Nanoparticles for dendritic cell-based immunotherapy

International Journal of Pharmaceutics 542 (2018) 253–265

Contents lists available at ScienceDirect

International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Review

Nanoparticles for dendritic cell-based immunotherapy a,b,⁎

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Tuan Hiep Tran , Thi Thu Phuong Tran , Hanh Thuy Nguyen , Cao Dai Phung , ⁎ Jee-Heon Jeongd, Martina H. Stenzele, Sung Giu Jinf, Chul Soon Yongd, Duy Hieu Truongg, , d,⁎ Jong Oh Kim a

Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City, Vietnam Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, Vietnam c The Institute of Molecular Genetics of Montpellier, CNRS, Montpellier, France d College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea e Centre for Advanced Macromolecular Design, School of Chemistry, University of New South Wales, Kensington, NSW 2052, Australia f Department of Pharmaceutical Engineering, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea g Institute of Research and Development, Duy Tan University, 03 Quang Trung, Da Nang, Vietnam b

A R T I C LE I N FO

A B S T R A C T

Keywords: Dendritic cells Nanoparticle Vaccine Cancer Immunotherapy

Crosstalk among immune cells has attracted considerable attention with the advent of immunotherapy as a novel therapeutic approach for challenging diseases, especially cancer, which is the leading cause of mortality worldwide. Dendritic cells—the key antigen-presenting cells—play a pivotal role in immunological response by presenting exogenous epitopes to T cells, which induces the self-defense mechanisms of the body. Furthermore, nanotechnology has provided promising ways for diagnosing and treating cancer in the last decade. The progress in nanoparticle drug carrier development, combined with enhanced understanding of the immune system, has enabled harnessing of anti-tumor immunity. This review focuses on the recent advances in nanotechnology that have improved the therapeutic efficacy of immunotherapies, with emphasis on dendritic cell physiology and its role in presenting antigens and eliciting therapeutic T cell response.

1. Introduction Cancer vaccination and immunotherapy have become promising alternatives or supplements to traditional and well-established cancer therapies such as surgery, chemotherapy, and radiotherapy by overcoming their disadvantages (Goforth et al., 2009; Krishnamachari and Salem, 2009; Park et al. 2017b). These approaches involve stimulation of the host’s immune system; specifically, they elicit potent tumorspecific cytotoxic T lymphocytes (CTLs) that can decrease the tumor mass and induce long-term tumor-specific memory response and protect against tumor recurrence. Dendritic cells (DCs) act as the starting points in this process by capturing antigens and monitoring the host’s response via direct interaction or/and indirect release of cytokines. In brief, the captured antigens are processed, and the resulting peptides form complexes with the major histocompatibility complex (MHC) class I or class II on the surface of DCs, via which they are presented to CD8+ or CD4+ T cells, respectively, thereby inducing immune response (Banchereau and Steinman, 1998; Steinman and Banchereau, 2007).

Therefore, DCs act as the bridge between the innate and adaptive immune systems and control both immune tolerance and response (Banchereau and Steinman, 1998; Mellman and Steinman, 2001). Depending on the characteristics of the fabricated complex, the immune system decides whether to eliminate the pathogens or induce production of long-term memory CD4+ T-cells. For therapeutic efficacy, the correct signals for anti-cancer therapy should be established by the high affinity of CD8+ T-cells and MHC class I, which allows the system to secrete granzymes and perforin—factors essential for cytotoxicity against cancer cells (Palucka and Banchereau, 2012). However, to educate the immune system for life-long response against tumor cells, priming of memory CD4+ T-cells is essential (Paulis et al., 2013). In addition to the MHCs, the DC-T cell cross-talk requires the presence of costimulatory molecules such as CD80 and CD86 on DCs and CD28 on T cells, and cytokines, which orientate T cell differentiation (Diebold, 2008). For old-fashioned DC-based immunotherapy, DCs are isolated from peripheral blood, followed by ex vivo maturation with tumor antigen

⁎ Corresponding authors at: Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City, Vietnam (T.H. Tran); Institute of Research and Development, Duy Tan University, 03 Quang Trung, Da Nang, Vietnam (D.H. Truong); College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea (J.O. Kim). E-mail addresses: [email protected] (T.H. Tran), [email protected] (D.H. Truong), [email protected] (J.O. Kim).

https://doi.org/10.1016/j.ijpharm.2018.03.029 Received 29 December 2017; Received in revised form 13 March 2018; Accepted 15 March 2018 Available online 16 March 2018 0378-5173/ © 2018 Elsevier B.V. All rights reserved.


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charged nanoparticles and hinder permeation through tissues. Moreover, cationic particles can affect cell membrane integrity or cause hemolysis and platelet aggregation; hence, particle charge should be balanced, for example, by shelling the nanoparticle surface with hydrophilic molecules such as polyethylene glycol (PEG) or maintaining a “neutral” positive charge (Grimaldi et al., 2017). In contrast, active targeting can be achieved by surface functionalization of nanoparticles with antibodies or ligands that specifically bind to the pathogen recognition receptors (PRRs) on the surface of DCs (Paulis et al., 2013). Amongst PRRs, toll-like receptors (TLRs) and several C-type lectin receptors (CLRs) such as cluster of differentiation 205 (CD205 or DEC205), C-type lectin domain family 9 member A (Clec9A), the mannose receptor, and dendritic cell inhibitory receptor 2 (DCIR2) are interesting targets for designing DC-based vaccines against cancer (Figdor et al., 2002). The therapeutic efficacy of a nanoparticle-based system depends on proper selection of carriers and antigens and/or adjuvants. Since the ideal therapy requires participation of both innate and adaptive immune responses, a balance in MHC-II-activating CD4+ T cells and MHC-I-eliciting CD8+ cytotoxic cells is required. In addition, the dendritic cells can be activated indirectly by cytokines derived from the inflammatory process, or directly by antigens or molecules on the surface of microorganisms by the pathogen recognition system (Pfaar et al., 2012). As a part of these mechanisms, TLRs act as potential targets for activating DCs using adjuvants such as lipopolysaccharide (LPS) and its derivatives, which is mediated by TLR-2 and TLR-4, or CpG motifs that bind and activate TLR-9 (Rakoff-Nahoum and Medzhitov, 2009). Activation and maturation are important for the ability of DCs to migrate to lymphoid organs, and prime and activate antigen-specific T cells. Therefore, tracking the expression of co-stimulatory molecules (e.g. CD40, CD80, and CD86) and the secretion of cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor alpha (TNF-α), and chemokine receptor 7 (CCR7) are critical aspects that should be considered for designing effective nanoparticle-based therapeutics. In the following sections of this review, we have summarized the characteristics of different types of nanoparticles as anticancer vaccines and immunotherapeutics.

