Dr. Gail L. Matters Profile

Dr. Gail L. Matters

at Penn State College of Medicine

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Publications (2)

Proceedings Article | 4 March 2019 Paper

Multiphoton and harmonic generation imaging methods enable direct visualization of drug nanoparticle carriers in conjunction with vasculature in fibrotic prostate tumor mouse model

Thomas Abraham, Gary Clawson, Christopher McGovern, Wade Edris, Xiaomeng Tang , James Adair, Gail Matters

Proceedings Volume 10881, 108811T (2019) https://doi.org/10.1117/12.2508833

KEYWORDS: Nanoparticles, Prostate, Tumors, Tissues, Second-harmonic generation, Collagen, 3D image processing, Visualization, Multiphoton microscopy, Harmonic generation

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Prostate cancer (PCA) is the most common cancer and the third most common cause of cancer death in men. Targeted nanoparticles (NPs) that deliver effective doses of chemotherapeutic drugs specifically to PCA could improve chemotherapy efficacy without the toxicities. In the relevant mouse models, the direct visualization of such drug nanoparticles along with the vasculature and fibrillar collagen matrix at submicron resolution are critically important for the accurate measurements of the drug distribution in the tissue matrix. Multiphoton microscopy, which uses ultra-short IR laser pulses as the excitation source, produces multiphoton excitation fluorescence (MPEF) signals from exogenous or endogenous fluorescent proteins and induces specific second harmonic generation (SHG) signals from non-centrosymmetric proteins such as fibrillar collagens. The objective here is to visualize and quantify the 3D distribution of an aptamer conjugated calcium phosphosilicate based drug nanoparticle carriers along with vasculature and tissue matrix in ex vivo thick mouse prostate tumor tissue with submicron resolution. Human prostate tumor xenografts were established in athymic mice by injecting prostate cell line derived from human (PC-3 cells) and were grown for 4 weeks. Near-infrared imaging agent indocyanine green (ICG) loaded calcium phosphosilicate nanoparticles (CPSNPs) including targeted CPSNPs bioconjugated with DNA Aptamer, empty non-ICG containing CPSNPs (Ghost) and Dil (for blood vessel painting) were injected into the tail vein. The spectral unmixing was performed to extract Dil signal from ICG signal using measured emission spectra. The 3D reconstructions and subsequent quantitation showed accumulation of ICG in blood capillaries versus tissue matrix. We here conclude that this multiphoton based multimodal imaging approach can provide spatially resolved 3D images with spectral specificities that are sensitive enough to identity and quantify the distributions of drug nanoparticle carriers in conjunction with vasculature and tissue matrix in prostate tumor with structural precision.

Proceedings Article | 25 April 2018 Paper

Bio-distribution of near infrared imaging agent loaded targeted drug nanoparticle carriers in highly fibrotic pancreatic tumor determined using multiphoton and harmonic generation imaging

Thomas Abraham, Gary Clawson, Samuel Linton, Christopher McGovern, Xiaomeng Tang , James Adair, Gail Matters

Proceedings Volume 10497, 1049729 (2018) https://doi.org/10.1117/12.2300517

KEYWORDS: Tumors, Nanoparticles, Second-harmonic generation, Multiphoton microscopy, Harmonic generation, Tissues, 3D image processing, Near infrared, Signal detection, Luminescence

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Pancreatic ductal adenocarcinoma (PDAC) tumors are highly fibrotic and poorly vascularized, making systemic delivery of standard chemotherapies ineffective. Targeted nanoparticles that deliver effective doses of chemotherapeutic drugs specifically to PDACs could improve chemotherapy efficacy without the toxicities. Multiphoton microscopy, which uses ultra-short femto-second laser pulses as the excitation source, is efficient in multiphoton excitation fluorescence (MPEF) of endogenous or exogenous fluorescent macromolecular systems and the induction of highly specific second harmonic generation (SHG) signals from non-centrosymmetric macromolecules such as fibrillar collagens. Much of the traditional histological and chemical procedures associated with conventional microscopy methods, which may alter the native structure of tissue samples, can be circumvented to generate spatially and spectrally accurate 3D morphological and fine structural information. Orthotopic PDAC xenografts were established by injecting epithelioid carcinoma cell line derived from human pancreas (PANC-1 cells) into the pancreas of athymic male nude mice and were grown for 4 weeks. Near-infrared imaging agent indocyanine green (ICG) loaded calcium phosphosilicate nanoparticles (CPSNPs) including targeted CPSNPs bioconjugated with DNA Aptamer (AP1153), non-targeted CPSNPs (with no aptamer bioconjugation) and empty non-ICG containing CPSNPs were injected into the tail vein (n=4 mice/group). At 18 hours post-injection, mice were sedated and whole animal imaging was performed. To assess cellular uptake in ex vivo, whole tumor cross-sections were then imaged to spatially and spectrally localize ICG loaded nanoparticles relative to fibrotic regions (fibrillar collagen) of the tumor using MPEF and SHG imaging. Ex vivo imaging of cross-sections of whole tumors showed that cellular uptake of the targeted CPSNPs was clearly enhanced compared to untargeted CPSNPs and the 3D reconstructions showed accumulation of CPSNPs in tumor cells within the surrounding fibrotic stroma. We here conclude that multiphoton based multi-dimensional and minimally invasive imaging modalities provide spatially resolved 3D images with spectral specificities, that are sensitive enough to detect near-infrared imaging agents and to identity the bio-distributions of targeted versus untargeted drug nanoparticles in pancreatic tumor tissues.

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