Application of Nanomedicine in Immunotherapy: Recent Advances and Prospects

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: closed (30 October 2022) | Viewed by 30396

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Special Issue Editors

Special Issue Information

Dear Colleagues,

Nanomedicine is a special area of medicine focused on the application of nanoparticles and drug nanocarriers to treat a wide variety of diseases, including cancer, infections, and auto-immune disorders. In the last decade, several original articles presented interesting results connecting these nanotechnologies with the activation of the immune system against different diseases. Probably the most prominent example of this was the RNA vaccines against COVID-19 when lipid nanoparticles were used to protect and deliver the nucleotides to the target cells. Of course, this is not the single application referred to as nanomedicine, and several others examples aiming at cancer therapy are also available in the literature. In this application, nanoparticles can be used to modulate the immune response, improving the oncological therapies. Thus, the aim of this Special Issue is to invite authors interested in the most recent science and technology applications of nanotechnology in immunotherapies against different diseases, including cancer, infections, and auto-immune conditions. We welcome submissions of original research, as well as review articles related to nanomedicine and immunological activation.

Dr. João Paulo Figueiró Longo
Dr. Luis Alexandre Muehlmann
Guest Editors

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Keywords

  • nanomedicine
  • immunotherapy
  • immune system
  • immune triggering
  • immune memory
  • innovation

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Published Papers (11 papers)

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Editorial

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3 pages, 215 KiB  
Editorial
Application of Nanomedicine in Immunotherapy: Recent Advances and Prospects
Pharmaceutics 2023, 15(7), 1910; https://doi.org/10.3390/pharmaceutics15071910 - 09 Jul 2023
Cited by 1 | Viewed by 741
Abstract
Nanomedicine is a special medical field focused on the application of nanotechnology to provide innovations for healthcare in different areas, including the treatment of a wide variety of diseases, including cancer [...] Full article