and transfusion back into the body. The next generation of DC vaccines involved pulsing of DCs with antigen-loaded nanoparticles or delivering antigens into the body to enable direct interaction with immature DCs in vivo, which improved the efficacy and convenience of the therapy (Hu et al., 2017). The current prophylactic and therapeutic vaccines focus on delivery of tumor-associated antigens (TAAs) and immunomodulators (adjuvants) to DCs. However, the poor immunogenicity, weak stability, and short in vivo half-life of the antigens have limited the potential of this approach. Fortunately, innovation in nanotechnology provided several advantages in preserving antigens as well as boosting the optimal conditions for their delivery (Kelly et al., 2017). In this review, we have summarized the current knowledge regarding DC-related immunity to devise various strategies for developing efficient therapeutic nanosystems. 2. Dendritic cells and nanoparticle immunotherapy: the devoted guard and potential partner Considering the pivotal role played by DCs in the immune system and the increase in knowledge regarding DC biology, interest in using nanoparticles as antigen delivery system and adjuvants targeting DCs has increased over the past few decades (Kasturi et al., 2011; Moon et al., 2011; Reddy et al., 2007; Xu et al., 2012, 2013). Owing to several beneficial physicochemical properties, these nanomaterials can protect antigens and adjuvants from premature enzymatic degradation and promote their cellular uptake into DCs via passive targeting or active targeting to DCs (Fig. 1), thereby enhancing the immunogenicity of antigens and modulating immune cell activities (Fernandez-Megia et al., 2007; van den Berg et al., 2010). For presentation to DCs, nanoparticles are typically administered via the subcutaneous route, from where they drain into lymph nodes. Therefore, passive delivery to DCs requires the nanocarriers to be welldesigned in terms of size, surface charge, surface hydrophobicity, and morphology. Passive targeting accelerates the uptake proficiency of nanoparticles < 200 nm in diameter, which can diffuse into lymph vessels to target lymph node-resident DCs, whereas particles with diameter > 500 nm have to be incorporated by skin-resident DCs for transportation to lymph nodes (Leak, 1971; Manolova et al., 2008). Although therapeutic efficacy can be achieved using large nanoparticles, it is likely that the optimal immune effects are observed with particles in the size range of 40–50 nm (Fifis et al., 2004). Regarding surface morphology, DC-targeted nanoparticles share many common features with other nanoparticles; for example, positively charged nanoparticles can be efficiently internalized by DCs in vitro by electrostatic interactions. However, the in vivo scenario is complicated by the presence of negatively charged components in the bio-physiological fluid (van den Berg et al., 2010), which possibly immobilize the positively

3. Inorganic material-based systems 3.1. Gold nanoparticles (AuNPs) AuNPs have been widely investigated as imaging agents and in combined phototherapy for cancer treatment owing to their beneficial characteristics such as biocompatibility, tunable surface chemistry for targeting and surface passivation, easy control of size and shape, and

Fig. 1. (a) Passive and (b) active targeting of nanovaccines to dendritic cells (DC).

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Fig. 2. (A) Dendritic cell labeling with radionuclide-embedded AuNP (RIe-AuNP), cancer immunotherapy and PET/Cerenkov emission-based tracking in vivo. Reprinted with permission from (Lee et al., 2016). (B) Schematics of this overall investigation and the mechanisms of NanoAu-Cocktail pulsed DC induction of antiviral T cell responses. Reprinted with permission from (Zhou et al., 2016).

and Amigorena, 2007; Villiers et al., 2010). By manipulating DCs ex vivo, Lee et al. synthesized a radionuclideembedded AuNP (RIe-AuNPs) using simple radio-labeling chemistry, followed by gold shell stabilization, with the aim of developing a highly sensitive and stable nuclear device (Fig. 2A) (Lee et al., 2016). The additional gold shell provided the spherical RIe-AuNPs with excellent stability even 3 days after being internalized by DCs. The RIe-AuNPs did not induce apoptosis in the DCs or alter the expression of phenotype

tractability using computed tomography (CT) imaging, which is readily available in most hospitals (Almeida et al., 2015; Boisselier and Astruc, 2009; Chen et al., 2005; Huang et al., 2006; Jain et al., 2006; Lee et al., 2012; Niikura et al., 2013; Sokolov et al., 2003; Tran et al., 2016). In terms of their behavior towards DCs, AuNPs do not exhibit any cytotoxicity or biological functions and accumulate inside cells, suggesting that AuNPs can be used as potential carriers for both imaging and cancer treatment (Fernández et al., 2015; Le Guével et al., 2015; Savina 255


