Numerical Simulation of Non-Spherical Submicron Particle Acceleration and Focusing in a Converging–Diverging Micronozzle

Submicron particles transported by a Laval-type micronozzle are widely used in micro- and nano-electromechanical systems for the aerodynamic scheme of particle acceleration and focusing. In this paper, the Euler–Lagrangian method is utilized to numerically study non-spherical submicron particle diffusion in a converging–diverging micronozzle flow field. The influence of particle density and shape factor on the focusing process is discussed. The numerical simulation shows how submicron particle transporting with varying shape factors and particle density results in different particle velocities, trajectories and focusing in a micronozzle flow field. The particle with a larger shape factor or larger density exhibits a stronger aerodynamic focusing effect in a supersonic flow field through the nozzle. In the intersection process, as the particle size increases, the position of the particle trajectory intersection moves towards the throat at first and then it moves towards the nozzle outlet. Moreover, the influence of the thermophoretic force of the submicron particle on the aerodynamic focusing can be ignored. The results will be beneficial in technological applications, such as micro-thrusters, microfabrication and micro cold spray.

Phase 1/2 Study of Topical Submicron Particle Paclitaxel for Cutaneous Metastases of Breast Cancer

Purpose: This Phase 1/2 study evaluated safety and efficacy of a topical submicron particle paclitaxel (SPP) in an anhydrous ointment base (SOR007), primarily in breast cancer patients with cutaneous metastases (CM).Methods: One of 3 concentrations of SOR007 SPP (0.15%, 1.0%, or 2.0%) was applied twice daily over an area of 50 cm2 under a 3+3 phase I design for up to 28 days, with the option for additional 28 days at the highest dose once safety was established. Efficacy was analyzed by lesion measurements and photographs to determine overall response rate (ORR), complete response (CR) and progression free survival by day 28 or 56.Results: Twenty-three subjects were enrolled, 21 with cutaneous metastases of breast cancer (CMOBC). Four subjects received SOR007 0.15%, three at a dose of 1.0% for a median of 28 days (range = 6 to 29 days), and sixteen at 2.0% for a median of 56 days (range = 42 to 60). All doses were well tolerated, and 19 subjects were evaluable for efficacy. At day 28 across all dose levels, 16% (95%CI: 3.4 to 39.6%) of subjects achieved an ORR and another 63.1% (95%CI: 34.9 to 96.8%) had stable disease (SD). The proportion of patients being progression free at 28 days across all treatments was 79% (95:CI: 54 to 94%). Conclusion: Application of SOR007 0.15%, 1.0%, and 2.0% to CM resulted in lesion stabilization or response in most subjects, with reduced lesion pain, and minimal systemic absorption of paclitaxel. A randomized, placebo-controlled trial to confirm these findings is warranted.NCT: #03101358

MCMV Centrifugal Enhancement: A New Spin on an Old Topic

Human cytomegalovirus (HCMV) is a ubiquitous pathogen infecting a majority of people worldwide, with diseases ranging from mild to life-threatening. Its clinical relevance in immunocompromised people and congenital infections have made treatment and vaccine development a top priority. Because of cytomegaloviruses’ species specificity, murine cytomegalovirus (MCMV) models have historically informed and advanced translational CMV therapies. Using the phenomenon of centrifugal enhancement, we explored differences between MCMVs derived in vitro and in vivo. We found centrifugal enhancement on tissue culture-derived virus (TCV) was ~3× greater compared with salivary gland derived virus (SGV). Using novel “flow virometry”, we found that TCV contained a distinct submicron particle composition compared to SGV. Using an inhibitor of exosome production, we show these submicron particles are not extracellular vesicles that contribute to centrifugal enhancement. We examined how these differences in submicron particles potentially contribute to differing centrifugal enhancement phenotypes, as well as broader in vivo vs. in vitro MCMV differences.

Submicron particle docetaxel intratumoral injection in combination with anti-mCTLA-4 into 4T1-Luc orthotopic implants reduces primary tumor and metastatic pulmonary lesions

We describe here characterization of the response of local and metastatic disease and immunomodulation following intratumoral (IT) injection of submicron particle docetaxel (SPD) administered alone or in combination with systemic antibody anti-mCTLA-4 (anti-mCTLA-4) in the metastatic 4T1-Luc2-1A4 (4T1) murine breast cancer model. In-life assessments of treatment tolerance, tumor volume (TV), and metastasis were performed (n = 10 animals/group). At study end, immune cell populations in tumor-site tissues and peripheral blood were analyzed using flow cytometry. Signs of distress typical of this aggressive tumor model occurred across all animals except for the combination treated which were asymptomatic and gained weight. TV at study end was significantly reduced in the combination group versus untreated [43% reduced (p < 0.05)] and vehicle controls [54% reduced (p < 0.0001)]. No evidence of thoracic metastasis was found in 40% of combination group animals and thoracic bioluminescence imaging (BLI) was reduced vs. untreated controls (p < 0.01). Significant elevations (p < 0.05) in CD4 + T, CD4 + helper T, Treg, and NKT cells were found in tumor and blood in SPD or combination treatment compared to controls or anti-mCTLA-4. Combination treatment increased tumor-associated CD8 + T cells (p < 0.01), peripheral B cells (p < 0.01), and tumor associated and circulating dendritic cells (DC) (p < 0.05). Tumor-associated NK cells were significantly increased in SPD ± anti-mCTLA-4 treatments (p < 0.01). Myeloid-derived suppressor cells (MDSC) were reduced in bloods in SPD ± anti-mCTLA-4 groups (p < 0.05). These data demonstrate that both SPD and anti-mCTLA-4 produce local anti-tumor effects as well as reductions in metastasis which are significantly enhanced when administered in combination.