471638 Development and Physicochemical Characterization of Acetalated Dextran Aerosol Particle Systems Designed for Deep Lung Delivery
Acetalated dextran is an acid-sensitive, biodegradable, and biocompatible polymer prepared in a one-step reaction by reversibly modifying dextran with acetal groups. This modification reverses the solubility properties of dextran from hydrophilic to hydrophobic, making it possible to form polymeric particles using standard emulsion or nanoprecipitation techniques. In contrast to other commonly used polymers such as poly (lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), and poly-ϵ-caprolactone (PCL), Ac-Dex exhibits attractive properties suitable for the controlled release of the payloads. By controlling the reaction time during the formation of Ac-Dex, the ratio of cyclic acetal groups with a slower degradation rate to acyclic acetal groups with a faster degradation rate can be adjusted. As a result, the degradation rate of resulting Ac-Dex can be tuned from hours to months to suit various applications. Moreover, the acid-sensitivity of Ac-Dex enable it to degrade faster in lower pH environments such as lysosomes in macrophage or tumor cells, resulting in faster release of drug in such environments, while controlling the release before reaching them. Furthermore, Ac-Dex degrades into neutral by-products, which avoids undesirable changes of the micro-environmental pH in the body. At last, Ac-Dex shows promising potential of targeted delivery, as the dextran chain can be further modified with a variety of functional moieties, which enhances the efficacy of therapeutic delivery to the targeted site.
There is no known comprehensive study on using Ac-Dex as an excipient for dry powder aerosol particulate formulations. In this study, we aimed to develop and characterize pulmonary delivery systems based on spray-dried Ac-Dex particles with capabilities of: (1) delivering particles to the deep lung, (2) targeting particles to a desired location, and (3) releasing therapeutics from particles in controlled rate. Two types of Ac-Dex with rapid (5min) or slow (3h) degradation rate were synthesized. Nanocomposite microparticle (nCmP) and microparticle (MP) system were successfully formulated using both kinds of Ac-Dex as excipients and curcumin (CUR) as model drug. MP were approximately 1.5 μm with wrinkled surfaces, while nCmP also exhibited wrinkled surfaces and disassociated into 200 nm nanoparticles on being dissolved in water. 3h Ac-Dex particles exhibited slower CUR release rates than 5min Ac-Dex particles. Release of CUR from nCmP systems was finished within 24 hours, while the release from the MP system can last for several days. All nCmP and MP system exhibited desirable aerodynamic diameters, which are suitable for deep lung delivery. Overall, the designed Ac-Dex aerosol particle systems have the potential of targeted and effective delivery of therapeutics in to the deep lung.
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