Self-Assembled Targeted Nanoparticles: Evolution of Technologies and Bench to Bedside Translation

摘要

Nanoparticles (NPs) have become an important tool in many industries including healthcare. The use of NPs for drug delivery and imaging has introduced exciting opportunities for the improvement of disease diagnosis and treatment. Over the past two decades, several first-generation therapeutic NP products have entered the market. Despite the lack of controlled release and molecular targeting properties in these products, they improved the therapeutic benefit of clinically validated drugs by enhancing drug tolerability and/or efficacy. NP-based imaging agents have also improved the sensitivity and specificity of different diagnostic modalities. The introduction of controlled-release properties and targeting ligands toward the development of next-generation NPs should enable the development of safer and more effective therapeutic NPs and facilitate their application in theranostic nanomedicine. Targeted and controlled-release NPs can drastically alter the pharmacological characteristics of their payload, including their pharmacokinetic and, in some cases, their pharmacodynamic properties. As a result, these NPs can improve drug properties beyond what can be achieved through classic medicinal chemistry.Despite their enormous potential, the translation of targeted NPs into clinical development has faced considerable challenges. One significant problem has been the difficulty in developing targeted NPs with optimal biophysicochemical properties while using robust processes that facilitate scale-up and manufacturing. Recently, efforts have focused on developing NPs through self-assembly or high-throughput processes to facilitate the development and screening of NPs with these distinct properties and the subsequent scale-up of their manufacture. We have also undertaken parallel efforts to integrate additional functionality within therapeutic and imaging NPs, including the ability to carry more than one payload, to respond to environmental triggers, and to provide real-time feedback.In addition, novel targeting approaches are being developed to enhance the tissue-, cell-, or subcellular-specific delivery of NPs for a myriad of important diseases. These include the selection of internalizing ligands for enhanced receptor-mediated NP uptake and the development of extracellular targeting ligands for vascular tissue accumulation of NPs. In this Account, we primarily review the evolution of marketed NP technologies. We also recount our efforts in the design and optimization of NPs for medical applications, which formed the foundation for the clinical translation of the first-in-man targeted and controlled-release NPs (BIND-014) for cancer therapy.