Focused ultrasound-enabled delivery of radiolabeled nanoclusters to the pons

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Ye D, Sultan D, Zhang X, Yue Y, Heo GS, Kothapalli SVVN, Luehmann H, Tai Y, Rubin JB, Liu Y, Chen H. (2018)
DOI: 10.1016/j.jconrel.2018.05.039 Link to article in Journal of Controlled Release

Abstract

The goal of this study was to establish the feasibility of integrating focused ultrasound (FUS)-mediated delivery of 64Cu-integrated gold nanoclusters (64Cu-AuNCs) to the pons for in vivo quantification of the nanocluster brain uptake using positron emission tomography (PET) imaging. FUS was targeted at the pons for the blood-brain barrier (BBB) disruption in the presence of systemically injected microbubbles, followed by the intravenous injection of 64Cu-AuNCs. The spatiotemporal distribution of the 64Cu-AuNCs in the brain was quantified using in vivo microPET/CT imaging at different time points post injection. Following PET imaging, the accumulation of radioactivity in the pons was further confirmed using autoradiography and gamma counting, and the gold concentration was quantified using inductively coupled plasma-mass spectrometry (ICP-MS). We found that the noninvasive and localized BBB opening by the FUS can successfully deliver the 64Cu-AuNCs to the pons. We also demonstrated that in vivo real-time microPET/CT imaging was a reliable method for monitoring and quantifying the brain uptake of 64Cu-AuNCs delivered by the FUS. This drug delivery platform that integrates FUS, radiolabeled nanoclusters, and PET imaging provides a new strategy for noninvasive and localized nanoparticle delivery to the pons with concurrent in vivo quantitative imaging to evaluate delivery efficiency. The long-term goal is to apply this drug delivery platform to the treatment of pontine gliomas.

Imaging Melphalan Therapy Response in Preclinical Extramedullary Myeloma with 18F-FDOPA and 18F-FDG PET

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Hathi D, DeLassus E, Achilefu S, McConathy J, Shokeen M. (2018)
DOI: 10.2967/jnumed.118.208744 download PDF from J Nucl Med

Abstract

Multiple myeloma (MM) is a debilitating neoplasm of terminally differentiated plasma B-cells that has resulted in over 13,000 deaths in 2017 alone. Combination therapies involving melphalan, a small molecule DNA alkylating agent, are commonly prescribed to patients with relapsed/refractory MM, which necessitates the stratification of responding patients to minimize toxicities and improve quality of life. Here, we evaluated the use of 18F-FDOPA, a clinically available positron emission tomography (PET) radiotracer with specificity to the L-type amino acid transporter-1 (LAT1), which also mediates melphalan uptake, for imaging melphalan therapy response in a preclinical immunocompetent model of MM.

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Nanotherapeutics for Multiple Myeloma

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Zheleznyak A, Shokeen M, Achilefu S. (2018)
DOI:10.1002/wnan.1526 or download PDF from Wiley Interdiscip Rev Nanomed Nanobiotechnol.

Abstract

Multiple myeloma (MM) is an age‐related hematological malignancy with an estimated 30,000 new cases and 13,000 deaths per year. A disease of antibody‐secreting malignant plasma B‐cells that grow primarily in the bone marrow (BM), MM causes debilitating fractures, anemia, renal failure, and hypercalcemia. In addition to the abnormal genetic profile of MM cells, the permissive BM microenvironment (BMM) supports MM pathogenesis. Read More

Ultrasmall visible-to-near-infrared emitting silver-sulfide quantum dots for cancer detection and imaging

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Tang R, Xu B, Shen D, Sudlow G, Achilefu, S. (2018)
DOI: 10.1117/12.2300944. Conference presentation and PDF in Proc. SPIE 10508, Reporters, Markers, Dyes, Nanoparticles, and Molecular Probes for Biomedical Applications X, 105080G

The large size of many near infrared (NIR) fluorescent nanoparticles prevents rapid extravasation from blood vessels and subsequent diffusion to tumors. This confines in vivo uptake to the peritumoral space and results in high liver retention. We developed a viscosity modulated approach to synthesize ultrasmall silver sulfide quantum dots (QDs) with distinct tunable light emission from visible to near-infrared in spectrum and a QD core diameter between less than 5 nm. Further functionalization of these Read More

