Therapeutic Cells via Functional Modification: Influence
of Molecular Properties of Polymer Grafts on In Vivo Circulation,
Clearance, Immunogenicity, and Antigen Protection
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Abstract
Modulation
of cell surface properties via functional modification
is of great interest in cell-based therapies, drug delivery, and in
transfusion. We study the in vivo circulation, immuogenicity, and
mechanism of clearance of hyperbranched polyglycerol (HPG)-modified
red blood cells (RBCs) as a function of molecular properties of HPGs.
The circulation half-life of modified cells can be modulated by controlling
the polymer graft concentration on RBCs; low graft concentrations
(0.25 and 0.5 mM) showed normal circulation as that of control RBCs.
Molecular weight of HPG did not affect the circulation of modified
RBCs. HPG grafting on RBCs reduced CD47 self-protein accessibility
in a graft concentration-dependent fashion. HPG-grafted RBCs are not
immunogenic, as is evident from their similar circulation profile
upon repeated administration in mice and monitoring over 100 days.
Histological examination of the spleen, liver, and kidneys of the
mice injected with modified RBCs revealed distinct differences, such
as elevated iron deposits and an increase in the number of CD45 expressing
cells at high graft concentration of HPGs (1.5 mM); no changes were
seen at low graft concentration. The absence of iron deposits in the
white pulp region of the spleen and its presence in the red pulp region
indicates that the clearance of functional RBCs occurs in the venous
sinuses mechanical filtering system, similar to the clearance of unmodified
senescent RBCs. HPG modification at grafting concentrations that yield
long circulation in mice produced camouflage of a large number of
minor blood group antigens on human RBCs, demonstrating its utility
in chronic transfusion. The normal circulation, nonimmunogenic nature,
and the potential to modulate the circulation time of modified cells
without toxicity make this HPG-based cell surface modification approach
attractive for drug delivery and other cell-based therapies