Research

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16 pages, 9406 KiB  
Article
Injectable Polypeptide Hydrogel Depots Containing Dual Immune Checkpoint Inhibitors and Doxorubicin for Improved Tumor Immunotherapy and Post-Surgical Tumor Treatment
Pharmaceutics 2023, 15(2), 428; https://doi.org/10.3390/pharmaceutics15020428 - 28 Jan 2023
Cited by 4 | Viewed by 1610
Abstract
In this work, we developed a strategy for local chemo-immunotherapy through simultaneous incorporation of dual immune checkpoint blockade (ICB) antibodies, anti-cytotoxic T-lymphocyte-associated protein 4 (aCTLA-4) and anti-programmed cell death protein 1 (aPD-1), and a chemotherapy drug, doxorubicin (Dox), into a thermo-gelling polypeptide hydrogel. [...] Read more.
In this work, we developed a strategy for local chemo-immunotherapy through simultaneous incorporation of dual immune checkpoint blockade (ICB) antibodies, anti-cytotoxic T-lymphocyte-associated protein 4 (aCTLA-4) and anti-programmed cell death protein 1 (aPD-1), and a chemotherapy drug, doxorubicin (Dox), into a thermo-gelling polypeptide hydrogel. The hydrogel encapsulating Dox or IgG model antibody showed sustained release profiles for more than 12 days in vitro, and the drug release and hydrogel degradation were accelerated in the presence of enzymes. In comparison to free drug solutions or hydrogels containing Dox or antibodies only, the Dox/aCTLA-4/aPD-1 co-loaded hydrogel achieved improved tumor suppression efficiency, strengthened antitumor immune response, and prolonged animal survival time after peritumoral injection into mice bearing B16F10 melanoma. Additionally, after injection of Dox/aCTLA-4/aPD-1 co-loaded hydrogel into the surgical site following tumor resection, a significantly enhanced inhibition on tumor reoccurrence was demonstrated. Thus, the polypeptide hydrogel-based chemo-immunotherapy strategy has potential in anti-tumor therapy and the prevention of tumor reoccurrence. Full article
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19 pages, 3641 KiB  
Article
mRNA-Loaded Lipid Nanoparticles Targeting Dendritic Cells for Cancer Immunotherapy
Pharmaceutics 2022, 14(8), 1572; https://doi.org/10.3390/pharmaceutics14081572 - 28 Jul 2022
Cited by 18 | Viewed by 4186
Abstract
Dendritic cells (DCs) are attractive antigen-presenting cells to be targeted for vaccinations. However, the systemic delivery of mRNA to DCs is hampered by technical challenges. We recently reported that it is possible to regulate the size of RNA-loaded lipid nanoparticles (LNPs) to over [...] Read more.
Dendritic cells (DCs) are attractive antigen-presenting cells to be targeted for vaccinations. However, the systemic delivery of mRNA to DCs is hampered by technical challenges. We recently reported that it is possible to regulate the size of RNA-loaded lipid nanoparticles (LNPs) to over 200 nm with the addition of salt during their formation when a microfluidic device is used and that larger LNPs delivered RNA more efficiently and in greater numbers to splenic DCs compared to the smaller counterparts. In this study, we report on the in vivo optimization of mRNA-loaded LNPs for use in vaccines. The screening included a wide range of methods for controlling particle size in addition to the selection of an appropriate lipid type and its composition. The results showed a clear correlation between particle size, uptake and gene expression activity in splenic DCs and indicated that a size range from 200 to 500 nm is appropriate for use in targeting splenic DCs. It was also found that it was difficult to predict the transgene expression activity and the potency of mRNA vaccines in splenic DCs using the whole spleen. A-11-LNP, which was found to be the optimal formulation, induced better transgene expression activity and maturation in DCs and induced clear therapeutic antitumor effects in an E.G7-OVA tumor model compared to two clinically relevant LNP formulations. Full article
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21 pages, 7636 KiB  
Article
Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines
Pharmaceutics 2022, 14(6), 1215; https://doi.org/10.3390/pharmaceutics14061215 - 07 Jun 2022
Cited by 7 | Viewed by 1834
Abstract
A new strategy to cause cell death in tumors might be the increase of intracellular polyamines at concentrations above their physiological values to trigger the production of oxidation metabolites at levels exceeding cell tolerance. To test this hypothesis, we prepared nanospermidine as a [...] Read more.
