Skip to main page content (V体育安卓版)
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site VSports app下载. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely V体育官网. .

. 2015 Sep;33(9):941-51.
doi: 10.1038/nbt.3330.

Principles of nanoparticle design for overcoming biological barriers to drug delivery

Elvin Blanco  1 , Haifa Shen  1   2 , Mauro Ferrari  1   3
Affiliations

Principles of nanoparticle design for overcoming biological barriers to drug delivery

Elvin Blanco et al. Nat Biotechnol. 2015 Sep.

Abstract

Biological barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biological barriers that a particle encounters upon intravenous administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery. VSports手机版.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Framework of sequential biological barriers to nanoparticle drug delivery. Upon intravenous administration, drug-containing nanoparticles encounter a number of sequential obstacles hindering efficacious, site-specific delivery to tumors. Nanoparticles undergo opsonization and subsequent uptake by resident macrophages of the MPS. This results in high accumulation of nanoparticles in organs, such as the spleen and the liver, contributing to nonspecific distribution of nanotherapeutics to healthy organs. Under normal flow conditions in blood vessels, size and geometry have been shown to vastly influence margination dynamics to vascular walls. Spherical particles of small size migrate in a cell-free layer, at a considerable distance from endothelial surfaces, limiting both active targeting strategies and effective accumulation through passive targeting mechanisms (e.g., EPR). Another substantial barrier to nanoparticle accumulation in tumors is the high intratumoral pressure, resulting from interrupted vasculature, the aggressive nature of cellular growth, fibrosis, a dense extracellular matrix and impaired lymphatics. Cellular internalization and endosomal escape prove to be formidable barriers, with size and surface decoration affecting route of internalization (e.g., clathrin versus caveolin) and intracellular fate. Endosomal compartmentalization of internalized nanoparticles, subjected to a low pH environment and enzymes, proves detrimental to cargo, especially to genetic material. Last but not least, upon entry into the cell, drug efflux pumps that confer therapy resistance expel chemotherapeutics from the cell. IFP, interstitial fluid pressure.
Figure 2
Figure 2
Strategies for nanoparticle biomimicry for MPS avoidance and prolonged circulation. Opsonization and sequestration by the MPS proves detrimental to long circulation times of nanoparticles. Several strategies have been used to ‘camouflage’ nanoparticles and prevent protein adsorption. PEGylation represents a classic strategy, wherein grafting of PEG to the surface provides a hydrating layer that hinders formation of a protein corona. In another strategy, CD47 peptides are attached to the surface of nanoparticles, after which macrophages identify the nanoparticle as ‘self’, whereby the nanoparticle avoids phagocytosis. Lastly, coating of nanoparticles with cell membranes extracted from autologous leukocytes and red blood cells (RBC) provides a biomimetic surface shown to substantially prolong in vivo circulation.
Figure 3
Figure 3
Nanoparticle flow, margination and adhesive properties in blood vessels are dependent on particle size and geometry. (a) Unlike spherical nanoparticles, nonspherical particles, such as those possessing discoidal geometries, are more prone to tumbling and oscillatory effects in vasculature, increasing greatly the propensity of nanoparticle–cell wall contact and potential extravasation through fenestrations in vasculature. (b,c) Once in contact with endothelial cells, the small size and surface area of conventional spherical nanoparticles (b) reduce the number of binding and contact points compared with larger, discoidal nanoparticles (c; as well as other nonspherical geometries), which can affect tumor accumulation and active targeting strategies.
Figure 4
Figure 4
Determinants of enhanced permeability of nanoparticles into tumor tissues. The EPR effect is a transport phenomenon characterized primarily by the presence of fenestrations in tumor vasculature that enables passive accumulation of nanoparticles in tumors. (a,i) Normal vasculature typically possesses tight interendothelial junctions that prevent extravasation of particles into tissues. The imbalance of several factors influences the size of fenestrations in tumor vasculature. (a,ii) As an example, VEGF and nitric oxide have been shown to increase the size of gaps in the endothelia. (b,i) Tumors oftentimes possess a dense extracellular matrix that prevents adequate penetration of nanoparticles into the tumor. (b,ii) MMP-2 and MMP-9 degrade the dense collagen matrix comprising the basement membrane. These in turn can be exploited pharmacologically (e.g., by administration of antifibrotics) to enhance the EPR effect for increased nanoparticle accumulation in tumors.
Figure 5
Figure 5
Nanoparticle size, shape and surface charge dictate biodistribution among the different organs including the lungs, liver, spleen and kidneys. (a) Spherical particles, including gold nanoparticles, liposomes and polymeric micelles/nanoparticles can vary in size and display disparate in vivo fates. Large rigid particles with diameters >2,000 nm accumulate readily within the spleen and liver, as well as in the capillaries of the lungs. Nanoparticles in the range of 100–200 nm have been shown to extravasate through vascular fenestrations of tumors (the EPR effect) and escape filtration by liver and spleen. As size increases beyond 150 nm, more and more nanoparticles are entrapped within the liver and spleen. Small-sized nanoparticles (<5 nm) are filtered out by the kidneys. (b) Novel ‘top-down’ and ‘bottom up’ fabrication techniques have enabled the exploration of different geometries of nanoparticles, including cylindrical and discoidal shapes, which have been shown to exhibit pronounced effects on pharmacokinetics and biodistribution. Different nanoparticle shapes exhibit unique flow characteristics that substantially alter circulating lifetimes, cell membrane interactions and macrophage uptake, which in turn affect biodistribution among the different organs. (c) Charge of nanoparticles stemming from distinct surface chemistries influences opsonization, circulation times and interaction with resident macrophages of organs comprising the MPS, with positively charged particles more prone to sequestration by macrophages in the lungs, liver and spleen. Neutral and slightly negatively charged nanoparticles have longer circulation lifetimes and less accumulation in the aforementioned organs of the MPS. In both b and c, the size of the nanoparticles is assumed to range from 20–150 nm. Individual panels represent in vivo fates of nanoparticles, taking into account singular design parameters of size, shape and surface charge independent of one another, and for this reason, respective scales vary from one panel to the next. It is important to note that in vivo biodistribution will undoubtedly vary based on the interplay of several of the above parameters.
See this image and copyright information in PMC

"V体育ios版" References

    1. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3:711–716. - V体育ios版 - PubMed
    1. Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov. 2005;4:145–160. - "VSports在线直播" PubMed
    1. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46:6387–6392. A seminal work on the EPR effect in cancer that essentially laid the foundation for the use of nanotherapeutics, including liposomes and polymer-drug conjugates, as treatment modalities. - PubMed
    1. Maeda H, Nakamura H, Fang J. The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliv Rev. 2013;65:71–79. - PubMed
    1. Azzopardi EA, Ferguson EL, Thomas DW. The enhanced permeability retention effect: a new paradigm for drug targeting in infection. J Antimicrob Chemother. 2013;68:257–274. - PubMed

Publication types

"VSports注册入口" LinkOut - more resources