Radionuclides transform chemotherapeutics into phototherapeutics for precise treatment of disseminated cancer

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Kotagiri N, Cooper ML, Rettig M, Egbulefu C, Prior J, Cui G, Karmakar P, Zhou M, Yang X, Sudlow G, Marsala L, Chanswangphuwana C, Lu L, Habimana-Griffin L, Shokeen M, Xu X, Weilbaecher K, Tomasson M, Lanza G, DiPersio JF, Achilefu S. (2018)
DOI: 10.1038/s41467-017-02758-9. Link to Free PMC article. Download PDF in Nature Communications. Link to caNanoLab samples.

Abstract

Most cancer patients succumb to disseminated disease because conventional systemic therapies lack spatiotemporal control of their toxic effects in vivo, particularly in a complicated milieu such as bone marrow where progenitor stem cells reside. Here, we demonstrate the treatment of disseminated cancer by photoactivatable drugs using radiopharmaceuticals.  An orthogonal-targeting strategy and a contact-facilitated nanomicelle technology enabled highly selective delivery and co-localization of titanocene and radiolabelled fluorodeoxyglucose in disseminated multiple myeloma cells. Selective ablation of the cancer cells was achieved without significant off-target toxicity to the resident stem cells. Genomic, proteomic and multimodal imaging analyses revealed that the downregulation of CD49d, one of the dimeric protein targets of the nanomicelles, caused therapy resistance in small clusters of cancer cells. Similar treatment of a highly metastatic breast cancer model using human serum albumin-titanocene formulation significantly inhibited cancer growth. This strategy expands the use of phototherapy for treating previously inaccessible metastatic disease.

Local Intratracheal Delivery of Perfluorocarbon Nanoparticles to Lung Cancer Demonstrated with Magnetic Resonance Multimodal Imaging

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Wu L, Wen X, Wang X, Wang C, Sun X, Wang K, Zhang H, Williams T, Stacy AJ, Chen J, Schmieder AH, Lanza GM, Shen B. (2018)
DOI: 10.7150/thno.21466 Link to Free PMC Article in Theranostics

Abstract

Eighty percent of lung cancers originate as subtle premalignant changes in the airway mucosal epithelial layer of bronchi and alveoli, which evolve and penetrate deeper into the parenchyma. Liquid-ventilation, with perfluorocarbons (PFC) was first demonstrated in rodents in 1966 then subsequently applied as lipid-encapsulated PFC emulsions to improve pulmonary function in neonatal infants suffering with respiratory distress syndrome in 1996. Subsequently, PFC nanoparticles (NP) were extensively studied as intravenous (IV) vascular-constrained nanotechnologies for diagnostic imaging and targeted drug delivery applications. Read More

Local Intratracheal Delivery of Perfluorocarbon Nanoparticles to Lung Cancer Demonstrated with Magnetic Resonance Multimodal Imaging

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Wu L, Wen X, Wang X, Wang C, Sun X, Wang K, Zhang H, Williams T, Stacy AJ, Chen J, Schmieder AH, Lanza GM, Shen B. (2018)
DOI: 10.7150/thno.21466 Link to Free PMC article or download PDF in Theranostics.

Abstract

Eighty percent of lung cancers originate as subtle premalignant changes in the airway mucosal epithelial layer of bronchi and alveoli, which evolve and penetrate deeper into the parenchyma. Liquid-ventilation, with perfluorocarbons (PFC) was first demonstrated in rodents in 1966 then subsequently applied as lipid-encapsulated PFC emulsions to improve pulmonary function in neonatal infants suffering with respiratory distress syndrome in 1996. Subsequently, PFC nanoparticles (NP) were extensively studied as intravenous (IV) vascular-constrained nanotechnologies for diagnostic imaging and targeted drug delivery applications.
Methods: This proof-of-concept study compared intratumoral localization of fluorescent paramagnetic (M) PFC NP in the Vx2 rabbit model using proton (1H) and fluorine (19F) magnetic resonance (MR) imaging (3T) following intratracheal (IT) or IV administration. MRI results were corroborated by fluorescence microscopy.

