(135f) Polymer Nanoparticles That Overcome the Mucus Barrier and Their Efficacy In a Mouse Model of Human Lung Cancer

Inhalation of polymeric nanoparticles holds promise for the localized delivery of diagnostic and therapeutic agents within the lungs. However, the highly viscoelastic and adhesive mucus layer that lines the airways is a critical barrier for conventional nanoparticles. Mucus layers rapidly immobilize standard nanoparticles, which are then removed from the lungs within minutes to hours via mucociliary clearance. As a result, controlled drug release in the lung airways for more than a few hours has been impossible to date, which strongly reduces the effectiveness of local drug therapies for diseases like lung cancer.

We have previously developed diblock ether-anhydride copolymers, composed of polyethylene glycol (PEG) and poly(sebacic anhydride) (PSA), and shown that these polymers are capable of: (i) efficient aerosolization into model lungs; (ii) biodegradation at rates that can be controlled by polymer chemistry, and (iii) sustained delivery of a wide range of drugs for several days. We have also recently shown that coating non-degradable latex nanoparticles with a dense surface layer of low MW PEG allows surprisingly large nanoparticles (up to 500 nm) to rapidly move through human mucus barriers.

Here we report that nanoparticles made using PEG-PSA block copolymers are capable of rapid transport in human mucus, the first such demonstration for a biodegradable polymer. Particles were incubated in native human cervicovaginal mucus and 20 second videos were captured using a high speed camera. Mean-square displacements and effective diffusivities were obtained from particle trajectories obtained through particle tracking software. PEG-PSA particles rapidly diffused through human mucus at rates >100-fold faster than similar-sized uncoated latex nanoparticles, biodegradable PSA nanoparticles, and PLGA nanoparticles.

Next, we show that the PEG-PSA polymer is capable of efficient encapsulation of etoposide, the front line drug for small cell lung cancer. In a single step process, drug was encapsulated up to 40% w/w into PEG-PSA particles. Etoposide was released from PEG-PSA particles in a sustained manner for up to 6 days in vitro, and retained cytotoxic activity in vitro against NCI-H82, a human small cell lung cancer.

Finally, etoposide-loaded particles were administered to nude mice bearing subcutaneous H82 tumor xenografts and tumor volume was measured over time. A single localized injection of etoposide in PEG-PSA particles suppressed tumor growth for over four weeks. In comparison, an equivalent dose of free etoposide injected locally or systemically over 3 days had no effect on tumor growth compared to non-treated control mice. Median survival of mice, as assessed by tumors reaching a volume of 1 cm³, increased from 15 days for local or systemic delivery of free etoposide, to 47 days for mice treated with a single dose of etoposide in PEG-PSA nanoparticles. Studies are currently underway to test the efficacy of this system following inhalation in an orthotopic lung tumor mouse model.