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. 2014 Apr 1;9(2):223-243.
doi: 10.1016/j.nantod.2014.04.008.

Challenges associated with Penetration of Nanoparticles across Cell and Tissue Barriers: A Review of Current Status and Future Prospects

Sutapa Barua  1 , Samir Mitragotri  1
Affiliations

Challenges associated with Penetration of Nanoparticles across Cell and Tissue Barriers: A Review of Current Status and Future Prospects

Sutapa Barua et al. Nano Today. .

Abstract

Nanoparticles (NPs) have emerged as an effective modality for the treatment of various diseases including cancer, cardiovascular and inflammatory diseases. Various forms of NPs including liposomes, polymer particles, micelles, dendrimers, quantum dots, gold NPs and carbon nanotubes have been synthesized and tested for therapeutic applications. One of the greatest challenges that limit the success of NPs is their ability to reach the therapeutic site at necessary doses while minimizing accumulation at undesired sites. The biodistribution of NPs is determined by body's biological barriers that manifest in several distinct ways. For intravascular delivery of NPs, the barrier manifests in the form of: (i) immune clearance in the liver and spleen, (ii) permeation across the endothelium into target tissues, (iii) penetration through the tissue interstitium, (iv) endocytosis in target cells, (v) diffusion through cytoplasm and (vi) eventually entry into the nucleus, if required. Certain applications of NPs also rely on delivery through alternate routes including skin and mucosal membranes of the nose, lungs, intestine and vagina. In these cases, the diffusive resistance of these tissues poses a significant barrier to delivery. This review focuses on the current understanding of penetration of NPs through biological barriers. Emphasis is placed on transport barriers and not immunological barriers. The review also discusses design strategies for overcoming the barrier properties.

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Figures

Figure 1
Figure 1
The major barriers at the (A) endothelium, (B) cellular, (C) skin level that NPs face during their transport to target cells. (A) NPs after intravenous injection circulate throughout the body and accumulate in the tumor passively through enhanced permeation and retention (EPR) effect. (B) Once the NPs are extravasated from the blood to the tumor site, it must bind to the cell membrane following an efficient entry inside the cell (endocytosis). NPs are then localized in late endosomes and nucleus, degraded in lysosomes or recycled back to the plasma membrane. (C) Skin poses the outer layer barrier to the body consisting of three layers: the stratum corneumepidermis and dermis. Figure (C) is taken from Ref. [257].
Figure 2
Figure 2
PTX delivery using polymeric NPs showed greater in vivo vascular retention than untargeted controls [42]. (A) H& E staining of an uninjured aorta and injured aorta with the endothelial layer removed. Schematic images of NPs delivered to (B) an abdominal aorta and (D) a left carotid injury (F) of a mouse model. (C) Fluorescence microscopic images of Alexa 647 dye conjugated PLGA targeting intact endothelial layers and injured aortas. (E) Left carotid arteries showed four fold more NPs than healthy right carotids. (G) NP retention was higher in left carotids than untargeted NPs (Figures from Ref. [42])
Figure 3
Figure 3
NP shape induced targeting of vascular endothelium as observed in synthetic microvascular networks (SMN) in vitro and lung and brain targeting in vivo [77]. (A) and (B) The SMN device incorporates the vascular physiology and shear rates on endothelial cell monolayer. (C) NPs coated with anti-OVA antibody adhere to the vascular channels of SMN when the channels are coated with OVA mimicking the specific interactions between targeted NPs and the vascular channels. (D) In vivo biodistribution of ICAM antibody coated NPs show preferential accumulation of lungs compared to liver. ICAM-coated nanorods show ~2-fold higher lung/liver ratio than ICAM-coated spheres. (E) Tf-coated nanorods accumulate in the brain ~7.5-fold more than Tf-coated spheres. (Figured from Ref. [77]).
Figure 4
Figure 4
NP shape affects their cellular uptake and therapeutic activity of the delivered drugs. (A) Top row: Scanning electron microscopy of spherical, rod and disk shaped particles prepared using film stretching method [69, 76]. Bottom row: Confocal microscopic images of intracellular uptake of spherical, rod and disk shaped particles after herceptin antibody coating [76]. Herceptin-coated rod-shaped NPs were taken up the most by BT-474 breast cancer cells. (B) Cancer cell growth inhibition data using Herceptin coated rods and spheres. Herceptin-coated rods (10 µg/ml) inhibited BT-474 breast cancer cell growth up to 50% using only 1 µg/ml herceptin presented on the particles. (C) Herceptin-coated CPT drug nanorods inhibited BT-474 cell growth synergistically using only 1 µg/ml CPT and 0.16 µg/ml hercpetin. Figures from Ref. [76]).
Figure 5
Figure 5
(A) RBC particle prepared by PRINT technology [97]. (B–E) Fluorescent images of RBCs with varying percent of cross-linkers. (F–H) RBC deformation in flow conditions. (I) Biodistribution of RBCs in mouse. (J–H) RBC particles (red) in lung tissues (purple: nuclei and green: F-actin). Scale bar=50µm (Figures from Ref. [97]).
Figure 6
Figure 6
Tumor homing of particle conjugated lymphocytes [99]. (A) Particle carrying T cells trafficked to EL4-OVA tumors. (B) No difference in the tumor homing potential of particle conjugated T cells versus unmodified OT-1 T cells. (C) Infiltration of NP decorated T cells into EG7-OVA tumors as determined by confocal microscopy. (D) Quantitative analysis particle-decorated and control OT-1 cells in tumors (Figures from Ref. [99]).
Figure 7
Figure 7
Confocal and transmission electron microscopic (TEM) images of intracellular distribution and subcellular targeting of Herceptin-coated camptothecin (CPT) drug nanorods in BT-474 breast cancer cells [75]. (A) Herceptin (red fluorescence)-coated CPT (blue fluorescence) nanorods enter the cells via receptor-mediated endocytosis. (B) Herceptin recycles back to the plasma membrane leaving CPT nanorods inside the cells as observed after 24 h of incubation. CPT nanorods (blue fluorescence) move close to the nucleus as it is seen from the confocal and TEM images. (C) Free Herceptin does not show this behavior sitting inside the cytoplasm even after 24 h. (D) DOX (red fluorescence in the Herceptin-CPT-DOX) enters the nucleus when delivered as Herceptin-CPT-DOX nanorods. (E) Retention of CPT nanorods close to the nucleus has been confirmed by TEM (Figures from Ref. [75])
Figure 8
Figure 8
(A) A cell penetrating peptide, SPACE has been identified using in vitro phage display in porcine skin [199]. (B) Schematic of an SPACE-decorated ethosome for penetration of siRNA into the skin [200]. (Figures from Refs. [199, 200]).
Figure 9
Figure 9
The effect of particle size on transport rates in cervicovaginal mucus [206]. (A) Particle size of 200 and 500 nm showed higher transport rates than 100 nm particles. (B) The average effective diffusivity (Deff) of the particles decreased in mucus. (C) The mean Deff values were greater for 200 and 500 nm particles than 100 nm particles (Figures from Ref.[206]).
Figure 10
Figure 10
(A) Microfluidic channel where tumor (red) and endothelial cells (green) were seeded [255]. (B) and (D) Fibrosarcoma cells (red) invade through the ECM gel (grey) toward the endothelium (green). (C) Endothelial cell cell junctions using a vascular endothelial-cadherin antibody. (E) and (F) Higher magnification images of fibrosarcoma cell migration to tumor cells. (Figures from Ref. [255]).
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