ABSTRACT
Over the past 50 years, drug delivery breakthroughs have enabled the approval of several important medicines. Often, this path starts with innovation from academic collaborations amongst biologists, chemists, and engineers, followed by the formation of a start-up company driving clinical translation and approval. An early wave featured injectable (i.e., intramuscular, subcutaneous) biodegradable polymeric microspheres to control drug release profiles for peptides and small molecules (e.g., Lupron Depot®, Risperdal Consta®). With these early successes for microspheres, research shifted to exploring systemic delivery by intravenous injection, which required smaller particle sizes and modified surface properties (e.g., PEGylation) to enable long circulation times. These new innovations resulted in the nanoparticle medicines Doxil® and Abraxane®, designed to improve the therapeutic index of cytotoxic cancer agents by decreasing systemic exposure and delivering more drug to tumors. Very recently, the first siRNA lipid nanoparticle medicine, Patisiran (Onpattro®), was approved for treating hereditary transthyretin-mediated amyloidosis. In this inspirational note, we will highlight the technological evolution of drug delivery from micro- to nano-, citing some of the approved medicines demonstrating the significant impact of the drug delivery field in treating many diseases.
Subject(s)
Drug Delivery Systems/methods , Drug Delivery Systems/trends , Clinical Trials as Topic , Drug Approval , Humans , Microtechnology , Nanoparticles , Peptides , Small Molecule LibrariesABSTRACT
Efforts to apply nanotechnology in cancer have focused almost exclusively on the delivery of cytotoxic drugs to improve therapeutic index. There has been little consideration of molecularly targeted agents, in particular kinase inhibitors, which can also present considerable therapeutic index limitations. We describe the development of Accurin polymeric nanoparticles that encapsulate the clinical candidate AZD2811, an Aurora B kinase inhibitor, using an ion pairing approach. Accurins increase biodistribution to tumor sites and provide extended release of encapsulated drug payloads. AZD2811 nanoparticles containing pharmaceutically acceptable organic acids as ion pairing agents displayed continuous drug release for more than 1 week in vitro and a corresponding extended pharmacodynamic reduction of tumor phosphorylated histone H3 levels in vivo for up to 96 hours after a single administration. A specific AZD2811 nanoparticle formulation profile showed accumulation and retention in tumors with minimal impact on bone marrow pathology, and resulted in lower toxicity and increased efficacy in multiple tumor models at half the dose intensity of AZD1152, a water-soluble prodrug of AZD2811. These studies demonstrate that AZD2811 can be formulated in nanoparticles using ion pairing agents to give improved efficacy and tolerability in preclinical models with less frequent dosing. Accurins specifically, and nanotechnology in general, can increase the therapeutic index of molecularly targeted agents, including kinase inhibitors targeting cell cycle and oncogenic signal transduction pathways, which have to date proved toxic in humans.
Subject(s)
Aurora Kinases/antagonists & inhibitors , Nanoparticles/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Animals , Aurora Kinases/metabolism , Bone Marrow/drug effects , Bone Marrow/pathology , Cell Line, Tumor , Drug Liberation , Female , Humans , Male , Mass Spectrometry , Mice , Mice, SCID , Organophosphates/chemistry , Organophosphates/pharmacokinetics , Organophosphates/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Rats, Nude , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
Historically, treatment of patients with cancer using chemotherapeutic agents has been associated with debilitating and systemic toxicities, poor bioavailability, and unfavorable pharmacokinetics. Nanotechnology-based drug delivery systems, on the other hand, can specifically target cancer cells while avoiding their healthy neighbors, avoid rapid clearance from the body, and be administered without toxic solvents. They hold immense potential in addressing all of these issues, which has hampered further development of chemotherapeutics. Furthermore, such drug delivery systems will lead to cancer therapeutic modalities that are not only less toxic to the patient but also significantly more efficacious. In addition to established therapeutic modes of action, nanomaterials are opening up entirely new modalities of cancer therapy, such as photodynamic and hyperthermia treatments. Furthermore, nanoparticle carriers are also capable of addressing several drug delivery problems that could not be effectively solved in the past and include overcoming formulation issues, multidrug-resistance phenomenon, and penetrating cellular barriers that may limit device accessibility to intended targets, such as the blood-brain barrier. The challenges in optimizing design of nanoparticles tailored to specific tumor indications still remain; however, it is clear that nanoscale devices carry a significant promise toward new ways of diagnosing and treating cancer. This review focuses on future prospects of using nanotechnology in cancer applications and discusses practices and methodologies used in the development and translation of nanotechnology-based therapeutics.
