Late-stage diagnosis of lung cancer occurs ~95% of the time due to late manifestation of its symptoms, necessitating rigorous treatment following diagnosis. Existing treatment methods are limited by lack of specificity, systemic toxicity, temporary remission, and radio-resistance in lung cancer cells. In this research, we have developed a folate receptor-targeting multifunctional dual drug-loaded nanoparticle (MDNP) containing a poly(N-isopropylacrylamide)-carboxymethyl chitosan shell and poly lactic-co-glycolic acid (PLGA) core for enhancing localized chemo-radiotherapy to effectively treat lung cancers. The formulation provided controlled releases of the encapsulated therapeutic compounds, NU7441 - a potent radiosensitizer, and gemcitabine - an FDA approved chemotherapeutic drug for lung cancer chemo-radiotherapy. The MDNPs showed biphasic NU7441 release and pH-dependent release of gemcitabine. These nanoparticles also demonstrated good stability, excellent hemocompatibility, outstanding in vitro cytocompatibility with alveolar Type I cells, and dose-dependent caveolae-mediated in vitro uptake by lung cancer cells. In addition, they could be encapsulated with superparamagnetic iron oxide (SPIO) nanoparticles and visualized by MRI in vivo. Preliminary in vivo results demonstrated the low toxicity of these particles and their use in chemo-radiotherapy to effectively reduce lung tumors. These results indicate that MDNPs can potentially be used as nano-vehicles to provide simultaneous chemotherapy and radiation sensitization for lung cancer treatment.

Traumatic brain injury (TBI) is known to alter the structure and function of the blood–brain barrier (BBB). Blunt force or explosive blast impacting the brain can cause neurological sequelae through the mechanisms that remain yet to be fully elucidated. For example, shockwaves propagating through the brain have been shown to create a mechanical trauma that may disrupt the BBB. Indeed, using tissue engineering approaches, the shockwave-induced mechanical injury has been shown to modulate the organization and permeability of the endothelium tight junctions. Because an injury to the brain endothelium typically induces a high expression of E-selectin, we postulated that upregulation of this protein after an injury can be exploited for diagnosis and potential therapy through targeted nanodelivery to the injured brain endothelium. To test this hypothesis, we engineered poly­(lactic-co-glycolic acid) (PLGA) nanoparticles to encapsulate therapeutic nonbiologics and decorated them with ligands to specifically target the E-selectin. A high level of the conjugated nanoparticles was found inside the injured cells. Repair of the injury site was then quantitatively measured and analyzed. To summarize, exploiting the tunable properties of PLGA, a targeted drug delivery strategy has been developed and validated, which combines the specificity of ligand/receptor interaction with therapeutic reagents. Such a strategy could be used to provide a potential theragnostic approach for the treatment of modulated brain endothelium associated with TBI.

Nanoparticles (NPs) can be used to locally deliver anti-restenosis drugs when they are infused directly to the injured arteries after intervention procedures such as angioplasty. However, the efficacy of transferring NPs via infusion to the arterial wall is limited, at least partially, due to poor NP retention on the inner artery wall. To improve NP retention, angioplasty balloons coated with drug-loaded NPs were fabricated via either layer-by-layer (LbL) electrostatic coating or acrylicbased hydrogel (AAH) coating techniques. Three types of NPs, namely poly (lactide-co-glycolide) (PLGA), biodegradable photo-luminescent PLGA and urethane doped polyester were studied. The transfer efficacy of NPs from various coatings to the arterial wall were further evaluated to find the optimal coating conditions. The ex vivo NP transfer studies showed significantly more NPs being transferred to the rat arterial wall after the angioplasty procedure by the AAH coating (95% transfer efficiency) compared to that of the LbL technique (60%) and dip coating (20%) under flow conditions (10 dyn/cm 2 ). Our results suggest that the AAH coating of drug-loaded NPs on the angioplasty balloon could potentially provide superior retention of drug-loaded NPs onto the arterial wall for a better local delivery of drug-loaded NPs to effectively treat arterial diseases.

Sufficient and sustained anti-thrombogenicity is essential for blood-contacting materials, because blood coagulation and thrombosis caused by platelet adhesion and activation on material surfaces may lead to functional failure and even fatal outcomes. Covalently conjugating antithrombogenic moieties into polymer, instead of surface modifying or blending, can maintain the anti-thrombogenicity of polymer at a high level over a time range. In this study, series of randomly crosslinked, elastic, biodegradable polyurethanes (PU-DPA) were synthesized through a one-pot and one-step method from polycaprolactone (PCL) diol, hexamethylene diisocyanate (HDI) and anti-thrombogenic drug, dipyridamole (DPA). The mechanical properties, hydrophilicity, in vitro degradation, and anti-thrombogenicity of the resultant PU-DPA polymers can be tuned by altering the incorporated DPA amount. The surface and bulk hydrophilicity of the polyurethanes decreased with increasing hydrophobic DPA amount. All PU-DPA polymers exhibited strong mechanical properties and good elasticity. The degradation rates of the PU-DPAs decreased with increasing DPA content in both PBS and lipase/PBS solutions. Covalently incorporating DPA into the polyurethane significantly reduced the platelet adhesion and activation compared to the polyurethane without DPA, and also can achieve sustained anti-thrombogenicity. The PU-DPA films also supported the growth of human umbilical vein endothelial cells. The attractive mechanical properties, blood compatibility, and cell compatibility of this anti-thrombogenic biodegradable polyurethane indicate that it has a great potential to be utilized for blood-contacting devices, and cardiovascular tissue repair and regeneration.