Delivery of nanomedicines to extracellular and intracellular compartments of a solid tumor

Abstract

Advances in molecular medicines have led to identification of promising targets on cellular and molecular levels. These targets are located in extracellular and intracellular compartments. The latter include cytosol, nucleus, mitochondrion, Golgi apparatus and endoplasmic reticulum. This report gives an overview on the barriers to delivering nanomedicines to various target sites within a solid tumor, the experimental approaches to overcome such barriers, and the potential utility of nanotechnology.

Fig.1

Processes for nanoparticulate carriers (NP) transport from injection site to target sites. (1) Transport and distribution to tumors and other organs via systemic circulation, including elimination by cells of reticuloendothelial system (RES). (2) Extravasation from tumor vasculature. (3) Interstitial transport to reach individual tumor cells. (4) Endocytosis and intracellular trafficking to sub-cellular organelles (early and late endosomes, lysosomes, Golgi complex, endoplasmic reticulum, cytosol, mitochondria, nucleus).

Fig.2

Determinants of interstitial transport of nanoparticulate carriers (NP) in tumors. (1) Absence of lymphatics reduces the clearance of interstitial fluid and soluble proteins, resulting in high interstitial fluid pressure (IFP), thus reducing the pressure gradient between microvascular pressure (MVP) and IFP and the associated convective transport. (2) Physical barriers due to presence of extracellular matrix proteins (Pr) or high cell density reduce diffusive and convective transport. (3) NP binding to proteins and cell membrane reduces the free concentration available for transport.

Fig.3

Effects of tumor priming on tumor perfusion and dispersion of nanoparticles (NP) in tumor matrix. (A) Effect of tumor priming on tumor perfusion. (B) Effect of tumor priming on NP dispersion in tumor matrix. NP (red fluorescence), perfused vessels (green fluorescence, perfusion marker 3,3-diheptyloxacarbocyanine iodide), NP merged with perfused vessels (yellow). Arrows indicate NP locations. Note the co-localization of NP with perfused vessels in the control group and the greater dispersion of NP away from vessels in the tumor priming group. Bar, 100 μm. (Reproduced from Ref [76])

Fig.4

Clathrin-mediated uptake of nanoparticles (NP) into cells. Passive-targeting NP are absorbed to cell membrane components via nonspecific binding, and active-targeting NP via specific binding to membrane receptors or antigens. The primary internalization of bound NP is the clathrin-mediated endocytosis. The recruited NP-binding cell surface components/receptors form clathrin-coated pits to wrap NP and internalization occurs upon complete wrapping.

Fig.5

Processes for endocytosis, intracellular vesicular formation and degradation. Caveolae-mediated endocytosis may avoid lysosomal degradation. Macropinocytosis is used as an example of clathrin- and caveolae-independent endocytosis.

Fig.6

Intracellular trafficking of nanoparticles (NP). NP can undergo several processes: (A) Transport from early endosome to late endosome and then to lysosomes, and undergoes degradation in lysosomes. (B) Released from early/late endosomes into the cytosol. (C) Transport from early/late endosome to Golgi complex and endoplasmic reticulum, followed by release to the cytosol. After reaching cytosol, NP may enter mitochondria (D) or nucleus (E).