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markers (MHC class I, MHC class II, CD86), cytokine levels, and cell migration, showing that the nanoparticle did not negatively affect DC biology. Furthermore, analysis of anti-tumor immune response in a mouse model with murine Lewis lung carcinoma cells (LLCs) showed that the smallest tumor size was observed in the group of mice immunized with labeled DCs pulsed with LLC lysates, indicating the potent anti-tumor effect of labeled DCs. In addition, the strong radioactivity (0.2 mg/kg) and excellent stability of RIe-AuNPs in human plasma, even after 24 h incubation at 37 °C, provided a sensitive imaging platform for long-term monitoring of DC migration to draining lymph nodes. In another study, Zhou et al. optimized the sizes of two different gold nanoparticles (AuNPs) to be 60 nm and 80 nm, respectively, for delivering an ovalbumin peptide (OVAp) and CpG oligodeoxynucleotides (CpG-ODNs) to bone-marrow derived DCs (Zhou et al., 2016). A combination of the optimal doses (25 µg/mL of each AuNP, 5.2 µg/mL OVAp, and 2.4 µg/mL CpG-ODNs) of these two nanoparticles (AuNP60/OVAp and AuNP80/CpG-ODNs), called nanoAu cocktail, co-delivered OVAp and CpG-ODNs to the same subcellular DC compartment (Fig. 2B). This was essential for immune efficacy (Blander and Medzhitov, 2006) and promotion of DC homing to lymphoid-tissues, especially to liver-draining lymph nodes, owing to high expression of CCR7 and rearrangement of the cytoskeleton. Furthermore, nanoAu cocktail-pulsed DCs increased the number of OVAp-specific CD8+ T cells in the liver-draining lymph nodes and spleen of mice by 6.5- and 3.4-fold than those induced by CpG-ODNs/OVAp-pulsed DCs, respectively. The robust enhancement in antigen-specific T cell responses induced by the cocktail indicates a potential protective mechanism against infective diseases and cancer. To observe its in vivo efficacy on mice, Almeida et al. injected AuNPs containing ovalbumin (OVA) and CpG subcutaneously into both flanks of mice for a total dose equivalent to 50 µg OVA and 4.7 µg CpG, respectively, followed by a booster dose after 10 days (Almeida et al., 2015). Results revealed that systemic antigen-specific immune responses and prophylactic/therapeutic efficacy in anti-tumor models were obtained when mice were administered AuNP-OVA and AuNPCpG. In similar experiments, Lee et al. used CpG and red fluorescent protein (RFP) as a model antigen to track the delivered AuNP-based vaccines to DCs in the target lymph node (Lee et al., 2012). Moreover, they injected phosphate buffer saline (PBS), RFP, AuNPs, RFP/AuNPs, or CpG/RFP/AuNPs into the footpads of mice five times following a predetermined schedule. Compared to other groups, tumor growth was significantly inhibited in groups treated with RFP/AuNPs and CpG/ RFP/AuNPs, and the effect of CpG/RFP/AuNPs was significantly more than that of RFP/AuNPs, indicating the efficacy of the system. Furthermore, Kang et al. investigated the effect of AuNP-based vaccine size on their deliverability to lymph nodes and ability to induce cytotoxic Tlymphocyte response using 10-, 22-, and 33-nm AuNPs containing OVA (Kang et al., 2017). In vitro and in vivo results revealed that larger vaccines in certain ranges were internalized better by DCs and elicited superior antigen-specific T-cell immunity (Fig. 3). Additionally, the size threshold for induction of multifunctional T-cell response was suggested to be in the range of 10–22 nm, highlighting the importance of size in vaccine development.

Fig. 3. Effects of gold nanoparticle-based vaccine size on lymph node delivery and cytotoxic T-lymphocyte responses. Reprinted with permission from (Kang et al., 2017).

ZnO core–shell multifunctional nanoparticles in an attempt to combine the magnetic property of SPIO and the photonic property of zinc oxide (Cho et al., 2011). Enhancement of the mean fluorescent intensity of the nanoparticle-loaded DCs compared to DC alone enabled application of confocal microscopy for nanoparticle monitoring. The core–shell nanoparticles efficiently loaded carcinoembryonic antigen (CEA) into DCs in a short incubation period (within one hour) without affecting the viability and phenotype of DCs. Tumor-bearing mice immunized with DCs pulsed with peptide-nanoparticle complexes showed significantly prolonged tumor growth and improved survival, which might result from the high efficiency of internalization of tumor antigens by DCs. The peptide-nanoparticle complexes also potently induced anti-CEA immune responses in CEA-transgenic mice as demonstrated by significant suppression of tumor growth and disruption of T-cell tolerance against CEA. To track the migration of DCs in vivo by MRI, Long et al. used SPIO to label granulocyte–macrophage colony stimulating factor (GM-CSF)transduced B16 melanoma cells for transferring these SPIO particles to endogenous DCs in situ (Long et al., 2009). Upon injection of SPIOlabeled tumor cells into the footpad of mice, the SPIO signal slowly appeared at the central region of lymph nodes from day 3 and lasted until day 8, whereas injection of free SPIO showed rapid appearance of the SPIO signal in the subcapsular area of the lymph nodes. Furthermore, the amount of labeled DCs migrating to the lymph nodes determined by MRI correlated highly with that measured by flow cytometry, suggesting that MRI could be a potential non-invasive tool for optimizing DC-based cancer immunotherapy via monitoring of DC trafficking. Many other non-invasive imaging techniques have also been used to monitor DC trafficking, such as bioluminescence imaging (Schimmelpfennig et al., 2005), positron emission tomography (PET) (Olasz et al., 2002), and planar gamma scintigraphy (de Vries et al., 2003). The integration of multiple imaging techniques will be highly favored for developing a multimodal imaging technique that can offset the weakness of each technique and yield detailed and accurate information. Inspired by this idea, fluorescent magnetic nanoparticles (αAP-fmNPs) were synthesized by simultaneous loading of iron oxide nanoparticles as an MRI contrast agent, indocyanine green (ICG) as a NIR fluorescent agent, and fusion peptide (α-AP), which contains αhelix peptide (α-peptide) and antigen peptide (AP) sequences, as an antigen model (Jin et al., 2016). α-AP-fmNPs exhibited absorption maxima in the NIR region at 731 and 792 nm, and the MRI contrast signals indicated the suitability of these nanoparticles for NIR and MRI imaging techniques. Almost all DCs were fluorescently labeled ex vivo upon exposure to 16 µg/mL α-AP-fmNPs owing to the incorporation of AP into α-AP-fmNPs. The application of magnetic pull force (MPF) enhanced accumulation of α-AP-fmNP-loaded DCs in the popliteal lymph nodes in the mouse footpad model as indicated by increased

