RESUMO
The search for vaccines that protect from severe morbidity and mortality because of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19) is a race against the clock and the virus. Here we describe an amphiphilic imidazoquinoline (IMDQ-PEG-CHOL) TLR7/8 adjuvant, consisting of an imidazoquinoline conjugated to the chain end of a cholesterol-poly(ethylene glycol) macromolecular amphiphile. It is water-soluble and exhibits massive translocation to lymph nodes upon local administration through binding to albumin, affording localized innate immune activation and reduction in systemic inflammation. The adjuvanticity of IMDQ-PEG-CHOL was validated in a licensed vaccine setting (quadrivalent influenza vaccine) and an experimental trimeric recombinant SARS-CoV-2 spike protein vaccine, showing robust IgG2a and IgG1 antibody titers in mice that could neutralize viral infection in vitro and in vivo in a mouse model.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , Imidazóis/uso terapêutico , Imunidade Inata/efeitos dos fármacos , Quinolinas/uso terapêutico , Animais , Vacinas contra COVID-19/imunologia , Colesterol/análogos & derivados , Colesterol/imunologia , Colesterol/uso terapêutico , Feminino , Humanos , Imidazóis/imunologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Glicoproteínas de Membrana/agonistas , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Polietilenoglicóis/uso terapêutico , Quinolinas/imunologia , Proteínas Recombinantes/imunologia , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/imunologia , Tensoativos/uso terapêutico , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistasRESUMO
Synthetic immune-stimulatory drugs such as agonists of the Toll-like receptors (TLR) 7/8 are potent activators of antigen-presenting cells (APCs), however, they also induce severe side effects due to leakage from the site of injection into systemic circulation. Here, we report on the design and synthesis of an amphiphilic polymer-prodrug conjugate of an imidazoquinoline TLR7/8 agonist that in aqueous medium forms vesicular structures of 200 nm. The conjugate contains an endosomal enzyme-responsive linker enabling degradation of the vesicles and release of the TLR7/8 agonist in native form after endocytosis, which results in high in vitro TLR agonist activity. In a mouse model, locally administered vesicles provoke significantly more potent and long-lasting immune stimulation in terms of interferon expression at the injection site and in draining lymphoid tissue compared to a nonamphiphilic control and the native TLR agonist. Moreover, the vesicles induce robust activation of dendritic cells in the draining lymph node in vivo.
Assuntos
Imidazóis/farmacologia , Glicoproteínas de Membrana/agonistas , Pró-Fármacos/farmacologia , Quinolinas/farmacologia , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , beta-Galactosidase/imunologia , Animais , Imidazóis/química , Imidazóis/metabolismo , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Glicoproteínas de Membrana/imunologia , Camundongos , Estrutura Molecular , Tamanho da Partícula , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Polietilenoglicóis/farmacologia , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Quinolinas/química , Quinolinas/metabolismo , Propriedades de Superfície , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , beta-Galactosidase/química , beta-Galactosidase/metabolismoRESUMO
The zebrafish embryo is a vertebrate well suited for visualizing nanoparticles at high resolution in live animals. Its optical transparency and genetic versatility allow noninvasive, real-time observations of vascular flow of nanoparticles and their interactions with cells throughout the body. As a consequence, this system enables the acquisition of quantitative data that are difficult to obtain in rodents. Until now, a few studies using the zebrafish model have only described semiquantitative results on key nanoparticle parameters. Here, a MACRO dedicated to automated quantitative methods is described for analyzing important parameters of nanoparticle behavior, such as circulation time and interactions with key target cells, macrophages, and endothelial cells. Direct comparison of four nanoparticle (NP) formulations in zebrafish embryos and mice reveals that data obtained in zebrafish can be used to predict NPs' behavior in the mouse model. NPs having long or short blood circulation in rodents behave similarly in the zebrafish embryo, with low circulation times being a consequence of NP uptake into macrophages or endothelial cells. It is proposed that the zebrafish embryo has the potential to become an important intermediate screening system for nanoparticle research to bridge the gap between cell culture studies and preclinical rodent models such as the mouse.
Assuntos
Nanopartículas , Peixe-Zebra , Animais , Embrião não Mamífero , Células Endoteliais/metabolismo , Macrófagos/metabolismo , Camundongos , Nanopartículas/metabolismoRESUMO
Conjugation of small molecule drug to lipid-polymer amphiphiles is a powerful strategy to alter the pharmacokinetic profile of these molecules by promoting binding to albumin or other serum molecules. Incorporation of a responsive linker between the lipid anchor and the polymer chain can be of interest to avoid indefinite binding of the conjugates to hydrophobic pockets of serum proteins or phospholipid membranes when reaching a target cell or tissue. Here, the synthesis of pH-sensitive lipid-polymer conjugates by reversible addition-fragmentation chain transfer (RAFT) polymerization using a RAFT chain transfer agent that is equipped with a pH-sensitive ketal bond between a cholesterol moiety and the trithiocarbonate RAFT chain transfer group is reported. It is demonstrated that in native form these conjugates exhibit a high affinity to albumin and cell membranes but loose this ability in response to a mild acidic trigger in aqueous medium.
