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 "cell-adhesive MPP" and perform thorough characterization of the nanoparticles, including particle size, drug loading, release kinetics, and diffusion speeds in fresh undiluted human mucus and mouse tracheal mucus.
In Aim 2, we will investigate nanoparticle retention in the lung airways of mice, and perform pharmacokinetic analysis of drugs released from MPP &cell-adhesive MPP as compared to CPan unencapsulated drug.
In Aim 3, we will evaluate the in vivo safety and efficacy of drug-loaded MPP and cell-adhesive MPP compared to CP and unencapsulated drug in an orthotopic mouse SCLC model. GLP manufacture and safety/tox will be performed on the lead product by year 4 or 5 by the Validation Core in close consultation with the FDA.
|Stark, Alejandro; Shin, Dong Jin; Pisanic 2nd, Thomas et al. (2016) A parallelized microfluidic DNA bisulfite conversion module for streamlined methylation analysis. Biomed Microdevices 18:5|
|Attaluri, Anilchandra; Seshadri, Madhav; Mirpour, Sahar et al. (2016) Image-guided thermal therapy with a dual-contrast magnetic nanoparticle formulation: A feasibility study. Int J Hyperthermia 32:543-57|
|Williford, John-Michael; Archang, Maani M; Minn, Il et al. (2016) Critical Length of PEG Grafts on lPEI/DNA Nanoparticles for Efficient in Vivo Delivery. ACS Biomater Sci Eng 2:567-578|
|Mukherjee, Amarnath; Kumar, Binod; Hatano, Koji et al. (2016) Development and Application of a Novel Model System to Study "Active" and "Passive" Tumor Targeting. Mol Cancer Ther 15:2541-2550|
|Yan, Lesan; Li, Xingde (2016) Biodegradable Stimuli-Responsive Polymeric Micelles for Treatment of Malignancy. Curr Pharm Biotechnol 17:227-36|
|Lesniak, Wojciech G; Oskolkov, Nikita; Song, Xiaolei et al. (2016) Salicylic Acid Conjugated Dendrimers Are a Tunable, High Performance CEST MRI NanoPlatform. Nano Lett 16:2248-53|
|Huang, Yu-Ja; Hoffmann, Gwendolyn; Wheeler, Benjamin et al. (2016) Cellular microenvironment modulates the galvanotaxis of brain tumor initiating cells. Sci Rep 6:21583|
|Dawidczyk, Charlene M; Russell, Luisa M; Searson, Peter C (2015) Recommendations for Benchmarking Preclinical Studies of Nanomedicines. Cancer Res 75:4016-20|
|Behnam Azad, Babak; Banerjee, Sangeeta R; Pullambhatla, Mrudula et al. (2015) Evaluation of a PSMA-targeted BNF nanoparticle construct. Nanoscale 7:4432-42|
|Song, Xiaolei; Airan, Raag D; Arifin, Dian R et al. (2015) Label-free in vivo molecular imaging of underglycosylated mucin-1 expression in tumour cells. Nat Commun 6:6719|
Showing the most recent 10 out of 109 publications