presentation of T- and B-cell epitopes as well as their in vivo immunogenicity [44].
Towards this goal, two structural analogues bearing a CD8
+ CTL peptide taken from
the sequence of human epidermal growth factor 2 (HER 420–429 ), a transmembrane
receptor-like glycoprotein with tyrosine kynase activity, were synthesized and compared. The results indicated that the position of the lipid moiety not only profoundly
affected the strength of immunotherapeutic efficacy, the uptake, and crosspresentation pathways for GLP in dendritic cells but also modulated the magnitude
of antitumor antibody and CD8
+ T-cell protective immunity. Particularly, after challenge inoculation with cancerous MO5 cells, regression of established tumors was
induced by both conjugates. However, the attachment of the palmitic acid moiety at the
peptide N-terminal afforded the most advantageous results, including (a) stronger and
longer lasting HER 420–429 -specific IFN-γ producing CD8
+ T-cell response, (b) stronger DC maturation together with the production of potent TLR-2-dependent T-cell
activation, and (c) higher inhibition of tumor growth.
These promising results suggest that RAFT scaffolds are suitable tools for engineering other potent synthetic anticancer vaccines with optimized structural variations,
including: (a) controlled multi-and heterotopic antigen presentation on a single cyclic
framework to mimic the heterogeneity of targeted cancers [45, 46], (b) a rigid structure
to provide epitopes with limited conformational freedom towards their optimized and
precise presentation for a cluster-recognizing tumor-specific antibody response, and (c)
an enhanced number of TACAs through real dendritic structures. Towards this goal,
and although immunogenicity of the related architectures have not yet been
investigated, second-generation dendri-RAFTs exhibiting various topologies have
been elaborated to access higher glycosidic valency, density, and spatial presentation
with various levels of rigidity [47]. Hence, new series of molecularly defined
hexadecavalent glycoclusters were synthesized in a controlled manner using robust
and versatile divergent protocols allowing successful oxime attachment. The iterative
strategy thus generated derivatives containing peripheral clustered Gal, Man, Lac, and
T F antigen analogue presented through flexible polylysine dendrons (5, 6, 7, and 8,
respectively) or constrained glycosylated cyclopeptides (9, 10, 11, and 12, respectively)
(Fig. 4). Binding assays were performed with model lectins and three human galectins
[47, 48] that highlighted the beneficial influence of the enhanced multivalency on their
inhibitory potencies and on their ability to protect cells from toxin and/or lectin binding.
It can be safely anticipated that the combination of these structural features with those
described earlier can provide NPs with enhanced anticancer vaccine properties.
3 Glycofullerenes
Fullerenes, the third allotropic form of carbon along with graphite and diamond,
represent a novel class of globular shaped molecules made exclusively of carbon
atoms. This intriguing structure has generated enthusiasm and many research efforts
over the past few years [49]. Hence, the chemical and physical features of C 60 (also
named Buckminsterfullerene), the most representative structure among fullerenes,
have extensively been explored. The intrinsic properties of fullerenes, such as size,
306
N. Kottari et al.
Towards this goal, two structural analogues bearing a CD8
+ CTL peptide taken from
the sequence of human epidermal growth factor 2 (HER 420–429 ), a transmembrane
receptor-like glycoprotein with tyrosine kynase activity, were synthesized and compared. The results indicated that the position of the lipid moiety not only profoundly
affected the strength of immunotherapeutic efficacy, the uptake, and crosspresentation pathways for GLP in dendritic cells but also modulated the magnitude
of antitumor antibody and CD8
+ T-cell protective immunity. Particularly, after challenge inoculation with cancerous MO5 cells, regression of established tumors was
induced by both conjugates. However, the attachment of the palmitic acid moiety at the
peptide N-terminal afforded the most advantageous results, including (a) stronger and
longer lasting HER 420–429 -specific IFN-γ producing CD8
+ T-cell response, (b) stronger DC maturation together with the production of potent TLR-2-dependent T-cell
activation, and (c) higher inhibition of tumor growth.
These promising results suggest that RAFT scaffolds are suitable tools for engineering other potent synthetic anticancer vaccines with optimized structural variations,
including: (a) controlled multi-and heterotopic antigen presentation on a single cyclic
framework to mimic the heterogeneity of targeted cancers [45, 46], (b) a rigid structure
to provide epitopes with limited conformational freedom towards their optimized and
precise presentation for a cluster-recognizing tumor-specific antibody response, and (c)
an enhanced number of TACAs through real dendritic structures. Towards this goal,
and although immunogenicity of the related architectures have not yet been
investigated, second-generation dendri-RAFTs exhibiting various topologies have
been elaborated to access higher glycosidic valency, density, and spatial presentation
with various levels of rigidity [47]. Hence, new series of molecularly defined
hexadecavalent glycoclusters were synthesized in a controlled manner using robust
and versatile divergent protocols allowing successful oxime attachment. The iterative
strategy thus generated derivatives containing peripheral clustered Gal, Man, Lac, and
T F antigen analogue presented through flexible polylysine dendrons (5, 6, 7, and 8,
respectively) or constrained glycosylated cyclopeptides (9, 10, 11, and 12, respectively)
(Fig. 4). Binding assays were performed with model lectins and three human galectins
[47, 48] that highlighted the beneficial influence of the enhanced multivalency on their
inhibitory potencies and on their ability to protect cells from toxin and/or lectin binding.
It can be safely anticipated that the combination of these structural features with those
described earlier can provide NPs with enhanced anticancer vaccine properties.
3 Glycofullerenes
Fullerenes, the third allotropic form of carbon along with graphite and diamond,
represent a novel class of globular shaped molecules made exclusively of carbon
atoms. This intriguing structure has generated enthusiasm and many research efforts
over the past few years [49]. Hence, the chemical and physical features of C 60 (also
named Buckminsterfullerene), the most representative structure among fullerenes,
have extensively been explored. The intrinsic properties of fullerenes, such as size,
306
N. Kottari et al.