Imaging of intranasal drug delivery to the brain.

Intranasal (IN) delivery is a rapidly developing area for therapies with great potential for the treatment of central nervous system (CNS) diseases. Moreover, in vivo imaging is becoming an important part of therapy assessment, both clinically in humans and translationally in animals. IN drug delivery is an alternative to systemic administration that uses the direct anatomic pathway between the olfactory/trigeminal neuroepithelium of the nasal mucosa and the brain. Several drugs have already been approved for IN application, while others are undergoing development and testing. To better understand which imaging modalities are being used to assess IN delivery of therapeutics, we performed a literature search with the key words "Intranasal delivery" and "Imaging" and summarized these findings in the current review. While this review does not attempt to be fully comprehensive, we intend for the examples provided to allow a well-rounded picture of the imaging tools available to assess IN delivery, with an emphasis on the nose-to-brain delivery route. Examples of in vivo imaging, for both humans and animals, include magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), gamma scintigraphy and computed tomography (CT). Additionally, some in vivo optical imaging modalities, including bioluminescence and fluorescence, have been used more in experimental testing in animals. In this review, we introduce each imaging modality, how it is being utilized and outline its strengths and weaknesses, specifically in the context of IN delivery of therapeutics to the brain.

Manganese-porphyrin-enhanced MRI for the detection of cancer cells: A quantitative in vitro investigation with multiple clinical subtypes of breast cancer.

Magnetic resonance imaging (MRI) contrast agents (CAs) are chemical compounds that can enhance image contrast on T1- or T2- weighted MR image. We have previously demonstrated the potential of MnCl2, a manganese-based CA, in cellular imaging of breast cancer using T1-weighted MRI. In this work, we examined the potential of another class of manganese-based CAs, manganese porphyrins (MnPs), for sensitive cellular detection of multiple clinical subtypes of breast cancer using quantitative MRI. Using a clinical 3.0-T MRI scanner, the relaxivities of two MnPs, MnTPPS4 and MnTPPS3NH2, and conventional Gd-DTPA (control) were measured in ultrapure water and their T1 contrast enhancement patterns were characterized in multiple clinical subtypes of breast cancer. The toxicity of the three CAs was evaluated in vitro. Compared to Gd-DTPA, both MnTPPS3NH2 and MnTPPS4 enabled a more sensitive multi-subtype detection of four breast cell lines at doses that posed no cytotoxic effects, with MnTPPS3NH2 producing the greatest positive enhancement. The superior T1 enhancement capabilities of MnPs over Gd-DTPA are statistically significant and are likely due to their greater cellular uptake and relaxivities. The results demonstrate that multiple clinical subtypes of breast cancer can be imaged on a 3.0-T MRI scanner using MnPs as T1 cellular CAs.

Manganese-enhanced MRI of minimally gadolinium-enhancing breast tumors.

PURPOSE: To investigate the potential of manganese (Mn)-enhanced MRI for sensitive detection and delineation of tumors that demonstrate little enhancement on Gd-DTPA. MATERIALS AND METHODS: Eighteen nude rats bearing 1 to 2 cm in diameter orthotopic breast tumors (ZR75 and LM2) were imaged on a 3 Tesla (T) clinical scanner. Gd-DTPA was administered intravenously and MnCl2 subcutaneously, both at 0.05 mmol/kg. T1 -weighted imaging and T1 measurements were performed precontrast, 10 min post-Gd-DTPA, and 24 h post-MnCl2 . Tumors were excised and histologically assessed using H&E (composition and necrosis) and CD34 (vascularity). RESULTS: Most tumors (78%) demonstrated little enhancement (< 20% change in R1 ) on Gd-DTPA. MnCl2 administration achieved greater and more uniform enhancement throughout the tumor mass (i.e., not restricted to the tumor periphery), with R1 changing over 20% in 72% of tumors. MnCl2 -induced R1 changes compared with Gd-induced changes were significantly greater in both ZR75 (P < 0.01) and LM2 tumors (P < 0.05). Histology confirmed very low vascularity in both tumor models, and necrotic areas were well delineated only on Mn-enhanced MRI. CONCLUSION: Mn-enhanced MRI is a promising approach for detection of low-Gd-enhancing tumors.

Manganese-enhanced magnetic resonance imaging for early detection and characterization of breast cancers.

