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162 I. F. Uchegbu
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Chapter 8
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Porous Si-Based Nanosystems
for Immunotherapy Applications
Jiachen Li, Gabriela Corrêa Carvalho, Marlus Chorilli,
and Hélder A. Santos
8.1 Immunotherapy
Immunotherapy refers to the treatment methods based on utilizing the immune
system or modulating the immune response to fight the diseases (Waldmann
2003). The typical early milestones in immunotherapy were the discovery of cowpox
immunization’s prevention to smallpox infection by Edward Jenner (1749–1823)
(Riedel 2005), the invention of the rabies vaccine by Louis Pasteur (1822–1895)
(Dubos 1951), showing that early immunotherapy was mainly used for the antiviral
J. Li
Department of Biomaterials and Biomedical Technology, The Personalized Medicine Research
Institute (PRECISION), University Medical Center Groningen (UMCG), University of
Groningen, Groningen, The Netherlands
G. C. Carvalho
Department of Biomaterials and Biomedical Technology, The Personalized Medicine Research
Institute (PRECISION), University Medical Center Groningen (UMCG), University of
Groningen, Groningen, The Netherlands
Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State
University (UNESP), Araraquara, Brazil
M. Chorilli
Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State
University (UNESP), Araraquara, Brazil
H. A. Santos (
Department of Biomaterials and Biomedical Technology, The Personalized Medicine Research
Institute (PRECISION), University Medical Center Groningen (UMCG), University of
Groningen, Groningen, The Netherlands
Drug Research Program Division of Pharmaceutical Chemistry and Technology, Faculty of
Pharmacy, University of Helsinki, Helsinki, Finland
e-mail:
✉)
h.a.santos@umcg.nl
© The Editor(s) (if applicable) and The Author(s), under exclusive license to
Springer Nature Switzerland AG 2024
I. F. Uchegbu et al. (eds.), Fundamentals of Pharmaceutical Nanoscience,
https://doi.org/10.1007/978-3-031-59478-6_8
165
166 J. Li et al.
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treatment. However, after over 200 years of development, modern immunotherapy
has been applied in various diseases treatment (Pardoll 2011; Cas ale and Stokes
2011), for example, cancer (Kirkwood et al. 2012; Mellman et al. 2011), rheumatoid
arthritis (Taylor et al.
phritis (Anders et al. 2023), sepsis (van der Poll 2001), and bacterial or viral
infections (van de Veerdonk et al.
2001; Meier et al. 2013; Fontana et al. 2018), glomerulone-
2022; Béné and Faure 2003).
8.2 Porous Silicon Nanoparticles (PSiNPs)
In the middle of 1950s, porous silicon (PSi) was fortuitously invented at Bell
Laboratories when trying to develop a fabrication method for microelectronic
circuits, but this material did not raise much interest until the 1980s, when the
high surface area of PSi was discovered (Sailor
1980s and the 1990s, the discovery of the quantum confinement effect and effective
photoluminescence in the nanostructure of the PSiNPs was discovered as well as the
biodegradability and the biocompatibility of the PSi (Li et al.
PSi-based materials, especially the PSiNPs, have been studied in biomedical
research (Santos et al. 2014; Savage et al. 2013). The expanding applications of
PSi mainly include bioimaging (Xia et al. 2021), biosensing (Moretta et al. 2021),
drug delivery (Stojanovic et al. 2016; Li et al. 2020a), tissue engineering (Coffe
2014), antibacterial therapies (Kim et al. 2021), and immunotherapy (Savage et al.
2013; Xu et al. 2022b), particularly in cancer immunotherapy (Xia et al. 2015;
Fontana et al. 2021).
2012). Shortly afterward, in the
2018b). Since then,
8.2.1 PSiNPs-Based Immunotherapy
Over the past decade, in addition to the advantages of PSi, such as having tunable
pore structures, easy surface modification, and excellent biodegradability (Li et al.
