Saturday, June 26, 2021

Design Considerations for a Successful Nanoparticle Delivery System

 Nanoparticles (NPs) are thought to have potential as novel intravascular probes for both diagnostic (e.g., imaging) and therapeutic purposes (e.g., drug delivery). 

Critical issues for successful nanoparticle delivery include the ability:

  • To target specific tissues and cell types 
    • Endocytosis (uptake into the cells)
    • Targeting agent (address tags)
  • To escape from the biological particulate filter 
    • Mononuclear Phagocyte System (MPS; clearance of unwanted particulate material)
    • Protection from Clearance by MPS 
      • Main NP research question—how is particulate material recognized and cleared?
In this article, we will cover the above five highlighted areas.  Note that the below topics are parts of the design considerations, but will not discussed here.
  • Reduction in toxicity while maintaining therapeutic effects
  • Greater safety and biocompatibility


Figure 1.  Endocytosis (Created by Mariana Ruiz Villarreal LadyofHats)

Endocytosis—Uptake into the Cells


Nanoparticles enter the cells by endocytosis. Endocytosis is a process of the uptake substances into the cell.  It is a form of active transport which includes:[92]
  • Pinocytosis (cell drinking) 
    • The uptake of small (<0.5 μm) particles into vesicles
  • Phagocytosis (cell eating)
    • The uptake of larger particles (>0.5 μm) by a process involving actin polymerization. 
Both can be receptor mediated. 

Figure 2.  Schematic representation of qdot targeting. (source: [95])
Intravenous delivery of qdots into specific tissues of the mouse. (Upper)
Design of peptide-coated qdots. (Lower)
Qdots were coated with either peptides only or with peptides and PEG.
PEG helps the qdots maintain solubility in aqueous solvents and minimize nonspecific binding.

Targeting Agent (Address Tags)


Biodegradable nanoparticles have been studied extensively for the fabrication of drug delivery systems.  The design considerations include controlling the release of drugs, stabilizing labile molecules (e.g., proteins, peptides, or DNA) from degradation, and site-specific drug targeting.

Nanoparticles (NPs) can be linked to biological molecules that can act as address tags.  Common address tags are:

Address tags can direct NPs to:

  • Specific sites within the body[90]
  • Specific organelles within the cell[95]
  • Follow specifically the movement of individual protein or RNA molecules in living cells[96]

For example, scientists were able to show that (See Figure 1):[91]

ZnS-capped CdSe qdots coated with a lung-targeting peptide accumulate in the lungs of mice after i.v. injection, whereas two other peptides specifically direct qdots to blood vessels or lymphatic vessels in tumors. 
Adding polyethylene glycol (PEG) to the qdot coating prevents nonselective accumulation of qdots in reticuloendothelial tissues.


These targeting agents should ideally be covalently linked to the nanoparticle and should be present in a controlled number per nanoparticle:

  • Multivalent nanoparticles
    • Bearing multiple targeting groups, can cluster receptors, which can activate cellular signaling pathways, and give stronger anchoring
  • Monovalent nanoparticles
    • Bearing a single binding site,[97-99] avoid clustering and so are preferable for tracking the behavior of individual proteins.

Figure 3.  Nanoparticle Uptake: The Phagocyte Problem (Source: [111])

Mononuclear Phagocyte System


Initially, Reticuloendothelial System (RES) denotes a system of specialized cells that effectively clear colloidal vital stains (so called because they stain living cells) from the blood circulation.  
The capture and clearance of unwanted particulate material from blood and lymph were considered to be the major function of the RES. 
As knowledge accumulated, the term RES was regarded as insufficient to describe resident phagocytes and their antecedents.  In 1969, a group of prominent pathologists/immunologists proposed the term Mononuclear Phagocyte System (MPS) as a more accurate term.[100]

The MPS is part of both humoral and cell-mediated immunity.  The trinity of MPS include:
which are distinguished on the basis of their morphology, function, and origin, yet collectively constitute the MPS.

Phagocytes and Nanoparticles


Issues plaguing nanomaterials circulation and targeting in humans can be attributed to:[104-110]
  • Rapid vascular filtration and clearance of therapeutics and diagnostics
  • Induction of host inflammatory responses due to non-specific recognition
  • Uptake of nanoconstructs by macrophages in vivo
Phagocytes are key cellular participants determining important aspects of host exposure to nanomaterials, initiating clearance, biodistribution and the tenuous balance between host tolerance and adverse nanotoxicity.[111] 
Macrophages in particular are believed to be among the first and primary cell types that process nanoparticles, mediating host inflammatory and immunological biological responses. 
These processes occur ubiquitously throughout tissues where nanomaterials are present, including the host mononuclear phagocytic system (MPS) residents in dedicated host filtration organs (i.e., liver, kidney spleen, and lung). 

Nanoparticle delivery vehicles designed to either avoid or specifically harness this host recognition system could improve payload delivery, reduce inflammatory effects and improve imaging and drug efficacy. 

Figure 4.  Adsorbed protein conformation can be affected by different particle surface properties.
Surface curvature, topography, hydrophilic/hydrophobic chemistry and
polymer coating steric barriers on nanoparticle surfaces are shown to
alter amounts and conformations of proteins adsorbed to surfaces. (Source: [111])


Protection from Clearance by MPS


The nanoparticle size and surface properties can be manipulated to avoid rapid clearance by phagocytic cells.  
Nanoparticle association with the host highly evolved mononuclear phagocytic system (MPS) is a function of particle opsonization upon contact with blood and rapid recognition of these opsonins via the MPS.[113,115] 
Surface-adsorbed proteins (opsonins) influence macrophage recognition and uptake of nanoparticles.[112-114]  Additionally, conformational protein rearrangements on nanoparticle surfaces alters protein epitope exposures to phagocytes.[116,117]  Certain epitopes have the capacity to activate macrophages.[113] 

Protein adsorption and subsequent phagocytic uptake appear dependent upon (see Figure 4):[111] 
  • Particle surface curvature[118,119]
  • Particle surface topography[120]
  • Particle surface energies (e.g., hydrophilicity/hydrophobicity)
  • Polymer coating steric barriers on nanoparticle surfaces
For example, hydrophilic polyethylene glycol (PEG) has often been immobilized in many forms and approaches to provide a brush-like steric barrier that is shown to reduce protein adsorption and is correlated with increased blood circulation times for some particles.[121] Dextran layers employed on commercial iron oxide MRI agent nanoparticles (i.e., Feridex™) may serve the same role.[121] 
Surface modification of NPs with polyethylene glycol (PEG) have improved drug delivery properties and prolonged circulation life time with enhanced protection from clearance by mononuclear phagocytic systems.[101-103]

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