3.2. Superparamagnetic nanoparticles Magnetic resonance imaging (MRI), which can capture three dimensional images of the whole body at high resolution, is an effective technique to track or monitor DC migration. Because of their low toxicity (de Vries et al., 2005; Kunzmann et al., 2011; Weissleder et al., 1989), ultrasmall superparamagnetic iron oxide (SPIO) particles have gained attention as MRI agents in cancer immunotherapy, especially after the approval of the USA Food and Drug Administration (FDA), as a liver (Feridex®; Resovist®) or lymph node imaging agent (Combidex®) (Harisinghani et al., 2003; Wang, 2011). Using an ex vivo DC-labeling approach, Cho et al. prepared Fe3O4256


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Fig. 4. (A) Bimodal imaging of MPF-promoted DC migration to the LN. a) Schematic representation of the α-AP-fmNP/MPF-based strategy for improving BMDCs migration in mice. The α-AP-fmNP-loaded BMDCs were injected into the hind-leg footpad and subjected to MPF treatment for promotion of migration to PLN. b-c) Optical imaging of BMDCs migration at 0 h (b) and 24 h (c) post-injection in the presence (+MPF, bottom panel) or absence (-MPF, top panel) of magnetic field exposure. d) Average fluorescence measurements from c). e) Representative MRI images of α-AP-fmNP-treated mice. MRI images reveal the accumulation of iron oxide particles in the PLN (blue arrow: BMDCs alone; red arrow: α-AP-fmNP-loaded BMDCs). Reprinted with permission from (Jin et al., 2016). (B) a) Schematic representation of the strategies used for the preparation of OVA-IONP and CpG-IONP micelles and for organic chemistry-free 67 Ga and Rhodamine labeling. b) The microdosed nanosystem with average diameter of ca. 40 nm is designed to provide effective lymphatic delivery of the vaccine components to secondary lymphoid organs such as the lymph nodes where uptake by DCs facilitates the induction of potent humoral and cellular immunity. Reprinted with permission from (Ruiz-de-Angulo et al., 2016). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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fluorescence signals and decreased MRI signals (Fig. 4A). In addition, the α-APOVA-fmNP-BMDCs-treated group showed increased CD8+ T cell proliferation, IFN-γ production, augmented antigen-specific killing activity, and markedly delayed tumor growth, especially in the presence of MPF. Mackay et al. synthesized hybrid imaging nanoprobes (HINP) by tethering negatively charged quantum dots (QDs) with positively charged SPIO nanoparticles (Mackay et al., 2011). The visible CdTe/ CdS/ZnS and NIR CdHgTe/CdS/ZnS QDs exhibited photoluminescence that can be used for two-photon microscopy and optical NIR imaging, respectively. The positively charged SPIO-DX-PAH core was formed by the association of dextran-coated SPIO (SPIO-DX) and polyallylamine chloride (PAH). The HINP was then stabilized by a transfecting reagent, poly-D-lysine hydrobromide, on the surface to enhance cell membrane permeability. The migration and homing of HINP-labeled DCs in mice could be observed by optical, two-photon imaging, and MRI. The superior stability of the nanoprobes might be applied for longitudinal cell tracking and imaging of biological targets in various disease models, including cancer. Recently, Ruiz-de-Angulo et al. reported the synthesis of iron oxide nanoparticle-filled micelles coated with 67Ga3+ and the model antigen OVA or pathogen mimetic CpG ODNs for in vivo single photon emission computed tomography (SPECT) imaging (Ruiz-de-Angulo et al., 2016). Using radiogallium (67Ga) labeling, SPECT efficiently tracked the delivery vehicles to DCs in the target lymph nodes. The 40-nm conjugated nanoparticles enhanced DC maturation and Th1-cytokine secretion, resulting in potent antigen-specific humoral and cellular immunity even in the presence of microdoses of the antigens or micelles (5 µg of OVA, 3–5 µg of CpG, and 7–53 µg of micelles). As a consequence, the system was able to retard tumor growth and protect against tumor challenge (Fig. 4B).

