Laryngoscopy Grade Improvement and Difficult Airway Resolution in Infants With Robin Sequence Undergoing Mandibular Distraction Osteogenesis: A Multi-Institutional Study.

OBJECTIVE: Mandibular distraction osteogenesis (MDO) aims to relieve tongue-based airway obstruction in Robin Sequence (RS). We investigated direct laryngoscopy grade (DLG) improvement and difficult airway (DA) resolution following MDO. DESIGN: Retrospective cohort analysis. SETTING: Three tertiary care institutions. PATIENTS: Sixty-four infants with RS who underwent a single MDO procedure in their first year of life were identified from January 2010 to January 2019. MAIN OUTCOME MEASURES: The primary outcome was DLG pre- and post-MDO. Secondary outcomes included DA designation, pre- and post-MDO polysomnographic assessment for obstructive sleep apnea (OSA), length of stay, need for gastrostomy, and major/minor adverse events. RESULTS: Median DLG improved from II pre-MDO to I at the time of distractor removal (n = 43, P < .001). No significant change was seen in patients with a third recorded time point (eg, palatoplasty; n = 78, P = .52). Twenty-six (47%) of 55 patients were designated as DA pre-MDO, and 10 (18%) of 55 patients retained the label post-MDO (P < .01). Five (50%) of these 10 patients appeared to be inappropriately retained. Median obstructive apnea-hypopnea index improved from 38.6 (range 31.2-62.8) pre-MDO to 2.9 (range 1-3.9) post-MDO (n = 12; P = .002). CONCLUSION: Mandibular distraction osteogenesis allowed for DLG improvement that was stably maintained as well as functional improvement in OSA, with minimal morbidity. Difficult airway designation persisted in the electronic record of some infants despite clinical resolution.

Tuning Nanoparticle Interactions with Ovarian Cancer through Layer-by-Layer Modification of Surface Chemistry.

Nanoparticle surface chemistry is a fundamental engineering parameter that governs tumor-targeting activity. Electrostatic assembly generates controlled polyelectrolyte complexes through the process of adsorption and charge overcompensation utilizing synthetic polyions and natural biomacromolecules; it can yield films with distinctive hydration, charge, and presentation of functional groups. Here, we used electrostatic layer-by-layer (LbL) assembly to screen 10 different surface chemistries for their ability to preferentially target human ovarian cancer in vitro. Our screen identified that poly-l-aspartate, poly-l-glutamate, and hyaluronate-coated LbL nanoparticles have striking specificity for ovarian cancer, while sulfated poly(ß-cyclodextrin) nanoparticles target noncancerous stromal cells. We validated top candidates for tumor-homing ability with a murine model of metastatic disease and with patient-derived ovarian cancer spheroids. Nanoparticle surface chemistry also influenced subcellular trafficking, indicating strategies to target the cell membrane, caveolae, and perinuclear vesicles. Our results confirm LbL is a powerful tool to systematically engineer nanoparticles and achieve specific targeting.

RNA-Peptide nanoplexes drug DNA damage pathways in high-grade serous ovarian tumors.

DNA damaging chemotherapy is a cornerstone of current front-line treatments for advanced ovarian cancer (OC). Despite the fact that a majority of these patients initially respond to therapy, most will relapse with chemo-resistant disease; therefore, adjuvant treatments that synergize with DNA-damaging chemotherapy could improve treatment outcomes and survival in patients with this deadly disease. Here, we report the development of a nanoscale peptide-nucleic acid complex that facilitates tumor-specific RNA interference therapy to chemosensitize advanced ovarian tumors to frontline platinum/taxane therapy. We found that the nanoplex-mediated silencing of the protein kinase, MK2, profoundly sensitized mouse models of high-grade serous OC to cytotoxic chemotherapy by blocking p38/MK2-dependent cell cycle checkpoint maintenance. Combined RNAi therapy improved overall survival by 37% compared with platinum/taxane chemotherapy alone and decreased metastatic spread to the lungs without observable toxic side effects. These findings suggest (a) that peptide nanoplexes can serve as safe and effective delivery vectors for siRNA and (b) that combined inhibition of MK2 could improve treatment outcomes in patients currently receiving frontline chemotherapy for advanced OC.

Highly scalable, closed-loop synthesis of drug-loaded, layer-by-layer nanoparticles.

Layer-by-layer (LbL) self-assembly is a versatile technique from which multicomponent and stimuli-responsive nanoscale drug carriers can be constructed. Despite the benefits of LbL assembly, the conventional synthetic approach for fabricating LbL nanoparticles requires numerous purification steps that limit scale, yield, efficiency, and potential for clinical translation. In this report, we describe a generalizable method for increasing throughput with LbL assembly by using highly scalable, closed-loop diafiltration to manage intermediate purification steps. This method facilitates highly controlled fabrication of diverse nanoscale LbL formulations smaller than 150 nm composed from solid-polymer, mesoporous silica, and liposomal vesicles. The technique allows for the deposition of a broad range of polyelectrolytes that included native polysaccharides, linear polypeptides, and synthetic polymers. We also explore the cytotoxicity, shelf life and long-term storage of LbL nanoparticles produced using this approach. We find that LbL coated systems can be reliably and rapidly produced: specifically, LbL-modified liposomes could be lyophilized, stored at room temperature, and reconstituted without compromising drug encapsulation or particle stability, thereby facilitating large scale applications. Overall, this report describes an accessible approach that significantly improves the throughput of nanoscale LbL drug-carriers that show low toxicity and are amenable to clinically relevant storage conditions.