A. Gonsalves, D. Dhamecha, J.U. Menon
University of Rhode Island,
Keywords: biomimetic nanoparticles, cancer drug delivery, lung cancer, combination therapy, PLGA
Summary:Lung cancer is an asymptomatic condition and is hence usually diagnosed at a late stage, necessitating rigorous treatment upon diagnosis. Current first-line of treatment for lung cancer such as cisplatin-based and gemcitabine-based combination treatments have disadvantages like poor response rate, rapid relapse, and severe side effects due to non-specific treatment. To overcome some of the above treatment limitations, drug-containing nanoparticles are now being investigated for inhalational drug delivery to treat lung cancer and other serious lung ailments. The lung, however, has a dynamic environment which is actively involved in eliminating or clearing foreign objects entering the respiratory system. Therefore, this research focuses on the development of a strategy to prevent rapid clearance of nanoparticles from the lung following inhalation, for effective treatment of lung cancer through combination therapy. We developed a novel formulation consisting of a poly lactic-co-glycolic acid nanoparticle (PLGA NP) core and a biomimetic lipid shell made of commercially-available lung surfactant (Infasurf) which contains >90% 1,2-dipalmitoyl-sn-glycero-3-phosphocholine lipid. PLGA NPs were formulated by conventional double emulsion-solvent evaporation method and characterized for its particle size, morphology and stability. Particle size (nm), zeta potential (mV) and polydispersity value of PLGA NPs was found to be 164 ± 2, -41.8 ± 0.8 and 0.098 ± 0.01 respectively whereas transmission electron microscopy (TEM) images clearly show the spherical morphology of the particles (Figure 1A). To coat PLGA NPs with biomimetic lipid surfactant, a standard thin film hydration method was used with minor modifications. Cholesterol was added to stabilise the lipid surfactant shell. The formulated lipid surfactant-coated PLGA NPs (LS-PLGA NPs) had a particle size, zeta potential and polydispersity value of 183 ± 2, -35.7 ± 0.5 and 0.103 ± 0.02 respectively. TEM images show that the LS-PLGA NPs are spherical, less than 200 nm in size and relatively uniformly dispersed (Figure 1B). Stability studies were done under accelerated stability condition, where the nanoparticles were dispersed in deionized water for one week at 25 ± 2°C. These studies showed minimal variation in particle sizes indicating that the PLGA NPs and LS-PLGA NPs are both stable (Figure 2). Drug release studies showed that the PLGA core has a characteristic bi-phasic release that takes place over 3 weeks while the LS shell demonstrated a burst release of encapsulated drug within 2-3 days. Cell viability studies on A549 lung adenocarcinoma cell line following nanoparticle treatment confirmed the cytocompatibility of the formulations (Figure 3). We are currently carrying out a detailed study on the interactions between our formulations and alveolar macrophages and lung cancer cells in vitro. We expect to see low uptake by alveolar macrophages and high uptake by lung cancer cells when treated with the LS-PLGA NP formulations. In vivo studies will also be done to determine the retention and biodistribution of the nanoparticles following inhalation.