A new strategy to cause cell death in tumors might be the increase of intracellular polyamines at concentrations above their physiological values to trigger the production of oxidation metabolites at levels exceeding cell tolerance. To test this hypothesis, we prepared nanospermidine as a carrier for spermidine penetration into the cells, able to escape the polyamine transport system that strictly regulates intracellular polyamine levels. Nanospermidine was prepared by spermidine encapsulation in nanomicelles and was characterized by size, zeta potential, loading, dimensional stability to dilution, and stability to spermidine leakage. Antitumor activity, ROS production, and cell penetration ability were evaluated in vitro in two neuroblastoma cell lines (NLF and BR6). Nanospermidine was tested as a single agent and in combination with nanofenretinide. Free spermidine was also tested as a comparison. The results indicated that the nanomicelles successfully transported spermidine into the cells inducing cell death in a concentration range (150–200 μM) tenfold lower than that required to provide similar cytotoxicity with free spermidine (1500–2000 μM). Nanofenretinide provided a cytostatic effect in combination with the lowest nanospermidine concentrations evaluated and slightly improved nanospermidine cytotoxicity at the highest concentrations. These data suggest that nanospermidine has the potential to become a new approach in cancer treatment. At the cellular level, in fact, it exploits polyamine catabolism by means of biocompatible doses of spermidine and, in vivo settings, it can exploit the selective accumulation of nanomedicines at the tumor site. Nanofenretinide combination further improves its efficacy. Furthermore, the proven ability of spermidine to activate macrophages and lymphocytes suggests that nanospermidine could inhibit immunosuppression in the tumor environment. Full article
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18 pages, 3616 KiB  
Article
Surface Functionalization of Silica Nanoparticles: Strategies to Optimize the Immune-Activating Profile of Carrier Platforms
Pharmaceutics 2022, 14(5), 1103; https://doi.org/10.3390/pharmaceutics14051103 - 21 May 2022
Cited by 4 | Viewed by 2541
Abstract
Silica nanoparticles (SiNPs) are generally regarded as safe and may represent an attractive carrier platform for nanomedical applications when loaded with biopharmaceuticals. Surface functionalization by different chemistries may help to optimize protein loading and may further impact uptake into the targeted tissues or [...] Read more.
Silica nanoparticles (SiNPs) are generally regarded as safe and may represent an attractive carrier platform for nanomedical applications when loaded with biopharmaceuticals. Surface functionalization by different chemistries may help to optimize protein loading and may further impact uptake into the targeted tissues or cells, however, it may also alter the immunologic profile of the carrier system. In order to circumvent side effects, novel carrier candidates need to be tested thoroughly, early in their development stage within the pharmaceutical innovation pipeline, for their potential to activate or modify the immune response. Previous studies have identified surface functionalization by different chemistries as providing a plethora of modifications for optimizing efficacy of biopharmaceutical (nano)carrier platforms while maintaining an acceptable safety profile. In this study, we synthesized SiNPs and chemically functionalized them to obtain different surface characteristics to allow their application as a carrier system for allergen-specific immunotherapy. In the present study, crude natural allergen extracts are used in combination with alum instead of well-defined active pharmaceutical ingredients (APIs), such as recombinant allergen, loaded onto (nano)carrier systems with immunologically inert and stable properties in suspension. This study was motivated by the hypothesis that comparing different charge states could allow tailoring of the binding capacity of the particulate carrier system, and hence the optimization of biopharmaceutical uptake while maintaining an acceptable safety profile, which was investigated by determining the maturation of human antigen-presenting cells (APCs). The functionalized nanoparticles were characterized for primary and hydrodynamic size, polydispersity index, zeta potential, endotoxin contamination. As potential candidates for allergen-specific immunotherapy, the differently functionalized SiNPs were non-covalently coupled with a highly purified, endotoxin-free recombinant preparation of the major birch pollen allergen Bet v 1 that functioned for further immunological testing. Binding efficiencies of allergen to SiNPs was controlled to determine uptake of API. For efficacy and safety assessment, we employed human monocyte-derived dendritic cells as model for APCs to detect possible differences in the particles’ APC maturation potential. Functionalization of SiNP did not affect the viability of APCs, however, the amount of API physisorbed onto the nanocarrier system, which induced enhanced uptake, mainly by macropinocytosis. We found slight differences in the maturation state of APCs for the differently functionalized SiNP–API conjugates qualifying surface functionalization as an effective instrument for optimizing the immune response towards SiNPs. This study further suggests that surface-functionalized SiNPs could be a suitable, immunologically inert vehicle for the efficient delivery of biopharmaceutical products, as evidenced here for allergen-specific immunotherapy. Full article
