Nanopharmacology - Nanomaterials for Medical Applications - page 317

Various leukocyte cell populations have been implicated in mediating the
anti-tumor effects of anti-CD40 and CpG therapies. 115 Activation of APCs such
as dendritic cells, macrophages, and B cells with TLR9 is known to potentiate
antigen cross-priming, the production of T H 1-skewed cytokines, and the induc-
tion of potent CTL and NK-cell responses. 210 Different studies have suggested
DCs, macrophages, B cells, or combinations thereof as the primary cells respon-
sible for priming potent CTL or NK-cell activity 173,174,211 or T-cell indepen-
dent 212 immune responses but the mechanisms of anti-CD40 tumor inhibition
are currently less well defined. 115 Analysis indicated that DCs and macrophages
had taken up CpG and rhodamine-labeled liposomes following the injection of
combination liposomes which indicated that the liposomal carriers had not pre-
vented them from reaching target APCs 115 and the tumor-draining lymph node
at a higher level than soluble free CpG.
The studies reported by Kwong's group showed that liposome NPs were
effective in carrying both the anti-CD40 and the CpG. 115 Coupling of these
ligands to the liposome surface retains them at a high level in the tumor and the
surrounding tissues following intratumoral injection, allowing presentation to
APCs at the tumor and the tumor-draining lymph node and at the same time,
restricting them from entering systemic circulation or reaching distal lymphoid
organs. 115
7.4.5 NMs for Vaccine Delivery
Recently, the use of <15 nm, water soluble, inorganic NPs as a vaccine-delivery
system for a blood stage malaria vaccine has been reported. 213 Amphiphilic
polymer-coated QD CdSe/ZnS NPs were modified with recombinant proteins,
rMSP1, via surface carboxyl groups to form rMSP1-QDs. In mice injected with
the rMSP1-QDs, the anti-MSP1 antibody responses were found to have 2-3 log
higher titers than those obtained with rMSP1 administered with the conventional
vaccine adjuvants, Montanide ISA51 and CFA ( Figure 7.6 ). 213 In addition, the
immune response (IL-4 and IFN-γ) ( Figure 7.7 ) 213 and induction of parasite
inhibitory antibodies were significantly higher in mice injected with rMSP1-
QDs. Antibody titers using the rMSP1-QDs were not affected by route of injec-
tion such as intraperitoneal (i.p.), intramuscular (i.m.), and subcutaneous (s.c.)
( Figure 7.7 ). 213 The high level of immunogenicity exhibited by the rMSP1-QDs
was achieved without further addition of other adjuvant components.
Bone marrow derived dendritic cells (BMDCs) were shown to efficiently
take up the NPs leading to their activation and the expression/secretion of key
cytokines, suggesting that this may be a mode of action for the enhanced immu-
nogenicity. 213 The RT-PCR quantification of expression of six cytokine genes
in QD-stimulated dendritic cells expressed and secreted markedly high levels
of pro-inflammatory cytokines (IL-6, IL-1a, TNF-a) and chemokines (CCL3,
CCL4, CXCL1) necessary for efficient immune responses, especially toward
a TH1-mediated immunity. 213 The level of chemokines produced showed that