encapsulation of two components in PLGA nanospheres exhibited significantly better performance than that of nanospheres delivering antigen alone, with 1.5- and 2.5-fold increases in antigen-specific T-cell proliferation and IFN-γ production, respectively (Diwan et al., 2002). Hamdy et al. co-loaded tyrosinase-related protein 2 (TRP2), a poorly immunogenic melanoma antigen, and synthetic 7-acyl lipid A, a TLR ligand, into PLGA nanoparticles to form TRP2/7acyl lipid A-NP (Hamdy et al., 2008). Upon vaccinating mice bearing melanoma B16 tumors with loaded or empty nanoparticles, IFN-γ secretion by activated TRP2specific CD8+ T cells in lymph nodes and spleen was significantly increased in the TRP2/7acyl lipid A-NP-treated group compared to the group treated with PLGA nanoparticles containing TRP2 alone (TRPNP) or empty nanoparticles (empty-NP). The elevated levels of pro-inflammatory cytokines (i.e. IL-2, IL-6, IL-12, IFN-γ, and TNF-α) and decreased level of vascular endothelial growth factor (VEGF) in the TRP2/7-acyl lipid A-NP-treated group demonstrated the superior immuno-stimulatory effects of this co-delivered NP in the tumor microenvironment. Most importantly, the average tumor area and weight in the TRP2/7acyl lipid A-NP-treated group were the smallest amongst the three groups tested, indicating the therapeutic anti-cancer effect of this vaccine (Fig. 5). Kokate et al. prepared CpG-coated PLGA nanoparticles encapsulating tumor-associated antigen (CpG-NP-Tag) using a modified double emulsion technique, followed by solvent evaporation (Kokate et al., 2016). The uptake of CpG-NP-Tag was significantly higher than that of the CpG-coated NPs (CpG-NP-blank) or antigen-encapsulated NPs (NP-Tag). CpG-NP-Tag enhanced DC maturation and activation as demonstrated by the upregulation of costimulatory surface maturation markers CD80, CD86, and IL-12. CpG-NP-Tag also attenuated tumor growth and exhibited tumor antiangiogenic effect, which might be mediated via IFN-γ and enhanced CTL function in mice. A combination of multiple adjuvants demonstrated synergistic effects on the activation of the immune system by triggering distinct signaling pathways. Lee et al. loaded polyriboinosinic: polyribocytidylic acid (I:C) and CpG-ODNs into PLGA nanoparticles with ovalbumin (OVA) (Soema et al., 2015). PLGA nanoparticles containing OVA and poly (I:C) or OVA and CpG-ODNs efficiently enhanced the MHC class Irestricted OVA presentation by approximately 2-fold compared to that of nanoparticles containing OVA alone. Moreover, a mixture (1:1) of nanoparticles co-loaded with OVA and poly (I:C) or OVA and CpGODNs (NP[OVA + poly I:C]/NP[OVA + CpG) considerably enhanced MHC class I-restricted antigen presentation by 2-fold and antigen-specific CD8+ T cell proliferation by 3-fold. Kasturi et al. designed a viruslike PLGA nanoparticle comprising MPL (TLR4 ligand), R837 (TLR7 ligand), or both ligands together with an antigen (ovalbumin or protective antigen (PA) from Bacillus anthracis or hemagglutinin (HA) from avian influenza H5N1 virus) (Kasturi et al., 2011). They observed that delivery of adjuvants and antigen in separate nanoparticles, namely, NP (MPL + R837) plus NP (Ag), was more effective than the delivery of both adjuvants and antigen in the same nanoparticle, with significant increase in antigen-specific IgG titers and CD4+ T-cell response to NP (MPL + R837) plus NP(Ag). In addition, they observed that delivery of antigen and both TLRs in separate nanoparticles, NP (MPL + R837) plus NP (Ag), resulted in remarkably higher immune response than that achieved by delivery of antigen and each adjuvant in the same nanoparticle, i.e. NP (Ag + MPL) or NP (Ag + R837). This synergistic action was shown to be mediated via the MyD88- and TRIF-dependent signaling pathway. The favorable characteristics of PLGA nanoparticles were also utilized for developing multimodal imaging techniques. Cruz et al. grafted antibodies recognizing the human DC-specific receptor DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) onto the surface of PLGA nanoparticles encapsulating iron oxide particles and fluorescent FITC-labeled TT peptide (Cruz et al., 2011). The DC-targeted nanoparticles could be detected in vitro at subcellular, cellular, and organism level by transmission electron microscopy (TEM), flow cytometry, and MRI, and they enhanced the presentation of

4. Organic material-based systems 4.1. Poly (D, L-lactic-co-glycolic acid) (PLGA) PLGA are aliphatic copolymers composed of two different monomers, lactic acid and glycolic acid. Owing to their biodegradable and biocompatible properties, PLGA has been extensively used in controlled delivery systems to encapsulate a wide variety of active compounds as well as antigens and/or adjuvants (Audran et al., 2003; Clawson et al., 2010; Diwan et al., 2002; Gupta et al., 1997; Hamdy et al., 2008; Han et al., 2017; Helson et al., 2008; Nguyen et al., 2015). These polymers are mainly used for parenteral administration in which they can provide a non-toxic platform to deliver and release antigens and adjuvants in a sustained manner (Choi and Han, 2018; Jiang et al., 2005; Johansen et al., 2000; O'hagan et al., 1991). It is well known that delivery of a cancer-associated antigen and/or an immunomodulator using PLGA nanoparticles could be advantageous for DC activation compared to the use of soluble antigens because of several benefits, such as protection from premature degradation, extended duration of antigen presentation, sustained release of adjuvants, and improved safety (Audran et al., 2003; Shen et al., 2006; Sutmuller et al., 2006; Tacken et al., 2011; Yang et al., 2004). Clawson et al. showed that a short peptide (Hp91) encapsulated in or conjugated to the surface of PLGA NPs activated DCs 5-fold and 20-fold more potently than the free peptide (Clawson et al., 2010). In another study, Diwan et al. (2002) prepared PLGA nanospheres in which tetanus toxoid (TT) was used as the model antigen and ODN comprising unmethylated bacterial DNA sequences with CpG motifs as the model adjuvant (Diwan et al., 2002). Upon subcutaneous immunization in mice, the codelivered nanospheres showed approximately 1.4-fold increase in antigen-specific T-cell proliferation and 3.3-fold increase in IFN-γ production compared to soluble TT and ODN in solution. In another approach, simultaneous delivery of antigens and adjuvants via the same nanoparticle demonstrated advantages over delivery of antigens alone. Diwan et al. also observed that co258


