Multistage nanoparticle delivery system for deep penetration into tumor tissue - PubMed (original) (raw)

Multistage nanoparticle delivery system for deep penetration into tumor tissue

Cliff Wong et al. Proc Natl Acad Sci U S A. 2011.

Erratum in

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.

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Conflict of interest statement

R.K.J. received commercial research grants from Dyax, AstraZeneca, and MedImmune; consultant fees from AstraZeneca/MedImmune, Dyax, Astellas-Fibrogen, Regeneron, Genzyme, MorphoSys, and Noxxon Pharma; and a speaker honorarium from Genzyme. R.K.J. owns stock in SynDevRx. No reagents or funding from these companies were used in these studies. There is no significant financial or other competing interest in the work.

Figures

Fig. 1.

Fig. 1.

QDGelNPs change their size in response to MMP-2. (A) Schematic of 100-nm QDGelNPs changing size to 10-nm QD NPs by cleaving away the gelatin scaffold with MMP-2, a protease highly expressed in tumor tissue. (B) GFC chromatograms of QDGelNPs at various times after incubation with MMP-2. Fluorescence signal at 565 nm is collected. (B Inset) Fluorescence spectrum of the peak at void volume for 2.2 h cleaving time shows that the signal originates from QDs on the QDGelNPs.

Fig. 2.

Fig. 2.

QDGelNP physical and in vitro characterization. (A) Epifluorescence image of QDGelNPs on a silicon substrate at 100× magnification. (Scale bar: 5 μm.) (B) DLS distribution of QDGelNP on day 1 and day 48 after synthesis and storage at 4 °C. (C) SEM image of QDGelNPs at 15,000× magnification. (Scale bar: 1 μm.) (C Inset) SEM image of individual QDGelNP at 35,000× magnification. (Scale bar: 100 nm.) (D) Histogram of QDGelNPs’ size distribution from image analysis of SEM image. (E and F) Kinetics of MMP-2–induced QD release from QDGelNPs. (E) QD-release curve from incubation of 0.1 mg (0.16 μM) of QDGelNPs with 230 ng of MMP-2. (F) QD release from incubation of 0.1 mg of QDGelNPs for 12 h with varying amounts of MMP-2. (G and H) FCS cross-correlograms of QDGelNPs before (G) and after (H) incubation with MMP-2.

Fig. 3.

Fig. 3.

Diffusion of SilicaQDs and QDGelNPs (before and after MMP-2 cleavage) in a collagen gel. (A and B) Fluorescence images of SilicaQDs (A) and QDGelNPs before MMP-2 cleavage (B) penetrating into the collagen gel. (C) Second-harmonic generation (SHG) signal shows the corresponding location of the collagen matrix. (Scale bars: 125 μm.) (D) Normalized intensity profile of SilicaQDs and QDGelNPs in collagen gel. (E and F) Fluorescence images of SilicaQDs (E) and QDGelNPs after MMP-2 cleavage (F) penetrating into the collagen gel. (G) SHG signal shows the corresponding location of the collagen matrix. (Scale bars: 125 μm.) (H) Normalized intensity profile of SilicaQDs and QDGelNPs after MMP-2 cleavage in collagen gel. Black line displays theoretical intensity profile for particles with diffusion coefficient of 2.3 × 10−7 cm2·s−1.

Fig. 4.

Fig. 4.

In vivo images of QDGelNPs and SilicaQDs after intratumoral coinjection into the HT-1080 tumor. QDGelNPs imaged 1 (A), 3 (B), and 6 h (C) after injection. SilicaQDs imaged 1 (D), 3 (E), and 6 h (F) after injection. (Scale bar: 100 μm.)

Comment in

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