2018b), PSi-based materials after specific surface modifications exhibited immuno-
genic characteristics, whether presented as microstructured or nanostructured based
materials (Xia et al. 2015; Ainslie et al. 2008; Meraz et al. 2012 ; Shahbazi et al.
2014a; Gu et al. 2012). Moreover, due to their smaller size, nanoparticles (NPs) have
some unique advantages, for example, they can directly deliver the antigens to the
dendritic cells in the lymph nodes, increasing the cross-presentation and the resultant
T cell activation (Smith et al.
therapy studies have been conducted and reported, mainly focusing on the immunogenicity of the PSiNPs, with different surface modifications, on the cell s of the
immune system (Shahbazi et al.
2023; Rahikkala et al. 2020), and on the fabrication of a series of PSiNP-based
nanoplatforms for cancer immunotherapy (Shahbazi et al. 2014b; Fontana et al.
2017, 2019; Li et al. 2022).
2013). In our group, several PSiNP-based immuno-
2014a; Li et al. 2020b; Shahbazi et al. 2013; Li et al.
8 Porous Si-Based Nanosystems for Immunotherapy Applications 167
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In this section, we will list the most recent studies on PSiNP-based immunother-
apy. We will discuss the immunogenic study of the PSiNP-based nanomaterials and
then introduce the specific PSiNP applications for cancer immunotherapy.
8.2.2 Immunogenic Study of the PSiNP-Based
Nanomaterials
In 2013, our group reported that PSiNPs with different surface chemistry modifications, even with similar size or pore volume, can result in different biological
responses both in vitro and in vivo (Shahbazi et al.
PSiNPs, including thermally oxidized PSiNPs (TOPSi), thermally carbonized
PSiNPS (TCPSi), (3-aminopropyl) triethoxysilane-functionalized thermally carbonized PSiNPs (APSTCPSi), thermally hydrocarbonized PSiNPs (THCPSi), and
undecylenic acid-functionalized THPSi (UnTHCPSi). Afterward, the five types of
PSiNPs were separately incubated with B cells, T cells, monocytes, macrophages,
and isolated human serum for the in vitro immunotoxicity and biocompatibil ity test.
In addition, the fabricated PSiNPs were intravenously injected into rats for in vivo
biochemical, hematological, and histopathological analysis. The in vitro results, for
example, the generation of reactive oxygen speci es (ROS) and the nitr ogen oxide
species (RNOS), indicated that after the incubation, the genotoxicity of the PSiNPs
to the immune cells is mainly due to the surface charge and surface hydrophilicity
(Fig.
8.1a–c). The hydrophilic TOPSi and TCPSi, both with negative charge sur-
faces, showed the lowest immunotoxicity, and the in vitro hemolytic results also
indicated similar results (Fig.
no obvious abnormalities were observed in tested organs and significant changes in
serum biochemical and hematological tests, indicating the excellent biocompatibility
of all the PSiNPs.
After the immunotoxicity and biocompatibility were confi rmed, especially for the
immune cells, Shahbazi et al. reported the immunological responses of the PSiNPs
with different surface chemistries to clarify the surface chemistry influence on the
immunomodulation of the PSiNPs and to show their potential in modulating the
immune system for future-related immunotherapeutic applications (Shahbazi et al.