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Fig. 5. Therapeutic anti-tumor immunity in mice vaccinated with TRP2180–188 containing NP. C57Bl/6 mice were injected s.c. at their upper right flank with 0.1 × 106 B16-F10 melanoma cells (day 0). Three days later, animals were randomly assigned to three treatment groups (8–10 mice per group). The three groups were s.c. vaccinated (in the lower right flank region) with either Empty-NP, TRP2-NP or TRP2/7-acyl lipid A-NP. Animals were given booster immunization with the same formulations at days 7 and 13. Tumor size was measured with vernier caliper every 2–3 days. The longest length and the length perpendicular to it were multiplied to obtain the tumor area in mm2. The mean tumor area ± standard error (S.E.) for each group was plotted vs. time (A). *Indicates significant differences (p < 0.05) in tumor area for mice immunized with TRP2/7-acyl lipid A-NP, compared with EmptyNP immunized mice. On day 21 animals were sacrificed and tumors were isolated and weighted separately. Tumor weights of individual mice for each vaccination group are shown as scatter plot (B). Averages of the tumor weights from each group are shown. The experiment was repeated one more time, and similar results were obtained. For each treatment group, the average percentage of mice that had tumor weights less than 0.3 g at the endpoint of the study (day 21) is shown in (C). Numbers below (C) represent the actual numbers of mice that had had tumor weights less than 0.3 g/total number of mice used for each group. Pictures of representative mice in each group at the endpoint of the study are shown in (D). Arrows indicate the position of tumors. Reprinted with permission from (Hamdy et al., 2008).

immunization with DCs pulsed by MPN-OVA in mice, OVA-specific CTL response was induced in draining lymph nodes. The presence of MPN in lymph nodes demonstrated the potential application of the MPN-based system as a bimodal imaging and delivery system in DC-based cancer immunotherapy.

the TT peptide to T cells, which suggests a valuable strategy for designing DC-targeted vaccines in vivo. Noh et al. loaded ovalbumin, MRI contrast agents, and NIR fluorophores (indocyanine green) into PLGA nanoparticles to fabricate multifunctional PLGA nanoparticles, namely, MPN-OVA (Noh et al., 2011). MNP-OVA was effectively internalized in DCs by phagocytosis, resulting in the presentation of OVA peptides on MHC class I molecules and enhancement of OVA-specific cross-presentation to OT-1 T cells and CD8-OVA1.3 T cell in vitro. Following 259


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4.2. Liposomes Liposomes are spherical lipid vesicles that contain one or more phospholipid bilayers. Because of their low toxicity, ease of preparation and scale-up, liposomes have been extensively investigated as a drug delivery system (Grimaldi et al., 2017; Park et al., 2017a; Ruiz-deAngulo et al., 2016; Torchilin, 2005). Over the past two decades, liposomes have also attracted considerable attention in tumor immunotherapy, but their potential applications have been hindered by shortage of simple methods for surface attachment of targeting molecules (Chikh and Schutze-Redelmeir, 2002; de Jong et al., 2007; Fukasawa et al., 1998; Gupta et al., 2017; Hoang et al., 2017; Ignatius et al., 2000; Serre et al., 1998). Using a design of experiments (DoE) approach, Soema et al. studied the effects of lipid and antigen concentrations of antigen-loaded liposomes on size, surface charge, and adjuvanticity (Soema et al., 2015). The obtained data were fitted into regression models, which then were utilized to predict and test the expression of DC maturation factors CD40, CD80, CD83, and CD86. The accuracy of the prediction models supported the use of this approach in developing liposomal vaccine adjuvants after investigating various parameters such as lipid composition, particles size, charge, and adjuvanticity (Fig. 6A).de Jong et al. observed that co-encapsulation of OVA and CpG in sterically-stabilized cationic liposomes enhanced the uptake of encapsulated ODN by macrophages and DCs in the lymph nodes by 2- to 9-fold, compared to free ODN uptake (de Jong et al., 2007). Subcutaneous administration of liposomes into mice upregulated the expression of activation markers CD69 and CD86 and elevated plasma levels of chemokines/cytokines, thereby inducing the innate immune response, and significantly enhancing the frequency of OVA-MHC tetramer-positive CD8 cells, IFN-γsecreting CD8+ cells, and cytotoxicity, thereby inducing potent antigen-specific immune responses. Furthermore, encapsulated ODN supported the adaptive immune responses against TAAs, and induced effective anti-tumor activity in efficacy studies using both xenogeneic E.G7-OVA and syngeneic B16 tumor models. Faham et al. used a mixture of disteroyl phosphocholine (DSPC), disteroyl phosphoethanolamine (DSPE), cholesterol, and polyethylene glycol (PEG) 750 for preparation of stealth liposomes (Faham et al., 2009). The DC-targeting function was created by separately engrafting two peptides derived from high-mobility box (HMGB1), namely pHMGB-89 and pHMGB-106, onto the surface of liposomes to induce DC activation and maturation. Intravenous injection of ovalbuminloaded liposomes into mice potently induced OVA-specific IFN-γ-producing CD8+ T lymphocytes and antibodies. Importantly, tumor growth and metastasis were inhibited after vaccination with liposomes engrafted with either of these peptides in mice challenged with highly metastatic B16-OVA melanoma (Fig. 6B). To directly target the surface molecules CD11c and DEC-205 on DCs, van Broekhoven et al. conjugated recombinant hexahistidinetagged forms of single chain antibody fragments to the surface of tumor-derived plasma membrane vesicles or stealth liposomes by a metal-chelating bond (Van Broekhoven et al., 2004). Flow cytometry analysis (in vitro) and fluorescent confocal microscopy (in vivo) showed that the engrafted liposomes enhanced the binding to DC by 4- to 8-fold compared to control cells. Incorporation of “danger signals” such as LPS, IFN-γ, or GM-CSF into B16-OVA-bearing liposomes generated strong antigen-specific T cell response and markedly protected against tumor growth. This further confirms the role of DEC-205 and CD11c as promising targets for robust immune responses (Bonifaz et al., 2002, 2004; Castro et al., 2008; Macri et al., 2016; Reddy et al., 2006). To utilize the application of magnetic nanoparticles in hyperthermia for cancer treatment, Tanaka et al. fabricated magnetite cationic liposomes (MCLs) consisting of colloidal magnetite and heat shock protein 70 (HSP70) (Tanaka et al., 2005). In an in vitro experiment, co-culture of DCs pulsed with tumor cells heated to 43 °C upregulated expression of MHC class I/II, costimulatory molecules (CD80, CD86), and

