| The development of nanocarriers for anticancer drugs is an important and active area of research as the low aqueous solubility, poor pharmacokinetics, and detrimental side effects of many chemotherapeutics may be overcome by these nanoscale delivery systems. In addition, the use of pH-sensitive nanocarriers can provide more targeted, controlled delivery. To this end, we have developed a new pH-responsive nanoparticle system for intracellular delivery of anticancer agents. The pH-responsiveness of these nanoparticles occurs due to a hydrophobic to hydrophilic transition occurring to the polymer under mildly acidic conditions. The nanoparticles are stable at pH 7.4 but swell at pH 5, triggering drug release under conditions similar to those in the endosome following endocytosis.;Responsive nanoparticles with an average diameter of 100 nm were synthesized using a miniemulsion polymerization process and were subsequently characterized by dynamic light scattering and electron microscopy, with swelling to a diameter of 1 microm observed at pH 5 but not at pH 7.4. Paclitaxel was successfully encapsulated within the nanoparticles, and release studies showed that the drug was readily released at pH 5 but not at pH 7.4. In addition, the ability of the delivered drug to reach the cytoplasm was observed using confocal microscopy, and the anticancer efficacy of the paclitaxel-loaded nanoparticles was measured using cancer cell lines in vitro. The potency of the paclitaxel-loaded nanoparticles was close to that of free drug, demonstrating that the drug was effectively delivered by the particles.;Following in vitro characterization, in vivo studies demonstrated the ability of the paclitaxel-loaded nanoparticles to prevent establishment of subcutaneous lung cancer and intraperitoneal mesothelioma tumors in mice whereas non-responsive nanoparticles and free drug did not. In addition, the ability of the responsive nanoparticles to migrate through lymph channels to local lymph nodes was demonstrated using near infrared imaging in a large animal model. Continued development of functional nanotechnologies, like the one described here for lung cancer and mesothelioma, will afford new treatment options for the local control of a wide variety of tumors which currently limit patient survival. |
