Biomedical Engineering Reference
In-Depth Information
of their circulation and biodistribution in the body at the tissue, cellular,
and sub-cellular level. This can be achieved by incorporating immune-
evading moieties and/or affinity molecules, that favor adhesion to either
general or specific biological markers, depending on the degree of selectiv-
ity required. In addition, when carriers are targeted to cellular receptors
involved in endocytic transport or coupled to cell penetrating peptides, or
if they are designed to modify the permeability of cellular barriers, they
also provide delivery to a variety of intracellular compartments, such as the
lysosome, cytosol, and nuclei [53]. When administered in vivo, therapeutic
agents are recognized as foreign substances and rapidly cleared from the
body. Clearance of foreign compounds in the body occurs mainly by the
reticuloendothelial system (RES), and other elements of the immune sys-
tem, as well as by renal filtration. For most applications, rapid clearance
is detrimental as it minimizes the chances of the delivered agent to reach
its targets in the body and accumulate there, at amounts amenable to ren-
der significant efficacy. This can be achieved by coating nanoparticles with
hydrophilic polymers/surfactants or formulating nanoparticles with bio-
degradable copolymers with hydrophilic characteristics, e.g., polyethylene
glycol (PEG), polyethylene oxide, polyoxamer, poloxamine, and polysorbate
80. PEG helps form a hydrophilic brush around NP cargoes and/or their
carriers, minimizing interactions with plasma opsonins, the complement,
professional phagocytes, and lymphocytes which provide specific immunity.
As a consequence, certain physiochemical properties of the cargo are al-
tered, allowing the platform to gain solubility and to remain elusive from
immune detection. This prolongs the circulation in the bloodstream from
a few hours to days, which favors lengthened medicinal effects and less fre-
quent administrations [54]. Another strategy to minimize drug removal
takes advantage of the natural mechanism by which red blood cells in the
body avoid clearance by elements of the innate immune system. This is the
case for CD47, a transmembrane protein that acts like a marker of the “self ”
by binding to its cognate receptor expressed on leukocytes. CD47 inhibits
phagocytosis, in part via regulation of the cytoskeleton and inhibition of en-
gulfing structures. Incorporation of CD47 on drug carrier surfaces reduces
attachment to neutrophils and macrophages, therefore prolonging circula-
tion and inhibiting inflammation [55]. In addition nanocarriers can also
improve control of the drug efficacy upon release in the case of therapeutic
interventions where the administration is local. Localized implantation of
bioactive agents embedded within porous matrices and/or hydrogels ca-
pable of responding to microenvironment properties can provide controlled
release and effects [56]. Encapsulation within these formulations can also
provide sustained release over prolonged periods of time, as oppose to bulk
delivery of a naked therapeutic, which can apply to the release of encapsu-
lated drugs and also bioactive substances produced by cells encapsulated
within these matrices [56].
