(724a) Inhalable Nanocomposites for Targeted Pulmonary Delivery and Applications in Lung Cancer Therapy

Pulmonary delivery facilitates direct, targeted application of bioactive materials to the lungs in a controlled manner and could serve as an effective treatment modality for lung cancer patients.  Certain medical conditions, such as asthma, implement targeted pulmonary delivery as a first line treatment and there is a growing interest in inhalable lung cancer treatment modalities.  Pulmonary administration of anti-cancer agents offers several advantages with the most important being higher local concentrations along with reduced systemic side effects.  Traditionally, inhaled therapies consist of small molecule drugs and excipients; however, targeted pulmonary delivery provides a platform for localizing novel nanoparticles to the lungs through direct, topical application.  Iron oxide (Fe₃O₄) magnetic nanoparticles (MNPs) have generated considerable interest in biomedicine and contain the unique ability to generate heat in the presence of an alternating magnetic field.  The heat generated from these particles can be used to trigger other therapies, increase transport of particles, and induce hyperthermia as a thermal treatment.  Hence, the incorporation of MNPs into dry powder formulations yields the ability to remotely heat these particles after deposition into the lung providing enhanced control over actuating the onset of therapy.  Additionally, hydrogel nanoparticles (HNPs) offer a unique platform for loading drug inside multifunctional particles that possess the ability respond to stimuli such as changes in heat and/or pH.  Here MNPs and HNPs were synthesized, characterized, and incorporated into inhalable powders.  Spray drying was used to formulate an array of inhalable dry powders consisting of varying combinations of MNPs, free cisplatin, and cisplatin-loaded HNPs (CDDP-HNPs) along with D-mannitol as an excipient.  These powders were characterized with a variety of physicochemical techniques, and their aerodynamic performance was determined with the Next Generation Impactor (NGI).  In vitro cell studies with human alveolar adenocarcinoma (A549) and human bronchioalveolar carcinoma (H358) cells were used to examine cytotoxicity of these materials as well as examine any changes in the activity of cisplatin.  Magnetic nanoparticles were successfully synthesized via aqueous co-precipitation of ferric and ferrous salts and dynamic light scattering revealed a hydrodynamic diameter of ~140 nm.  Hydrogel nanoparticles composed of methacrylic acid and poly(ethylene glycol) were successfully synthesized in the presence of surfactant through thermally initiated radical polymerization with ammonium persulfate at 85°C.  The resulting HNPs showed a hydrodynamic diameter of ~100 nm at a pH above the pKa of MAA and large agglomerates (>1 μm) below their pKa.  Resulting HNPs were imbibed with cisplatin at a pH of 7.2 and the loading and release profiles of cisplatin were measured using inductively coupled plasma optical emission spectrometry (ICP-OES).  Cytotoxicity studies revealed that cisplatin retained its activity and that the MNPs and HNPs are relatively non-toxic.  These results illustrate the potential of these materials for inhalable lung cancer treatment modalities and display the versatility of combining nanotechnology with cancer therapy.