2014a). Similar to this research wor k, we also fabricated PSiNPs with different
surface chemistries, TOPSi, TCPSi, APSTCPSi, THCPSi, UnTHCPSi, poly(methyl
vinyl ether-alt-maleic acid)-conjugated APSTCPSi (APM) and UnTHCPSiconjugated with polyethyleneimine (UnP) (Fig. 8.1f) and we chose dendritic cells
(DCs) derived from human monocytes as the immune cell line to investigate the
immunological response of the PSiNPs. The ex vitro experimental results indicated
that after the co-incubation with different types of PSiNPs, the immunological
response of the DCs showed significant differences according to the surface chemistry of the PSiNPs. The TOPSi and THCPSi both induced much higher
immunostimulatory response than other groups, followed by UnTHCPSi, UnP,
8.1d, e). Fu rthermore, the in vivo results showed that
2013). We fabricated different
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Fig. 8.1 Immunogenic studies of the PSiNPs-based nanomaterials. (a) Intracellular ROS assessment of the immune cells after 6 h co-incubation with different concentrations of PSiNPs. (b)
Intracellular ROS assessment of the immune cells after 24 h co-incubation with different concentrations of PSiNPs. (c) RNOS production by the immune cells after 24 h co-incubation with
different concentrations of PSiNPs. (d, e) Monitored hemolysis of the human erythrocytes after
the incubation with different concentrations of PSiNPs within 24 h. (Copyright © 2013, Elsevier).
(f) Structural scheme of the PSiNPs with different surface chemistries. (g) The percentage of human
monocytes-derived DCs with CD80, CD86, CD83, and HLA-DR expression after DCs were
incubated with 25 μg/mL PSiNPs with different surface chemistries for 48 h. (Copyright © 2014,
Elsevier). (h) Related gene expression of the iNOS, TNF-α, CD86, IL-23, and CD 206 of RAW
246.7 macrophage cells after 24 h incubation with different concentrations of R-BSA, PSiNPs, and
R-BSA@PSiNPs. (i) ROS assessment of RAW 246.7 macrophage cells after 24 h incubation with
different concentrations of R-BSA@PSiNPs. (Copyright © 2023, American Chemical Society)
and APM, while the TCPSi and APSTCPSi could hardly induce the
immunoactivation of the DCs, no matter the nature of the surface protein expression
(Fig. 8.1g), T cells proliferation, and cytokine secretion. Based on these results, we
found that the immunostimulatory effect of the PSiNPs seems to be related to their
surface oxidation degree, PSiNPs with more oxygen or nitrogen on the outmost
backbone layer inducing lower stimulatory effect on the immune cell s.
Recently, in another study of the immuno modulatory effect of PSi-based
nanomaterials, Li et al. loaded the rhodamine-conjugated bovine serum albumins
(R-BSA) on the PSiNPs via the hydrophobic interactions in order to fabricate the
R-BSA@PSiNPs nanocomposites. Since rhodamine can target the mitochondria and
the modified BSA induces macrophage polarization to the proinflammation subtype,
RAW 264.7 macrophage cells were used as the cell line for the immunostimulation
8 Porous Si-Based Nanosystems for Immunotherapy Applications 169
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test. The in vitro experimental results showed that compared with R-BSA alone,
R-BSA loaded onto PSiNPs as the carrier (R-BSA@PSiNPs) augmented the macrophages polarization to the proinflammatory M1 type, boosting the
immunostimulation capacity of the R-BSA, which is in line with the in vivo experimental results and the R-BSA coating also improved the PSiNPs biocompatibility
with the macrophages. Furthermore, the explorations at the cell level indicated that
mitochond
the
pathways
indicating the
against the infection diseases or cancer.
rial-generated ROS can trigger the downstream signaling transduction
for
macrophage polarization to the proinflammation type (Fig.
the
potential of the R-BSA@PSiNPs as the immunostimulatory agent
8.1h, i),
8.2.3 Applications of PSiNPs-Based Immunotherapy
Platforms
Vaccines can be used to prevent and treat the diseases by activating the immune
system for the specific antigen, for example, virus, bacterial, or tumor (Zepp
Saxena et al. 2021). In addition, with the rapid development of nanomedicines and
the advantages of the nanomaterials, such as the capacity to load antigen or adjuvant
and the small size for easier lymph node delivery, nanovaccines have become
important in the field of immunotherapy (Singh 2021; Bhardwaj et al. 2020),
particularly in cancer immunotherapy (Zhang et al. 2019; Luo et al. 2017). After
the initial studies on the immunostimulatory effect of PSiNPs (Savage et al. 2013;
Xia et al.
for cancer immunotherapy also have been reported, as mentioned above.
for cancer immunotherapy studies (Fontana et al.
capillary microfluidics to encapsulate the TOPSi with biodegradable and biocompatible acetalated dextran (AcDEX) or spermine-modified AcDEX (SpAcDEX) to
produce the nanovaccine core, TOPSi@AcDEX NPs, and TOPSi@SpAcDEX NPs.
