Review pubs.acs.org/molecularpharmaceutics
Theranostics: Are We There Yet? Sonke Svenson* Drug Delivery Solutions LLC, 16 Temple Street, Arlington, Massachusetts 02476, United States ABSTRACT: The U.S. National Institutes of Health through the National Cancer Institute (NCI) have been charged with the goal of eliminating death and suffering from cancer by the year 2015. In order to achieve this very ambitious goal, the development of novel nanotechnology-based devices and therapeutics that are capable of one or more clinically important functions is envisioned. There is great hope and expectation in the development of theranostic nanocarriers, which combine diagnostic and therapeutic agents in one entity. Main delivery approaches include prodrugs, liposomes, polymersomes, and polymeric micelles and nanoparticles. Diagnostic and therapeutic agents are physically entrapped or conjugated to the nanocarriers, or they are conjugated to carefully designed polymers which subsequently form nanocarriers. This focus discusses pros and cons of the different theranostic approaches and tries to answer the question which approach has the highest probability to translate into the clinic and benefit patients. Carefully designed polymers, conjugated with diagnostic and therapeutic agents, that either self-assemble or can be processed to form nanocarriers offer clear advantages over random physical entrapment or conjugation of these agents to existing nanocarriers. These polymers can optionally be fitted with terminal stabilizing or anchoring functionalities and a targeting ligand. However, the need for nanocarriers that are subjected to the enhanced permeability and retention (EPR) effect to carry ligands for active targeting still needs to be demonstrated. Thirty-seven of the 41 nanocarrier-based formulations that are on the market or are under investigation at different levels of clinical development rely on passive targeting. The answer to the title question, not surprisingly, can only be no, but very promising approaches are being developed that have the potential to translate into the clinic and meet regulatory requirements. KEYWORDS: theranostic nanocarriers, liposomes, polymersomes, polymeric micelles, polymeric nanoparticles, diagnostic and therapeutic agents, functionalized polymers, nanomedicine
1. INTRODUCTION The U.S. National Institutes of Health through the National Cancer Institute (NCI) have been charged with the goal of eliminating death and suffering from cancer by the year 2015. In order to achieve this very ambitious goal, the development of novel nanotechnology-based devices and therapeutics that are capable of one or more clinically important functions, including detecting cancer at its earliest stages, pinpointing its location within the body, delivering anticancer drugs specifically to malignant cells, and determining if these drugs are killing malignant cells, is envisioned. The NCI Alliance for Nanotechnology in Cancer was approved in July 2004 and provided with US$145 million for phase I (2005−2010). The alliance identified six major challenge areas, including “Multifunctional Therapeutics”, i.e., nanoscale devices that integrate diagnostic and therapeutic functions, targeting properties, and control of the spatial and temporal release of therapeutic agents while monitoring the effectiveness of these agents.1 The scientific strategy for phase II (2010−2015) of the program was formulated based on the lessons learned from phase I, the evolving strategy of the National Nanotechnology Initiative (NNI), and the input of the extramural community. Phase II of the program, funded with approximately US$30 million per © 2013 American Chemical Society
year, promotes early diagnosis and improved monitoring of therapeutic efficacy.2 This combination of therapy and diagnostics in a single treatment is often referred to as “multifunctional” or, increasingly, as “theranostic”, a term originally used to describe the two-step process of diagnostic therapy for individual patients, namely, first, to test patients for possible reaction to a new medication and, second, to tailor their personalized treatment based on these test results.3 At this still early stage of development of the field both terms, multifunctional and theranostic (sometimes also called theragnostic) are often used interchangeably with no clear definition of potential differences. One should also note that multifunctional and theranostic nanocarriers often contain a targeting ligand as a third component of the particle composition. Special Issue: Theranostic Nanomedicine with Functional Nanoarchitecture Received: Revised: Accepted: Published: 848
November 9, 2012 January 18, 2013 January 22, 2013 February 4, 2013 dx.doi.org/10.1021/mp300644n | Mol. Pharmaceutics 2013, 10, 848−856
Molecular Pharmaceutics
Review
combination therapy.4−8 Nanocarriers are an ideal platform for theranostics because particles with sizes below 100 nm are able to take full advantage of the irregularly dilated and leaky tumor blood vessels with pore sizes in excess of 100 nm and extravasate into tumor tissues. Together with the reduced lymphatic drainage of tumor tissues, this enhanced permeability and retention (EPR) effect leads to tumor accumulation of nanocarriers. At the same time, nanocarriers larger than 10 nm in size can avoid first pass renal clearance (threshold of 8−10 nm), leading to extended circulation times, and also avoid extravasation from intact blood vessels (pore size