Fig. 6. (A) Overview of the study concept. An experimental design describing liposomes with various lipid compositions and peptide concentrations is generated with DoE software. Liposomes are formulated according to the design. Then, liposomes characteristics such as size, zeta potential and liposome-induced dendritic cell maturation are determined for each liposome formulation. Models are subsequently fitted to the generated data. Finally, these models can be used to predict the liposome characteristics of liposomes with an untested lipid composition. Reprinted with permission from (Soema et al., 2015). (B) PMVs engrafted with pHMGB-89 and pHMGB-106 induce potent anti-tumor immunity. C57/BL6 mice were challenged with 2 × 105 B16-OVA cells injected i.v. (day 0). Separate groups of five challenged mice were then vaccinated at days 2, 8 and 14 with: PBS, or B16-OVA-derived PMVs (3 × 105 cell-equivalents) engrafted with L2 (L2-PMVs), pHMGB-89 (pHMGB-89-PMVs) or pHMGB-106 (PMV-pHMGB-106), as indicated. At day 21, the lungs were removed and examined for tumor metastases and the number of tumor foci counted with an inverted microscope. The bar graph in (A) shows the mean number of tumor foci ± SEM in the lungs for each group of mice as indicated (**p < 0.001). Representative images of lungs from each group of mice indicating the extent of tumor growth/metastases are shown in (B). Reprinted with permission from (Faham et al., 2009).

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atom encapsulated inside the carbon cage, which facilitates its application as an MRI contrast agent. It can form approximately 22 nmdiameter aggregates in physiological saline, namely [Gd@C82(OH)22]n nanoparticle (Yang et al., 2010). Yang et al. showed that the nanoparticle stimulated the production of cytokines (IL-12p70, TNF-α) and promoted the expression of DC co-stimulatory (CD80, CD83, CD86) and MHC (HLA-ABC and HLA-DR) molecules, resulting in CCL19-responsive phenotypic maturation of DCs. The ovalbumin-specific Th1-mediated immune response in vivo was promoted in the presence of the nanoparticle, suggesting a novel usage of [Gd@C82(OH)22]n nanoparticle in cancer therapy. Sokolova et al. synthesized multiple-shell calcium phosphate (CaP) nanoparticles from a calcium phosphate core by subsequent precipitation and functionalization with oligonucleotide-calcium phosphate shells for codelivery of hemagglutinin antigen and TLR ligands CpG and poly (I:C) (Sokolova et al., 2010). CaP nanoparticles functionalized with CpG, poly (I:C), or a combination of both upregulated CD80 and CD86, enhanced the release of IL-12p70, IL-2, and TNF-α compared to soluble CpG or poly (I:C). Moreover, treatment of DCs with functionalized CaP nanoparticles induced significantly stronger T cell proliferation than treatment with hemagglutinin alone. These results illustrated the ability of functionalized CaP nanoparticles in inducing both innate and adaptive immunity, which might induce potent tumor antigen-specific immune responses depending on the antigens encapsulated. Graphene oxide nanosheets were prepared and loaded with a peptide from the anti-apoptotic protein survivin, which is widely expressed in malignant gliomas (Wang et al., 2014). The peptide-loaded GO triggered a stronger anti-glioma immune response in vitro compared to graphene oxide alone or free peptide, as indicated by higher percentage of tumor growth inhibition and secreted IFN-γ. No significant changes in the viability and phenotype of DCs were observed upon incubation with graphene oxide, highlighting the negligible adverse effects of graphene oxide on DCs. Yb- and Er-doped NaY/GdF4 upconversion nanoparticles (UCNPs)

chemokine receptor CCR7, thereby inducing DC maturation. Following injection of MCLs into tumors in mice, the tumor temperature could be maintained precisely at 43 °C under AMF radiation without affecting normal tissues. The combination of MCL-induced hyperthermia and DC therapy in tumor-bearing mice demonstrated higher rate of complete tumor regression and survival (in 6/10 mice for over 100 days) and acquired antitumor immunity via activation of both CTLs and natural killer cells compared to control, hyperthermia alone, or DC therapy alone. This highlights a novel cancer therapy using MCL-based hyperthermia and intra-tumoral DC injection for patients with advanced malignancies. 5. Other nanoparticulate systems Sheng and colleagues synthesized a mannose-based polyamidoamine (PAMAM) dendrimer conjugated with ovalbumin to form mannosylated dendrimer OVA (MDO) (Sheng et al., 2008). Compared to free OVA, MDO-pulsed DCs potently induced OVA-specific CD8+ and CD4+ T cell proliferation in vitro, which may result from the highavidity binding of MDA to DC surfaces and moderate stimulation of DC maturation. OVA-specific CD4+ and CD8+ T cells and antibody response were upregulated after immunization of mice challenged with B16-OVA tumor cells with MDO-pulsed DCs. Importantly, pre-immunization with MDO displayed prolonged tumor growth and resulted in better survival in mice challenged with B16-OVA tumor cells. CpG-loaded cationic gelatin nanoparticles were produced by covalently conjugating cholamine chloride hydrochloride to the surface of preformed gelatin nanoparticles, followed by physically adsorbing CpG onto the cationic surface (Bourquin et al., 2008). Treatment with OVA and CpG-loaded nanoparticles effectively increased OVA-specific CD8+ T cell number and induced OVA-specific protective antitumor response in mice challenged with B16-OVA compared to OVA alone (Fig. 7). Gd@C82(OH)22 is a C82 fullerene derivative, the surface of which is modified with approximately 22 hydroxyl groups, with a gadolinium

