(524f) Lung Targeting with Triggered Release Using Gel Microparticles with Encapsulated Nanoparticles
The American Cancer Society estimated that in 2009, 1,479,000 new cancer cases would be diagnosed in the United States of which 219,000 would be lung and bronchus related. Although only the second most prevalent type of cancer, lung cancer is the most lethal accounting for a projected 159,000 deaths in the United States. National Cancer Institute assesses that results of standard treatment are generally poor with only a 15 percent 5-year survival rate for combined cancer stages. Challenges facing the current chemotherapy drugs include, hydrophobicity of therapeutic agents, excessive systemic toxicity in healthy tissues and inability to specifically target lung tumors. The drug delivery system described herein aims to overcome these challenges by selectively targeting the lung to deliver hydrophobic anti-cancer drugs and enabling triggered drug release.
The design of the human lung affords unique targeting options. Delivery via inhalation of anti-cancer drugs has been explored; however, low absorption and poor lung distribution of drugs has limited this avenue. A more promising approach involves passive targeting of the lung via the venous blood stream. The lung receives the entire venous blood supply from the heart and passes it through the intricate capillary beds on the alveoli. Large particles in the venous blood are thus trapped in these capillary beds. This filtering phenomenon can be used to selectively deliver particles to the lung. Such delivery methods have been safely employed in pulmonary perfusion diagnostic agents; however the use of this novel delivery route for chemotherapeutic drugs has not been appreciated or utilized by the drug delivery community.
The lung-specific delivery system employs both passive and active targeting to intravenously deliver anti-cancer drugs to tumor cells. The first layer of the delivery system is a poly(ethylene glycol) based gel microparticle (GMP) designed to take advantage of the venous lung filtration pathway and passively accumulate in the lungs after intravenous injection into the body. The second layer of the delivery system consists of nanoparticles (NP) embedded in the GMP matrix. The NPs are loaded with anti-cancer drugs and their surfaces can be decorated with ligands to actively target cancer cells once released from the gel matrix.
The size and modulus of the GMPs affect the targeting, accumulation and clearance from the lungs. Once deposited, triggered drug release from the GMP is controlled by two mechanisms. First, the GMP matrix is synthesized with crosslink junctions with tunable degradation kinetics. The construct involve PEG-di-(lactide-co-acrylate) chains where the number of lactide repeats controls the rate of hydrolysis. The hydrolysis of the network controls the release of the NPs from the network. In addition, a second level of release is provided by release of pro-drug conjugates from the NP core. Conjugation of hydrophobic lipids to the active drug via hydrolytically unstable acetal or orthoester linkages enables release of the drug from the NP core. This dual level of control of release enables precise tailoring of drug release in the lung. This dual-delivery system affords the ability to sustain a high concentration of anti-cancer drugs in the lungs while minimizing the systemic exposure and accordingly reducing the side effects.