Aerosol delivery of chemotherapeutics is an attractive strategy for treating lung cancer as it offers high local drug levels and limited systemic exposure. However, many chemotherapeutic agents have poor aqueous solubility, which presents significant formulation challenges. Encapsulation of such drugs in polymeric nanoparticles (NPs) can overcome solubility issues and improve their delivery to tumor cells. In addition, NPs enable sustained drug release and prolonged drug exposure in the deep lungs and limit drug entrapment in the nasopharyngeal region.

In our studies, we investigated NPs formulated from the biodegradable polymer, poly(D,L-lactide-co-glycolide) (PLGA), for inhalation delivery of paclitaxel. NPs were aerosolized using ultrasonic atomization. Aerosol output (20 μg drug/min) and mass median aerodynamic diameter (1.57 μm) of the aerosol droplets were measured using a cascade impactor. Particle deposition studies in mice showed that inhalation delivery of NP-encapsulated paclitaxel results in high drug concentration (14 μg/g) in the lungs following a 33 minute exposure.

Following deposition in the lungs, penetration of NPs within the tumor occurs predominantly through diffusion. The tumor extracellular matrix (ECM) is a dense and tortuous network of biopolymers which significantly hinder effective intratumoral distribution of NPs. The presence of leaky blood vessels in the tumor also leads to the formation of cross-linked fibrin clot in the ECM. We hypothesized that degrading fibrin in the tumor ECM will lead to enhanced intratumoral distribution of NPs.

In order to improve the tumor penetration, we surface functionalized NPs with fibrinolytic enzymes, streptokinase and tissue plasminogen activator (tPA). NPs were characterized for particle size (∼240 nm), zeta potential (∼-20 mV) and drug loading (∼10% w/w). We used a plasmin generation assay to quantify the amount of active enzyme on the surface of NPs. We also compared the diffusion of NPs across fibrin gels using an in vitro transwell assay. We found that enzyme-functionalized NPs diffused through fibrin gels more efficiently than non-functionalized NPs. In vivo studies in tumor bearing mice also demonstrated a greater intratumoral distribution of enzyme-functionalized NPs compared to non-functionalized NPs.

In conclusion, our studies show that inhalation delivery of NP-encapsulated paclitaxel results in high drug concentrations in the lungs. Further, functionalization of NPs with fibrinolytic enzymes can improve their transport through tumor ECM. Future studies will examine the pharmacokinetics and anticancer efficacy of aerosolized enzyme-functionalized NPs in an orthotopic mouse model of lung cancer.

Citation Format: Ameya R. Kirtane, Timothy Wiedmann, Jayanth Panyam. Surface-functionalized nanoparticles for inhalation delivery of chemotherapeutics to lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4466. doi:10.1158/1538-7445.AM2014-4466