Protein nanoparticles as drug carriers in clinical medicine

Advances in nanomedicine are providing sophisticated functions to precisely control the behavior of nanoscale drugs and diagnostics. Strategies that coopt protease activity as molecular triggers are increasingly important in nanoparticle design, yet the pharmacokinetics of these systems are challenging to understand without a quantitative framework to reveal nonintuitive associations. We describe a multicompartment mathematical model to predict strategies for ultrasensitive detection of cancer using synthetic biomarkers, a class of activity-based probes that amplify cancerderived signals into urine as a noninvasive diagnostic. Using a model formulation made of a PEG core conjugated with protease-cleavable peptides, we explore a vast design space and identify guidelines for increasing sensitivity that depend on critical parameters such as enzyme kinetics, dosage, and probe stability. According to this model, synthetic biomarkers that circulate in stealth but then activate at sites of disease have the theoretical capacity to discriminate tumors as small as 5 mm in diameter-a threshold sensitivity that is otherwise challenging for medical imaging and blood biomarkers to achieve. This model may be adapted to describe the behavior of additional activity-based approaches to allow cross-platform comparisons, and to predict allometric scaling across species.compartmental modeling | activity-based probes | cancer diagnostics | urine biomarkers | nanomedicine T he clinical management of cancer is increasingly dependent on the discovery of new biomarkers and the development of ultrasensitive technologies to detect them at a stage when therapeutic interventions may be effective (1, 2). However, despite their growing importance, biomarkers lack predictive power to impact patient outcomes during the earliest stages of disease. The challenges are multifaceted: Biomarkers are shed from tumors at rates that vary by four orders in magnitude (3), are significantly diluted in blood, and circulate for short periods. Recent mathematical studies showed that tumors may remain undetectable with blood biomarkers for an entire decade following tumorigenesis, reaching 1-2.5 cm in diameter (4, 5). To increase sensitivity, major research areas include the development of ultrasensitive in vitro diagnostic platforms (6-11), as well as methods to increase biomarker production by solid tumors (12, 13). These approaches are designed to measure the quantity, or abundance, of a disease biomarker.In contrast to abundance-based methods, activity-based probes are a class of agents that are administered in prodiagnostic form but produce strong diagnostic signals after enzymatic activation (14, 15). These approaches rely on disease-associated enzymes as catalysts to produce a detection signal, of which proteases are particularly potent because the cleavage of peptide bonds is irreversible, and a single protease can cleave many substrates to amplify signals. However, activity-based probes operate within a narrow time window and are activated by offtarget...

Section: Discussionsupporting

confidence: 64%

Mathematical framework for activity-based cancer biomarkers

Kwong

Dudani

Carrodeguas

et al. 2015

“…Several biomaterials including polymeric nanoparticles and liposomes have been developed for applications in drug delivery, some of which are already available in the market (3)(4)(5). These biomaterials enhance the therapeutic benefit of drugs via sustained release, reduced side-effects, and effective targeting (6).…”

mentioning

confidence: 99%

Red blood cell-mimicking synthetic biomaterial particles

Doshi

Zahr

Bhaskar³

et al. 2009

338

280

Biomaterials form the basis of current and future biomedical technologies. They are routinely used to design therapeutic carriers, such as nanoparticles, for applications in drug delivery. Current strategies for synthesizing drug delivery carriers are based either on discovery of materials or development of fabrication methods. While synthetic carriers have brought upon numerous advances in drug delivery, they fail to match the sophistication exhibited by innate biological entities. In particular, red blood cells (RBCs), the most ubiquitous cell type in the human blood, constitute highly specialized entities with unique shape, size, mechanical flexibility, and material composition, all of which are optimized for extraordinary biological performance. Inspired by this natural example, we synthesized particles that mimic the key structural and functional features of RBCs. Similar to their natural counterparts, RBC-mimicking particles described here possess the ability to carry oxygen and flow through capillaries smaller than their own diameter. Further, they can also encapsulate drugs and imaging agents. These particles provide a paradigm for the design of drug delivery and imaging carriers, because they combine the functionality of natural RBCs with the broad applicability and versatility of synthetic drug delivery particles.biomimetic ͉ drug delivery ͉ erythrocyte ͉ imaging ͉ nanotechnology

“…Organic nanotherapeutics under development today include liposomes with single or multiple bilayered membrane structures built from natural or synthetic lipids (97), dendrimer constructs, albumin-bound formulations (94), and polymeric nanoparticles engineered from biocompatible and biodegradable polymers. A common theme across these systems is that the NP delivery vehicle itself contains the engineering handles for controlling the drug PK and PD.…”

Section: Organic Nanoparticles For Drug Deliverymentioning

confidence: 99%

Nanotechnologies for biomedical science and translational medicine

Heath

2015

In 2000 the United States launched the National Nanotechnology Initiative and, along with it, a well-defined set of goals for nanomedicine. This Perspective looks back at the progress made toward those goals, within the context of the changing landscape in biomedicine that has occurred over the past 15 years, and considers advances that are likely to occur during the next decade. In particular, nanotechnologies for health-related genomics and single-cell biology, inorganic and organic nanoparticles for biomedicine, and wearable nanotechnologies for wellness monitoring are briefly covered.nanotechnology | biotechnology | nanomedicine