Very early cancer detection is the key to improving cure. Our objective was to investigate manganese (Mn)-enhanced magnetic resonance imaging (MRI) for very early detection and characterization of breast cancers. Eighteen NOD scid gamma mice were inoculated with MCF7, MDA, and LM2 breast cancer cells and imaged periodically on a 3 T scanner beginning on day 6. T1-weighted imaging and T1 measurements were performed before and 24 hours after administering MnCl2. At the last imaging session, Gd-DTPA was administered and tumors were excised for histology (hematoxylin-eosin and CD34 staining). All mice, except for two inoculated with MCF7 cells, developed tumors. Tumors enhanced uniformly on Mn and showed clear borders. Early small tumors (≤ 5 mm3) demonstrated the greatest enhancement with a relative R1 (1/T1) change of 1.57 ± 0.13. R1 increases correlated with tumor size (r  =  -.34, p  =  .04). Differences in R1 increases among the three tumor subtypes were most evident in early tumors. Histology confirmed uniform cancer cell distribution within tumor masses and vasculature in the periphery, which was consistent with rim-like enhancement on Gd-DTPA. Mn-enhanced MRI is a promising approach for detecting very small breast cancers in vivo and may be valuable for very early cancer detection.

Photoacoustic detection and optical spectroscopy of high-intensity focused ultrasound-induced thermal lesions in biologic tissue.

PURPOSE: The aims of this study are: (a) to investigate the capability of photoacoustic (PA) method in detecting high-intensity focused ultrasound (HIFU) treatments in muscle tissues in vitro; and (b) to determine the optical properties of HIFU-treated and native tissues in order to assist in the interpretation of the observed contrast in PA detection of HIFU treatments. METHODS: A single-element, spherically concaved HIFU transducer with a centre frequency of 1 MHz was utilized to create thermal lesions in chicken breast tissues in vitro. To investigate the detectability of HIFU treatments photoacoustically, PA detection was performed at 720 and 845 nm on seven HIFU-treated tissue samples. Within each tissue sample, PA signals were acquired from 22 locations equally divided between two regions of interest within two volumes in tissue - a HIFU-treated volume and an untreated volume. Optical spectroscopy was then carried out on 10 HIFU-treated chicken breast specimens in the wavelength range of 500-900 nm, in 1-nm increments, using a spectrophotometer with an integrating sphere attachment. The authors' optical spectroscopy raw data (total transmittance and diffuse reflectance) were used to obtain the optical absorption and reduced scattering coefficients of HIFU-induced thermal lesions and native tissues by employing the inverse adding-doubling method. The aforementioned interaction coefficients were subsequently used to calculate the effective attenuation coefficient and light penetration depth of HIFU-treated and native tissues in the wavelength range of 500-900 nm. RESULTS: HIFU-treated tissues produced greater PA signals than native tissues at 720 and 845 nm. At 720 nm, the averaged ratio of the peak-to-peak PA signal amplitude of HIFU-treated tissue to that of native tissue was 3.68 ± 0.25 (mean ± standard error of the mean). At 845 nm, the averaged ratio of the peak-to-peak PA signal amplitude of HIFU-treated tissue to that of native tissue was 3.75 ± 0.26 (mean ± standard error of the mean). The authors' spectroscopic investigation has shown that HIFU-treated tissues have a greater optical absorption and reduced scattering coefficients than native tissues in the wavelength range of 500-900 nm. In fact, at 720 and 845 nm, the ratio of the optical absorption coefficient of HIFU-treated tissues to that of native tissues was 1.13 and 1.17, respectively; on the other hand, the ratio of the reduced scattering coefficient of HIFU-treated tissues to that of native tissues was 13.22 and 14.67 at 720 and 845 nm, respectively. Consequently, HIFU-treated tissues have a higher effective attenuation coefficient and a lower light penetration depth than native tissues in the wavelength range 500-900 nm. CONCLUSIONS: Using a PA approach, HIFU-treated tissues interrogated at 720 and 845 nm optical wavelengths can be differentiated from untreated tissues. Based on the authors' spectroscopic investigation, the authors conclude that the observed PA contrast between HIFU-induced thermal lesions and untreated tissue is due, in part, to the increase in the optical absorption coefficient, the reduced scattering coefficient and, therefore, the deposited laser energy fluence in HIFU-treated tissues.