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. 2016 Jul 11;2(7):1108-1120.
doi: 10.1021/acsbiomaterials.6b00111. Epub 2016 Jun 6.

Acidic pH-targeted chitosan capped mesoporous silica coated gold nanorods facilitate detection of pancreatic tumors via multispectral optoacoustic tomography

Matthew R Zeiderman  1 , Desiree E Morgan  2 , John D Christein  2 , William E Grizzle  2 , Kelly M McMasters  1 , Lacey R McNally  1
Affiliations

Acidic pH-targeted chitosan capped mesoporous silica coated gold nanorods facilitate detection of pancreatic tumors via multispectral optoacoustic tomography

Matthew R Zeiderman et al. ACS Biomater Sci Eng. .

Abstract

We present a cancer nanomedicine based on acidic pH targeted gold nanorods designed for multispectral optoacoustic tomography (MSOT). We have designed gold nanorods coated with mesoporous silica and subsequently capped with chitosan (CMGs). We have conjugated pH-sensitive variant 7 pHLIP peptide to the CMGs (V7-CMG) to provide targeting specificity to the acidic tumor microenvironment. In vitro, treatment of S2VP10 and MiaPaca2 cells with V7-CMG containing gemcitabine resulted in significantly greater cytotoxicity with 97% and 96.5% cell death, respectively than gemcitabine alone 60% and 76% death at pH 6.5 (S2VP10 pH 6.5 p=0.009; MiaPaca2 pH 6.5 p=0.0197). In vivo, the V7-CMGs provided the contrast and targeting specificity necessary for MSOT of retroperitoneal orthotopic pancreatic tumors. In the in vivo S2VP10 model, the V7-CMG particle preferentially accumulated within the tumor at 17.1 MSOT a.u. signal compared with 0.7 MSOT a.u. in untargeted CMG control in tumor (P = 0.0002). Similarly, V7-CMG signal was 9.34 MSOT a.u. in the S2013 model compared with untargeted CMG signal at 0.15 MSOT a.u. (P = 0.0004). The pH-sensitivity of the targeting pHLIP peptide and chitosan coating makes the particles suitable for simultaneous in vivo tumor imaging and drug delivery.

Keywords: MSOT; acidic pH; active targeted nanoparticles; chitosan; gold nanorod; mesoporous silica; multispectral optoacoustic tomography; pHLIP; pancreatic cancer.

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Figures

Figure 1
Figure 1
Construction scheme of V7-CMG-780 particles.
Figure 2
Figure 2
Characterization of nanoparticles. (A) Transmission electron micrograph of particles indicates the 102 nm diameter. (B) Dynamic light scattering indicates size distribution of the particles by intensity with the peak value at 108 nm (C) The optoacoustic spectra of CMG, IR-780 dye, and CMG-780 nanoparticles was obtained using tissue phantoms with MSOT. Both CMG and IR-780 demonstrate single, characteristic peaks appropriate peaks for each particle or dye. The peak for CMG-780 is bimodal, reflective of both CMG and IR-780 components. Because CMG-780 contains photoabsorbing components (gold nanorod and IR-780), the characteristic spectral peak is influenced by both components. The spectral shift of the CMG-780 to include a broader shoulder is likely due to the influence of the absorption of the gold nanorod on IR-780, resulting in slight alteration to the absorption spectra of IR-780. This optoacoustic spectra was used to calibrate the MSOT to only detect foci of contrast which demonstrates bimodal absorption spectra as the MSOT laser and detectors scan through the NIR spectra.
Figure 3
Figure 3
In vitro binding analyses of 10 nM CMG-ICG and V7-CMG-ICG demonstrate acidic pH-targeted delivery of nanoparticle ICG dye cargo at acidic pH. Odyssey infrared imaging (A) and dosimetry analysis (B) demonstrate greatly enhance delivery of cargo by the V7 targeted particle at acidic pH. There is minimal dye delivery at pH 6.5 or 7.4 by CMG. Treatment with V7-CMG-ICG demonstrated 31X greater ICG signal at pH 6.5 compared to pH 7.4 (A&B). Dosimetry studies were confirmed by flow cytometry for cells treated with CMG-ICG (C) and V7-CMG-ICG (D). Cells treated with V7-CMG-ICG demonstrated nearly 25X greater nanoparticle delivery to S2VP10L cells treated in pH 6.5 media (602 mean counts) compared to pH 7.4 media (24.4 mean counts). Untargeted CMG-ICG cargo dye delivery at pH 6.5 (198 mean counts) was nearly 5X greater than that at pH 7.4 (44.8 mean counts). Importantly, nanoparticle uptake was 3X greater at pH 6.5 by V7-CMG-ICG than the untargeted CMG-ICG (602 vs. 198 mean counts).
Figure 4
Figure 4
Drug release assay of gemcitabine loaded CMG particles. The release of gemcitabine from CMG (CMG-Gem) was conducted over 8 hours (shown) and measured up to 96 hours using UV-Vis spectroscopy. Maximal drug release was nearly achieved at less than 1 hour. As the release of gemcitabine did not substantially after the initial 8 hours at any pH including pH 7.4, the first 8 hours are shown. The release curves demonstrate minimal release of gemcitabine from CMG-Gem at pH 7.4 over the course of 96 hours.
Figure 5
Figure 5
Cell viability assays of S2VP10 (A) and MiaPaca2 (B) pancreatic adenocarcinoma cell lines treated with 300nM gemcitabine, V7-CMG empty, or 300nM V7-CMG-Gem for 24 hours. In S2VP10 cells, treatment with V7-CMG-Gem at pH 6.5 results in statistically significant enhanced cell death compared to both pH 6.5 and 6.8 gemcitabine alone (*p=0.0091 and *p=0.0284, respectively). In MiaPaca2 cells, treatment with V7-CMG-Gem significantly increased cell death at both pH 6.5 and 6.8 compared to gemcitabine alone (*p=0.0197 and *p=0.0336, respectively). At pH 7.4, V7-CMG-Gem protects cells from exposure to gemcitabine compared to treatment with gemcitabine alone at pH 7.4 to the cells in both S2VP10 and MiaPaca2 cells (tp=0.9652 and tp=0.9532, respectively). V7-CMG does not increase cell death relative to same pH PBS control at pH 7.4, 6.8, or 6.5 in either cell line (p>0.05).
Figure 6
Figure 6
Multispectral, orthogonal views of S2VP10 and S2013 models injected with V7-CMG-780 particles as observed using MSOT. Overlay images of the spectra for CMG-780, oxy-hemoglobin, and deoxy-hemoglobin demonstrate the vascular supply to the tumor (red), hypoxic tumor environment (blue), and CMG-780 (yellow).
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