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Review
. 2012 Jun;14(2):282-95.
doi: 10.1208/s12248-012-9339-4. Epub 2012 Mar 10.

Challenges in development of nanoparticle-based therapeutics

Neil Desai  1
Affiliations
Review

Challenges in development of nanoparticle-based therapeutics

Neil Desai. AAPS J. 2012 Jun.

Abstract

In recent years, nanotechnology has been increasingly applied to the area of drug development. Nanoparticle-based therapeutics can confer the ability to overcome biological barriers, effectively deliver hydrophobic drugs and biologics, and preferentially target sites of disease. However, despite these potential advantages, only a relatively small number of nanoparticle-based medicines have been approved for clinical use, with numerous challenges and hurdles at different stages of development. The complexity of nanoparticles as multi-component three dimensional constructs requires careful design and engineering, detailed orthogonal analysis methods, and reproducible scale-up and manufacturing process to achieve a consistent product with the intended physicochemical characteristics, biological behaviors, and pharmacological profiles. The safety and efficacy of nanomedicines can be influenced by minor variations in multiple parameters and need to be carefully examined in preclinical and clinical studies, particularly in context of the biodistribution, targeting to intended sites, and potential immune toxicities. Overall, nanomedicines may present additional development and regulatory considerations compared with conventional medicines, and while there is generally a lack of regulatory standards in the examination of nanoparticle-based medicines as a unique category of therapeutic agents, efforts are being made in this direction. This review summarizes challenges likely to be encountered during the development and approval of nanoparticle-based therapeutics, and discusses potential strategies for drug developers and regulatory agencies to accelerate the growth of this important field.

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Figures

Fig. 1
Fig. 1
Enhanced drug delivery to solid tumors using nanoparticles or macromolecules (8). A Passive delivery (EPR). After IV injection, nanoparticles accumulate in tumors through leaky and permeable tumor vasculature and impaired lymphatic system. B EPR + targeted delivery. “Targeted” nanoparticles or macromolecules bind to cancer cell receptors resulting in potentially improved drug delivery. (Adapted from Nanomedicine, June 2010, vol. 5, no. 4, pp 597–615 with permission of Future Medicine Ltd.)
Fig. 2
Fig. 2
Abraxane (nab-paclitaxel) schematic
Fig. 3
Fig. 3
nab-paclitaxel (ABI-007) transcytosis across endothelial cells as an assay demonstrating “biological function” or transport due to albumin (22). Transcytosis of paclitaxel across human umbilical vascular endothelial cells was significantly enhanced in nab-paclitaxel compared with Cremophor-based paclitaxel (Taxol). The enhanced transcytosis of nab-paclitaxel was inhibited by β-methyl cyclodextrin (BMC), a known inhibitor of the gp60/caveolar transport
Fig. 4
Fig. 4
Cryo TEM image of nab-paclitaxel showing spherical nanoparticle
Fig. 5
Fig. 5
Undesirable precipitation and instability seen with an attempted albumin-paclitaxel formulation modeled as a copy for nab-paclitaxel. Reconstituted suspensions in saline were monitored for 24 h a 40°C. No precipitation was seen with nab-paclitaxel. a Image for the copied product at magnification of ×400 showing large visible particles; b higher magnification image of copied product at ×1,000 clearly shows needle-shaped crystals of paclitaxel
See this image and copyright information in PMC

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