles (diameter, 12 nm) was improved by vascular normalization in mammary tumors, while hindering the delivery of larger nanoparticles (diameter, 125 nm).”
• Control of Polymeric Nanoparticle Size to Improve Therapeutic Delivery (2015, background): “developed 100-nm crosslinked gelatin NPs that contained 10-nm quantum dots, and showed that gelatin NPs were delivered to tumor site by the EPR effect and then gradually degraded by proteases within the tumor microenvironment, allowing smaller quantum dot NPs to penetrate deeper into the tumor tissu”