Fig. 7. CpG-loaded nanoparticles elicit an OVA-specific antitumor response. In brief, s.c. B16-OVA or B16 tumors were implanted s.c. in C57BL/6 mice after four immunizations with 50 g OVA and 100 g free CpG or NP-bound CpG (n = 5). (A) Immunization with OVA and NP-CpG significantly reduced growth of B16-OVA tumors compared to untreated mice (p < 0.03 at all time points from day 6) or to mice treated with OVA alone (*, p < 0.02 from day 13). No effect of immunization was seen in the wild-type B16 tumors (n.s. at all time points). (B) In mice with B16-OVA tumors, immunization with OVA and NP-CpG increased survival times compared with untreated mice (p = 0.009) or to mice treated with OVA alone (p = 0.003). No effect of immunization on survival was seen in the wild-type B16 tumors. Similar results were obtained in two independent experiments. Reprinted with permission from (Bourquin et al., 2008).

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Fig. 8. Schematic illustration of antigen-loaded upconversion nanoparticles (UCNPs) for DC stimulation, tracking and vaccination in DC-based immunotherapy. Reprinted with permission from (Xiang et al., 2015).

However, the dosing, timing, and scheduling of the combination therapy should be carefully considered. The adverse side effects of DC vaccines, especially autoimmune responses, are another major concern when designing DC-based vaccines. Certain peptides or tumor-lysate antigens that are used to fabricate cancer vaccines occur on healthy tissues rather than on neoplastic tissues (Houghton, 1994), which might lead to a potential risk of autoimmune diseases as shown in mice models (Ludewig et al., 2000). Therefore, precautionary measures must be adopted to reduce the risks of potential and fatal autoimmune responses. It is noteworthy that although immense progress has been made in nanotechnology and immunotherapy in the last decade, more extensive research is required to usher in the era of immunotherapy. The following basic points should be considered before successfully designing a cancer nanotherapeutic: 1) targeted increase in cytotoxic T cell population for therapeutic effect or memory T cell population for prophylactic treatment, 2) understanding of the variation in the subsets of DCs because of differences in population and properties of myeloid or plasmacytoid DCs, 3) selection of antigens as well as adjuvants, which will define the signal transmission pathway and subsequent immune response, 4) evaluation of the materials and characteristics of carriers for effective therapy, and 5) development of tools and methods for evaluating the efficacy of DC nanoimmunotherapy.

were coated with polyethylene glycol (PEG) and polyethylenimine (PEI) to fabricate UCNP-PEG-PEI (UPP) nanoparticles (Xiang et al., 2015) (Fig. 8). The model antigen OVA was adsorbed onto the surface of the dual-polymer-coated UPP nanoparticles forming an UPP@OVA complex via electrostatic interactions. The UPP@OVA dramatically enhanced DC internalization by approximately 5-fold compared to OVA alone. Mice injected with UPP@OVA complex-labeled DCs exhibited strong luminescence signal in popliteal lymph nodes after 48 h owing to the ultra-sensitive detection limit of as few as 50 DCs in mouse by upconversion luminescence (UCL) imaging. Importantly, DCs pulsed with UPP@OVA complex efficiently promoted T cell proliferation and production of cytokines (IFN-γ, TNF-α), and effectively induced the OVA-specific immune responses in immunized mice to selectively kill the OVA-expressed melanoma cells (B16-OVA cells) compared to DCs pulsed with free OVA or fresh DCs. 6. Concluding remarks and future perspectives: look back to move forward In this review, we have highlighted the potential of a wide variety of nanoparticles as delivery platforms of antigens and adjuvants for improving DC-based cancer immunotherapy. First, nanoparticles were able to deliver different types of antigens, especially TAAs, and adjuvants to dendritic cells, which promoted the therapeutic efficacy of DC-based immunotherapy and facilitated anti-tumor immunity. Second, nanoparticles can be used in combination with a multitude of imaging techniques such as fluorescence imaging, MRI, and optical imaging to monitor DC trafficking in vitro and/or in vivo and optimize DC-based immunotherapy. Many DC vaccines have been clinically tested for treatment of different types of cancer such as melanoma (Nestle et al., 1998; Romano et al., 2011; Thurner et al., 1999), prostate cancer (Kantoff et al., 2010; Small et al., 2000, 2007), and glioma (Yamanaka et al., 2005; Yu et al., 2001). However, the number of vaccinations was limited because of the process of withdrawing blood from patients for preparing these autologous vaccines from cultured peripheral blood mononuclear cells (PBMCs). Considering the aforementioned disadvantages and the various mechanisms via which tumors can prevent antigen presentation and interfere with DC maturation (Palucka and Banchereau, 2012), the combinations of immunotherapy and other standard-of-care regimes such as radiotherapy, chemotherapy, targeted therapy, surgery, and adoptive cellular therapy are strongly favored for better clinical efficacy (Pardoll, 2012). Recent clinical trials combining immunotherapy with radiotherapy (Formenti and Demaria, 2013; Kalbasi et al., 2013) or chemotherapy (Lynch et al., 2012; Maio et al., 2013) have shown better therapeutic efficacy or synergistic enhancement of antitumor activities compared to each regime alone. Preclinical data in mouse model also demonstrated the benefits of combining immunotherapy and targeted therapy (Balachandran et al., 2011; Khalili et al., 2012; Knight et al., 2013) or surgery (Kwon et al., 1999; Loi et al., 2013; Uno et al., 2006).

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