Inhalation of chemotherapeutics has shown significant promise in humans in enhancing lung cancer response rates while reducing systemic toxicity. We h3^othesize that the efficacy and safety of inhaled chemo will be improved by an inhalable prolonged delivery strategy, since free drug is rapidly cleared from the airways by systemic absorption combined with mucus clearance mechanisms. Key to the potential of this effort is the recent development ofa mucus-penetrating nanoparticle (MPP) platform technology capable of providing delivery of controlled concentrations of drug locally to the lung airways over more sustained periods than previously possible viith conventional nanotechnologies. While conventional nanoparticles (CP) are easily immobilized in the outermost gel layer of mucus that is cleared rapidly from the lung by ciliary action, we discovered that particles coated with non-mucoadhesive polymers rapidly penetrate human mucus barriers. By penetrating the surface mucus layer, we hypothesize that MPP will;(1) avoid rapid elimination from the lung airways, (ii) provide prolonged delivery of chemotherapeutics locally and, thereby, (iii) significantly improve drug efficacy against SCLC, (iv) minimize systemic toxicity, and (v) provide enhanced efficacy when combined with systemic chemo regimens, where the systemic dose required may potentially be reduced. We will prepare biodegradable MPP loaded with frontline chemotherapeutic agents for SCLC, and evaluate them against unencapsulated drug and drug loaded in CP that are identical to the MPP, excluding the non-mucoadhesive coatings.
In Aim 1, we will formulate MPP and

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA151838-04
Application #
8545552
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
2013-09-13
Project End
2015-07-31
Budget Start
2013-09-13
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$231,339
Indirect Cost
$105,001
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Song, Xiaolei; Yang, Xing; Ray Banerjee, Sangeeta et al. (2015) Anthranilic acid analogs as diamagnetic CEST MRI contrast agents that feature an intramolecular-bond shifted hydrogen. Contrast Media Mol Imaging 10:74-80
Srivastava, Amit K; Bulte, Jeff W M (2014) Seeing stem cells at work in vivo. Stem Cell Rev 10:127-44
Nimmagadda, Sridhar; Pullambhatla, Mrudula; Lisok, Ala et al. (2014) Imaging Axl expression in pancreatic and prostate cancer xenografts. Biochem Biophys Res Commun 443:635-40
Li, Yang; Foss, Catherine A; Pomper, Martin G et al. (2014) Imaging denatured collagen strands in vivo and ex vivo via photo-triggered hybridization of caged collagen mimetic peptides. J Vis Exp :e51052
Bulte, Jeff W M; Schmieder, Anne H; Keupp, Jochen et al. (2014) MR cholangiography demonstrates unsuspected rapid biliary clearance of nanoparticles in rodents: implications for clinical translation. Nanomedicine 10:1385-8
Bhatnagar, Akrita; Wang, Yuchuan; Mease, Ronnie C et al. (2014) AEG-1 promoter-mediated imaging of prostate cancer. Cancer Res 74:5772-81
Das, Samarjit; Bedja, Djahida; Campbell, Nathaniel et al. (2014) miR-181c regulates the mitochondrial genome, bioenergetics, and propensity for heart failure in vivo. PLoS One 9:e96820
Williford, John-Michael; Wu, Juan; Ren, Yong et al. (2014) Recent advances in nanoparticle-mediated siRNA delivery. Annu Rev Biomed Eng 16:347-70
Shallal, Hassan M; Minn, Il; Banerjee, Sangeeta R et al. (2014) Heterobivalent agents targeting PSMA and integrin-?v?3. Bioconjug Chem 25:393-405
Yang, Xing; Yadav, Nirbhay N; Song, Xiaolei et al. (2014) Tuning phenols with Intra-Molecular bond Shifted HYdrogens (IM-SHY) as diaCEST MRI contrast agents. Chemistry 20:15824-32

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