Then the cancer cell membrane (CCM) derived from MDA-MB-231 cells and the
Tyrosinase-related protein-2 (Trp2) were chosen as two types of anti gens to separately coat on or conjugate with the TOPSi@AcDEX NPs or TOPSi@SpAcDEX
NPs, forming the TOPSi@AcDEX@CCM nanovaccine and TOPSi@SpAcDEX
nanovaccine. The KG-1 macrophages, B cells with dendritic cell morphology
(BDCM), and peripheral blood monocytes (PBMC) were chosen as the immune
cell models for the immunological response test. The in vitro experimental results
showed that after the co-incubation between the immune cells and nanovaccines, the
fabricated TOPSi@AcDEX NPs and TOPSi@SpAcDEX NPs both can induce the
immunostimulatory response and also work as vaccine adjuvants to load the cancer
antigen (Fig.
cells and induced the immunostimulatory effects and the PBMC co-incubated with
TOPSi@AcDEX@CCM effectively inhibited the proliferation of the MDA-MB-
2015; Meraz et al. 2012, 2014; Shahbazi et al. 2014a), PSiNP-nanovaccine
In our group, Flavia et al. fabricated two kinds of the PSiNP-based nanovaccines
). First, we used glass
2017
8.2a–e). Moreover, the two nanovaccines both activated the immune
2010;
170 J. Li et al.
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231 cell s, further showing the potential and ability of such nanovaccines against
cancer cells.
In order to further verify the antitumor effect of nanovaccines based on these
PSiNPs, our group, Flavia et al. fabricated another two TOPSi@AcDEX-based
multistage nanovaccines for cancer immunotherapy studies (Fontana et al.
2019).
Since the CCM was proven to have the capacity to act as the antigen for
nanovaccine-based materials (Yang et al.
2018; Fang et al. 2014; Li et al. 2018a),
the CCM derived from aggressive melanoma B16.F10 cells and less aggressive
melanoma B16.OVA cells was coextruded with the TOPS i@AcDEX NPs to form
two other types of nanovaccines, NanoCCM (Fig.
8.2h). In addition, for better
therapeutic outcomes, the checkpoint inhibitor, Anti-CTLA-4 antibody was injected
into the melanoma-bearing mice as an additional treatment. The DCs, JAWS II cells
were chosen as the immune cell model for the immunoactivation test. The in vitro
results showed that after the co-incubation with the TOPSi@AcDEX-based
nanovaccines, the co-expression of the CD80 and CD86 significantly increased
compared with the control group, indicating the immunostimulatory effect of the
NanoCCM and their capacity to activate the antigen-presentation cells (APCs)
(Fig. 8.2g). Then our in vivo experimental results further indicated that no matter
whether an aggressive tumor model or a less aggressive tumor model was used, the
injected NanoCCM led to antitumor immune responses and effectively inhibited
tumor growth (Fig. 8.2h). The immunological test further indicated that the tumor
microenvironment (TME) was modified and there was increased CD8
+
T cell
priming. In addition, with the combination of Anti-CTLA-4, much better tumor
inhibition was achieved, showing the clinical potential of the NanoCCM for cancer
immunotherapy.
The PSiNPs-based nanova ccines have proven their ability to act against the
cancer cells and tumor through their activating immune system. In these
nanovaccines, the PSiNPs work as the vaccine adjuvant with a strong
immunostimulatory effect and their ability to load the cancer antigens, but considering the clinical future, if the nanovaccines reach the bloodstream, the adjuvant
could induce systemic inflammation due to their strong immunostimulation (Liu
et al.