A highly sensitive non-enzymatic glucose sensor based on Cu/Cu2O/CuO ternary composite hollow spheres prepared in a furnace aerosol reactor

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Lin LY, Karakocak BB, Kavadiya S, Soundappan T, Biswas P. (2018)
DOI: https://doi.org/10.1016/j.snb.2017.12.035 download PDF from Sensors and Actuators B: Chemical.

Abstract:

A novel ternary composite, Cu/Cu2O/CuO hollow spheres (HSs), synthesized using an aerosol furnace reactor (FuAR) was investigated for the first time as a non-enzymatic electrochemical biosensor for glucose detection. The composite HSs were synthesized by aerosolizing a mixture of copper nitrate, citric acid, and ammonia through a FuAR. Interestingly, the addition of ammonia played a crucial role in the in-situ formation of hollow Cu/Cu2O/CuO ternary composites.

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Perfusion-based fluorescence imaging method delineates diverse organs and identifies multifocal tumors using generic near-infrared molecular probes

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Miller J, Wang ST, Orukari I, Prior J, Sudlow G, Su X, Liang K, Tang R, Hillman EMC, Weilbaecher KN, Culver JP, Berezin MY, Achilefu S. (2018)
DOI: 10.1002/jbio.201700232 Download PDF in Journal of Biophotonics.

Abstract

Rapid detection of multifocal cancer without the use of complex imaging schemes will improve treatment outcomes. In this study, dynamic fluorescence imaging was used to harness differences in the perfusion kinetics of near‐infrared (NIR) fluorescent dyes to visualize structural characteristics of different tissues. Using the hydrophobic nontumor‐selective NIR dye cypate, and the hydrophilic dye LS288, a high tumor‐to‐background contrast was achieved, allowing the delineation of diverse tissue types while maintaining short imaging times. By clustering tissue types with similar perfusion properties, the dynamic fluorescence imaging method identified secondary tumor locations when only the primary tumor position was known, with a respective sensitivity and specificity of 0.97 and 0.75 for cypate, and 0.85 and 0.81 for LS288. Histological analysis suggests that the vasculature in the connective tissue that directly surrounds the tumor was a major factor for tumor identification through perfusion imaging. Although the hydrophobic dye showed higher specificity than the hydrophilic probe, use of other dyes with different physical and biological properties could further improve the accuracy of the dynamic imaging platform to identify multifocal tumors for potential use in real‐time intraoperative procedures.

Injectable Hydrogels for Localized Chemotherapy and Radiotherapy in Brain Tumors

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Puente P, Fettig N, Luderer MJ, Jin A, Shah S, Muz B, Kapoor V, Goddu SM, Salama NN, Tsien C, Thotala D, Shoghi K, Rogers B, Azab AK. (2018)
DOI: 10.1016/j.xphs.2017.10.042 Download PDF in Journal of Pharmaceutical Sciences.

Abstract

Overall survival of patients with newly diagnosed glioblastoma (GBM) remains dismal at 16 months with state-of-the-art treatment that includes surgical resection, radiation, and chemotherapy. GBM tumors are highly heterogeneous, and mechanisms for overcoming tumor resistance have not yet fully been elucidated. An injectable chitosan hydrogel capable of releasing chemotherapy (temozolomide [TMZ]) while retaining radioactive isotopes agents (iodine, [131I]) was used as a vehicle for localized radiation and chemotherapy, within the surgical cavity. Release from hydrogels loaded with TMZ or 131I was characterized in vitro and in vivo and their efficacy on tumor progression and survival on GBM tumors was also measured. The in vitro release of 131I was negligible over 42 days, whereas the TMZ was completely released over the first 48 h. 131I was completely retained in the tumor bed with negligible distribution in other tissues and that when delivered locally, the chemotherapy accumulated in the tumor at 10-fold higher concentrations than when delivered systemically. We found that the tumors were significantly decreased, and survival was improved in both treatment groups compared to the control group. Novel injectable chemo-radio-hydrogel implants may potentially improve the local control and overall outcome of aggressive, poor prognosis brain tumors.