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13 pages, 1727 KiB  
Article
Induction of Immunogenic Cell Death by Photodynamic Therapy Mediated by Aluminum-Phthalocyanine in Nanoemulsion
Pharmaceutics 2022, 14(1), 196; https://doi.org/10.3390/pharmaceutics14010196 - 14 Jan 2022
Cited by 18 | Viewed by 2255
Abstract
Photodynamic therapy (PDT) has been clinically employed to treat mainly superficial cancer, such as basal cell carcinoma. This approach can eliminate tumors by direct cytotoxicity, tumor ischemia, or by triggering an immune response against tumor cells. Among the immune-related mechanisms of PDT, the [...] Read more.
Photodynamic therapy (PDT) has been clinically employed to treat mainly superficial cancer, such as basal cell carcinoma. This approach can eliminate tumors by direct cytotoxicity, tumor ischemia, or by triggering an immune response against tumor cells. Among the immune-related mechanisms of PDT, the induction of immunogenic cell death (ICD) in target cells is to be cited. ICD is an apoptosis modality distinguished by the emission of damage-associated molecular patterns (DAMP). Therefore, this study aimed to analyze the immunogenicity of CT26 and 4T1 treated with PDT mediated by aluminum-phthalocyanine in nanoemulsion (PDT-AlPc-NE). Different PDT-AlPc-NE protocols with varying doses of energy and AlPc concentrations were tested. The death mechanism and the emission of DAMPs–CRT, HSP70, HSP90, HMGB1, and IL-1β–were analyzed in cells treated in vitro with PDT. Then, the immunogenicity of these cells was assessed in an in vivo vaccination-challenge model with BALB/c mice. CT26 and 4T1 cells treated in vitro with PDT mediated by AlPc IC50 and a light dose of 25 J/cm2 exhibited the hallmarks of ICD, i.e., these cells died by apoptosis and exposed DAMPs. Mice injected with these IC50 PDT-treated cells showed, in comparison to the control, increased resistance to the development of tumors in a subsequent challenge with viable cells. Mice injected with 4T1 and CT26 cells treated with higher or lower concentrations of photosensitizer and light doses exhibited a significantly lower resistance to tumor development than those injected with IC50 PDT-treated cells. The results presented in this study suggest that both the photosensitizer concentration and light dose affect the immunogenicity of the PDT-treated cells. This event can affect the therapy outcomes in vivo. Full article
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18 pages, 3575 KiB  
Article
Immunomodulatory Nanoparticles Mitigate Macrophage Inflammation via Inhibition of PAMP Interactions and Lactate-Mediated Functional Reprogramming of NF-κB and p38 MAPK
Pharmaceutics 2021, 13(11), 1841; https://doi.org/10.3390/pharmaceutics13111841 - 02 Nov 2021
Cited by 21 | Viewed by 3138
Abstract
Inflammation is a key homeostatic process involved in the body’s response to a multitude of disease states including infection, autoimmune disorders, cancer, and other chronic conditions. When the initiating event is poorly controlled, severe inflammation and globally dysregulated immune responses can occur. To [...] Read more.
Inflammation is a key homeostatic process involved in the body’s response to a multitude of disease states including infection, autoimmune disorders, cancer, and other chronic conditions. When the initiating event is poorly controlled, severe inflammation and globally dysregulated immune responses can occur. To address the lack of therapies that efficaciously address the multiple aspects of the dysregulated immune response, we developed cargo-less immunomodulatory nanoparticles (iNPs) comprised of poly(lactic acid) (PLA) with either poly(vinyl alcohol) (PVA) or poly(ethylene-alt-maleic acid) (PEMA) as stabilizing surfactants and investigated the mechanisms by which they exert their inherent anti-inflammatory effects. We identified that iNPs leverage a multimodal mechanism of action by physically interfering with the interactions between pathogen-associated molecular patterns (PAMPs) and bone marrow-derived macrophages (BMMΦs). Additionally, we showed that iNPs mitigate proinflammatory cytokine secretions induced by LPS via a time- and composition-dependent abrogation of NF-κB p65 and p38 MAPK activation. Lastly, inhibition studies were performed to establish the role of a pH-sensing G-protein-coupled receptor, GPR68, on contributing to the activity of iNPs. These data provide evidence for the multimodal mechanism of action of iNPs and establish their potential use as a novel therapeutic for the treatment of severe inflammation. Full article
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Review