2014
; Jiang et al.
2017; Irvine et al. 2015); thus if the nanovaccine cannot
prevent the occurrence of the solid tumor, it is very important for better immunotherapy to break the physical and physiological barriers (Bodey et al. 2000; van der
Burg et al. 2016; Ukidve et al. 2021), for example, by taking advantage of the
immunosuppressive TME. To overcome the mentioned problems, Li et al. fabricated
another PSiNPs-based nanovaccine for cancer immunotherapy (Li et al.
2022). Here
we fabricated PSiNPs@Au NPs with weak-immunostimulatory effects as the adjuvant and then the CCM derived from the 4T1 cancer cells was encapsulated on the
PSiNPs@Au NPs core by the coextrusion method to prepare a biomimetic
nanovaccine, CCM@PSiNPs@Au (Fig.
8.2i). The bone marrow–derived DCs
(BMDCs) and splenocytes were chosen as the immunological test model for the
in vitro experiment s. The in vitro experimental results showed that after the
co-incubation with PSiNPs@Au NPs, the CD80 and CD86 co-expression of
BMDCs did not show a significant increase compared with the control group, but
8 Porous Si-Based Nanosystems for Immunotherapy Applications 171
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Fig. 8.2 Applications of PSiNPs-based for immunotherapeutic applications. (a) Percentage of
CD86-positive immune cells after 72 h co-incubation with the fabricated nanovaccines of different
concentrations or free lipopolysaccharide (LPS). (b) Percentage of CD80-positive immune cells
after 72 h co-incubation with the fabricated nanovaccines of different concentrations or free LPS. (c)
Percentage of CD80- and CD86-positive cells in KG 1 cells after the co-incubation with the
fabricated APTES (a nonimmunostimulatory PSiNPs)-based antigen-presenting systems. (d) Percentage of CD80- and CD86-positive cells in BDCM cells after the co-incubation with the
fabricated APTES (a nonimmunostimulatory PSiNPs)-based antigen-presenting systems. (e) Percentage of CD80- and CD86-positive cells in PBMC cells after the co-incubation with the fabricated
APTES (a nonimmunostimulatory PSiNPs)-based antigen-presenting systems. (Copyright © 2016,
Wiley-VCH). (f) Structural scheme of the NanoCCM. (g) Percentage of CD80- and CD86-positive
cells in JAW II cells after the 48 h co-incubation with the 100 μg/mL NanoCCM, 100 μg/mL
NanoCCM+ 1 μg/mL anti-CTLA-4 antibody, and free LPS. (h) Tumor growth curve after the
treatment. (Copyright © 2019, American Chemical Society). (i) Transmission Electron Microscope
(TEM) images of the CCM@(PSiNPs@Au) nanovaccine. (j) Percentage of CD80- and CD86positive cells in BMDCs after the cells were incubated with the culture medium (group 1), with
about 1.6 × 10
CCM@(PSiNPs@Au) nanovaccine (group 4), and free LPS. (k) IFN-γ assessment of the
splenocytes after incubation with inactivated BMDCs (group 1), with BMDCs activated by CCM
(group 2), with BMDCs activated by PSiNPs@Au NPs (group 3), and with BMDCs activated by
CCM@(PSiNPs@Au) nanovaccine (group 4). (Copyright © 2022, Wiley-VCH). (l) The percentage
of CD80- and CD86-positive cells in KG-1 cells after the 48 h co-incubation with the 50 μg/mL
nanosytems. (Copyrigh t © 2018, Wiley-VCH)
6
CCM (group 2), with 100 μg/mL PSiNPs@Au NPs (group 3), with 100 μg/mL
the CCM@PSiNPs@Au nanovaccine induced higher activation of the DCs when
compared with that in PSiNPs@Au group and free CCM group due to the higher
internalization of the cancer-related antigen. These results mean that even just with
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