Pharmaceutical Engineering: Smart Drug Delivery Systems for Targeting the Tumor Microenvironments
The design and development of sophisticated nanoparticles for the targeted delivery of therapeutic drugs to solid tumors holds great promise not only for improving treatment efficacy but also for reducing systemic toxicity. However, the currently low delivery efficiency (about 1-5 % of the injected dose) and the limited tumor penetration of nanoparticles remain two major challenges. Here we report a class of nanoscale superstructures with unusual pH-responsive and size-switching properties for targeting the acidic tumor microenvironment as well as for improved drug tumor penetration. Specifically, the supernanostructurs are constructed by using pegylated polymethacrylate copolymers containing tertiary amine groups (sensitive to pH), and the protonation or deprotonation of these tertiary amines induces a dramatic hydrophobic-hydrophilic transition which drives rapid assembly or disassembly on the nanoscale. For drug loading, this pH-sensitive copolymer is first linked to a polyaminoamine dendrimer (4the generation, MW 14K, with 64 terminal amine groups) via a stable amide bond, which is then conjugated to a platinum prodrug molecules via a succinct anhydride linker (cleavable). Once internalized into tumor cells, the platinum prodrug is converted to the active drug cisplatin by redox chemical reductions involving ascorbic acid (vitamin C) and other reducing agents. These superstructures have a relatively large size of about 80 nm at neutral pH (blood circulation), but once deposited in the acidic tumor microenvironment (pH ~6.5-7.0), they undergo a dramatic and sharp size transition within a very narrow range of acidity (less than 0.1-0.2 pH units), and dissociate rapidly into the dendrimer building blocks (less than 10 nm in diameter). This rapid size-switching feature can not only facilitate nanoparticle extravasation and accumulation via the enhanced permeability and retention (EPR) effect, but also allows faster nanoparticle diffusion and improved tumor penetration. Using both multicellular spheroids and poorly-permeable BxPC-3 pancreatic tumor models, we have systematically studied the pharmacokinetics, organ distribution, tumor penetration, and treatment efficacy for this class of pH-sensitive nanoparticle prodrugs. We have also carried out comparative studies of pH sensitive and insensitive nanostructures with similar size, surface charge, and chemical composition. The results demonstrate demonstrate that the high pH sensitivity and particle size switching are indeed viable strategies for improving drug penetration and therapeutic efficacy. This work was supported by grants from the US National Institutes of Health (U54 CA119338, RC2 CA148265, and R01CA163256).
Dr. Shuming Nie is the Wallace H. Coulter Distinguished Chair Professor in Biomedical Engineering at Emory University and the Georgia Institute of Technology, Director of the Emory-Georgia Tech Cancer Nanotechnology Program, and Founding Dean of the College of Engineering and Applied Sciences of Nanjing University (China). His academic research is in the areas of molecular engineering and nanotechnology, with a focus on bioconjugated nanoparticles for cancer molecular imaging, molecular profiling, and targeted therapy. His major academic achievements include the discovery of colloidal metal nanoparticles that are able to amplify the efficiencies of surface-enhanced Raman scattering (SERS) by 14-15 orders of magnitude, his pioneering work on water-soluble semiconductor quantum dots for biomedical applications, and his breakthrough work in developing multifunctional smart nanoparticles for integrated biomedical imaging and therapy, including image-guided cancer surgery. Professor Nie has published over 300 papers, patents, and book chapters, have delivered more than 500 invited lectures around the world, and have trained over 30 doctoral students and postdoctoral fellows who are now making an impact at top academic institutions and biotech companies. His scholarly work has been cited over 54,000 times with an h-index of 84 (Google Scholar). Professor Nie received his BS degree from Nankai University (Tianjin, China) in 1983, earned his MS and PhD degrees from Northwestern University (Evanston, Illinois, 1984-1990), and did postdoctoral research at the Georgia Institute of Technology and Stanford University (1990-1994).