Overcoming in vivo barriers to targeted nanodelivery

Abstract

Nanoparticles have been investigated as promising nanocarriers for delivery of imaging and therapeutic agents for several decades, but have met with limited success. Although enormous progress in the fields of nanotechnology and nanoscience has been achieved, basic discoveries have not yet translated into effective targeted therapies. Nanoparticles can potentially improve the pharmacokinetics and pharmacodynamics of drugs; however, the complexity of in vivo systems imposes multiple barriers that severely inhibit efficiency and have to be overcome to fully exploit the theoretical potential of nanoparticles. Here, we address two major challenges to effective systemic nanodelivery. Both limited penetration across the vascular endothelium and uptake by the reticuloendothelial system (RES) substantially impede effectiveness of nanoparticle delivery into tissues. Although the design of nanoparticles with extended circulation half-life is essential, it is not sufficient for effective penetration of nanoparticles across the formidable barrier formed by the vascular endothelium. Current nanodelivery systems rely on passive transvascular exchange and tissue accumulation. They require high dosages to create large concentration gradients that drive nanoparticles passively across the blood-tissue interface. However, passive accumulation has resulted in only a fractional dosage of nanoparticles penetrating into target tissue. This inevitably diminishes therapeutic efficacy and aggravates potential side effects. Although there are multiple ways to augment passive delivery, active delivery of targeted nanoparticles across the vascular endothelium could significantly increase the therapeutic index and decrease side effects of nanoparticle-based drug delivery systems. Use of active transendothelial transport pathways, such as caveolae, may provide an effective solution to both target and deliver nanoparticles.

Anti-inflammatory Nanoparticle for Prevention of Atherosclerotic Vascular Diseases

“…In the bloodstream, PLGA-NPs of this size can escape from clearances in the kidneys and reticuloendothelial system, which prolongs the blood retention time. This results in effective drug delivery to the target site with increased vascular permeability 42,43) . In addition, inflammatory cells, especially monocytes/macrophages, take up these sized particles, suggesting the potential of PLGA-NPs as a platform for novel anti-inflammatory therapies.…”

Controlled Release Strategies for Bone, Cartilage, and Osteochondral Engineering—Part II: Challenges on the Evolution from Single to Multiple Bioactive Factor Delivery

“…316,317 Some examples of imaging modalities include magnetic nanoparticles for cell labeling and observation by magnetic resonance imaging and quantum dots, carbon nanotubes, or radionuclides for in vivo observation of cells by positron-emission tomography (PET) or single-photonemission computed tomography. [318][319][320] Although PET provides great sensitivity, it lacks spatial resolution.…”

ICAM-1 and Nanomedicine

“…3,4 Considerable research, particularly studies conducted in subcutaneous mouse tumor models, has demonstrated this effect over the last decade, but the magnitude of the extravascular delivery has depended on high intravascular overdosing of agents, prolonging particle systemic half-life (eg, pegylation), and decreasing particle size. 5 Unfortunately, clinical hope for the enhanced permeability and retention effect has waned with recognition that this mechanism is severely curtailed in nonsubcutaneous tumor mouse models, larger mammalian preclinical models, and humans.…”