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36 pages, 2843 KiB  
Review
Superparamagnetic Iron Oxide Nanoparticles for Immunotherapy of Cancers through Macrophages and Magnetic Hyperthermia
Pharmaceutics 2022, 14(11), 2388; https://doi.org/10.3390/pharmaceutics14112388 - 05 Nov 2022
Cited by 15 | Viewed by 3500
Abstract
Cancer immunotherapy has tremendous promise, but it has yet to be clinically applied in a wider variety of tumor situations. Many therapeutic combinations are envisaged to improve their effectiveness. In this way, strategies capable of inducing immunogenic cell death (e.g., doxorubicin, radiotherapy, hyperthermia) [...] Read more.
Cancer immunotherapy has tremendous promise, but it has yet to be clinically applied in a wider variety of tumor situations. Many therapeutic combinations are envisaged to improve their effectiveness. In this way, strategies capable of inducing immunogenic cell death (e.g., doxorubicin, radiotherapy, hyperthermia) and the reprogramming of the immunosuppressive tumor microenvironment (TME) (e.g., M2-to-M1-like macrophages repolarization of tumor-associated macrophages (TAMs)) are particularly appealing to enhance the efficacy of approved immunotherapies (e.g., immune checkpoint inhibitors, ICIs). Due to their modular construction and versatility, iron oxide-based nanomedicines such as superparamagnetic iron oxide nanoparticles (SPIONs) can combine these different approaches in a single agent. SPIONs have already shown their safety and biocompatibility and possess both drug-delivery (e.g., chemotherapy, ICIs) and magnetic capabilities (e.g., magnetic hyperthermia (MHT), magnetic resonance imaging). In this review, we will discuss the multiple applications of SPIONs in cancer immunotherapy, focusing on their theranostic properties to target TAMs and to generate MHT. The first section of this review will briefly describe immune targets for NPs. The following sections will deal with the overall properties of SPIONs (including MHT). The last section is dedicated to the SPION-induced immune response through its effects on TAMs and MHT. Full article
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17 pages, 1792 KiB  
Review
An Overview on Immunogenic Cell Death in Cancer Biology and Therapy
Pharmaceutics 2022, 14(8), 1564; https://doi.org/10.3390/pharmaceutics14081564 - 27 Jul 2022
Cited by 10 | Viewed by 3853
Abstract
Immunogenic cell death (ICD) is a modality of regulated cell death that is sufficient to promote an adaptive immune response against antigens of the dying cell in an immunocompetent host. An important characteristic of ICD is the release and exposure of damage-associated molecular [...] Read more.
Immunogenic cell death (ICD) is a modality of regulated cell death that is sufficient to promote an adaptive immune response against antigens of the dying cell in an immunocompetent host. An important characteristic of ICD is the release and exposure of damage-associated molecular patterns, which are potent endogenous immune adjuvants. As the induction of ICD can be achieved with conventional cytotoxic agents, it represents a potential approach for the immunotherapy of cancer. Here, different aspects of ICD in cancer biology and treatment are reviewed. Full article
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26 pages, 2430 KiB  
Review
Activation of Cellular Players in Adaptive Immunity via Exogenous Delivery of Tumor Cell Lysates
Pharmaceutics 2022, 14(7), 1358; https://doi.org/10.3390/pharmaceutics14071358 - 27 Jun 2022
Cited by 5 | Viewed by 2092
Abstract
Tumor cell lysates (TCLs) are a good immunogenic source of tumor-associated antigens. Since whole necrotic TCLs can enhance the maturation and antigen-presenting ability of dendritic cells (DCs), multiple strategies for the exogenous delivery of TCLs have been investigated as novel cancer immunotherapeutic solutions. [...] Read more.
Tumor cell lysates (TCLs) are a good immunogenic source of tumor-associated antigens. Since whole necrotic TCLs can enhance the maturation and antigen-presenting ability of dendritic cells (DCs), multiple strategies for the exogenous delivery of TCLs have been investigated as novel cancer immunotherapeutic solutions. The TCL-mediated induction of DC maturation and the subsequent immunological response could be improved by utilizing various material-based carriers. Enhanced antitumor immunity and cancer vaccination efficacy could be eventually achieved through the in vivo administration of TCLs. Therefore, (1) important engineering methodologies to prepare antigen-containing TCLs, (2) current therapeutic approaches using TCL-mediated DC activation, and (3) the significant sequential mechanism of DC-based signaling and stimulation in adaptive immunity are summarized in this review. More importantly, the recently reported developments in biomaterial-based exogenous TCL delivery platforms and co-delivery strategies with adjuvants for effective cancer vaccination and antitumor effects are emphasized. Full article
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23 pages, 1306 KiB  
Review
Nanotechnology in Immunotherapy for Type 1 Diabetes: Promising Innovations and Future Advances
Pharmaceutics 2022, 14(3), 644; https://doi.org/10.3390/pharmaceutics14030644 - 15 Mar 2022
Cited by 4 | Viewed by 3463
Abstract
Diabetes is a chronic condition which affects the glucose metabolism in the body. In lieu of any clinical “cure,” the condition is managed through the administration of pharmacological aids, insulin supplements, diet restrictions, exercise, and the like. The conventional clinical prescriptions are limited [...] Read more.
Diabetes is a chronic condition which affects the glucose metabolism in the body. In lieu of any clinical “cure,” the condition is managed through the administration of pharmacological aids, insulin supplements, diet restrictions, exercise, and the like. The conventional clinical prescriptions are limited by their life-long dependency and diminished potency, which in turn hinder the patient’s recovery. This necessitated an alteration in approach and has instigated several investigations into other strategies. As Type 1 diabetes (T1D) is known to be an autoimmune disorder, targeting the immune system in activation and/or suppression has shown promise in reducing beta cell loss and improving insulin levels in response to hyperglycemia. Another strategy currently being explored is the use of nanoparticles in the delivery of immunomodulators, insulin, or engineered vaccines to endogenous immune cells. Nanoparticle-assisted targeting of immune cells holds substantial potential for enhanced patient care within T1D clinical settings. Herein, we summarize the knowledge of etiology, clinical scenarios, and the current state of nanoparticle-based immunotherapeutic approaches for Type 1 diabetes. We also discuss the feasibility of translating this approach to clinical practice. Full article
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