Assuntos
Lipídeos , Polímeros , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , PolimerizaçãoRESUMO
The advent of immunotherapy is a game changer in cancer therapy with monoclonal antibody- and T cell-based therapeutics being the current flagships. Small molecule immunotherapeutics might offer advantages over the biological drugs in terms of complexity, tissue penetration, manufacturing cost, stability, and shelf life. However, small molecule drugs are prone to rapid systemic distribution, which might induce severe off-target side effects. Nanotechnology could aid in the formulation of the drug molecules to improve their delivery to specific immune cell subsets. In this review we summarize the current efforts in changing the pharmacokinetic profile of small molecule immunotherapeutics with a strong focus on Toll-like receptor agonists. In addition, we give our vision on limitations and future pathways in the route of nanomedicine to the clinical practice.
Assuntos
Anticorpos Monoclonais/farmacocinética , Antineoplásicos/farmacocinética , Imunoterapia , Nanomedicina , Neoplasias/terapia , Bibliotecas de Moléculas Pequenas/farmacocinética , Anticorpos Monoclonais/química , Antineoplásicos/química , Humanos , Neoplasias/imunologia , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Interactive materials that can respond to a trigger by changing their morphology, but that can also gradually degrade into a fully soluble state, are attractive building blocks for the next generation of biomaterials. Herein, we design such transiently responsive polymers that exhibit UCST behaviour while gradually losing this property in response to a hydrolysis reaction in the polymer side chains. The polymers operate within a physiologically relevant window in terms of temperature, pH, and ionic strength. Whereas such behaviour has been reported earlier for LCST systems, it is at present unexplored for UCST polymers. Furthermore, we demonstrate that, in contrast to LCST polymers, in aqueous medium the UCST polymer forms a coacervate phase below the UCST, which can entrap a hydrophilic model protein, as well as a hydrophobic dye. Because of their non-toxicity, we also provide inâ vivo proof of concept of the use of this coacervate as a protein depot, in view of sustained-release applications.
Assuntos
Materiais Biocompatíveis/química , Transição de Fase , Polímeros/química , Proteínas/química , Temperatura , Hidrólise , PolimerizaçãoRESUMO
Uncontrolled systemic inflammatory immune triggering has hampered the clinical translation of several classes of small-molecule immunomodulators, such as imidazoquinoline TLR7/8 agonists for vaccine design and cancer immunotherapy. By taking advantage of the inherent serum-protein-binding property of lipid motifs and their tendency to accumulate in lymphoid tissue, we designed amphiphilic lipid-polymer conjugates that suppress systemic inflammation but provoke potent lymph-node immune activation. This work provides a rational basis for the design of lipid-polymer amphiphiles for optimized lymphoid targeting.
Assuntos
Imunidade Inata , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Animais , Colesterol/química , Imidazóis/química , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Fatores Imunológicos/farmacologia , Lipídeos/química , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Polímeros/química , Quinolinas/química , Quinolinas/farmacologia , Células RAW 264.7 , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismoRESUMO
Small molecule immuno-modulators such as agonists of Toll-like receptors (TLRs) are attractive compounds to stimulate innate immune cells toward potent antiviral and antitumor responses. However, small molecules rapidly enter the systemic circulation and cause "wasted inflammation". Hence, synthetic strategies to confine their radius of action to lymphoid tissue are of great relevance, to both enhance their efficacy and concomitantly limit toxicity. Here, we demonstrate that covalent conjugation of a small molecule TLR7/8 agonist immunomodulatory to a micelle-forming amphiphilic block copolymer greatly alters the pharmacokinetic profile, resulting in highly efficient lymphatic delivery. Moreover, we designed amphiphilic block copolymers in such a way to form thermodynamically stable micelles through π-π stacking between aromatic moieties, and we engineered the block copolymers to undergo an irreversible amphiphilic to hydrophilic transition in response to the acidic endosomal pH.
Assuntos
Linfonodos/efeitos dos fármacos , Polímeros/farmacologia , Tensoativos/farmacologia , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Humanos , Concentração de Íons de Hidrogênio , Linfonodos/imunologia , Micelas , Modelos Moleculares , Estrutura Molecular , Polímeros/química , Tensoativos/química , Termodinâmica , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologiaRESUMO
The quest for new potent and safe adjuvants with which to skew and boost the immune response of vaccines against intracellular pathogens and cancer has led to the discovery of a series of small molecules that can activate Toll-like receptors (TLRs). Whereas many small molecule TLR agonists cope with a problematic safety profile, amphotericin B (AmpB), a Food and Drug Administration approved antifungal drug, has recently been discovered to possess TLR-triggering activity. However, its poor aqueous solubility and cytotoxicity at elevated concentrations currently hampers its development as a vaccine adjuvant. We present a new class of transiently thermoresponsive polymers that, in their native state, have a phase-transition temperature below room temperature but gradually transform into fully soluble polymers through acetal hydrolysis at endosomal pH values. RAFT polymerization afforded well-defined block copolymers that self-assemble into micellar nanoparticles and efficiently encapsulate AmpB. Importantly, nanoencapsulation strongly reduced the cytotoxic effect of AmpB but maintained its TLR-triggering capacity. Studies in mice showed that AmpB-loaded nanoparticles can adjuvant an RSV vaccine candidate with almost equal potency as a highly immunogenic oil-in-water benchmark adjuvant.
Assuntos
Acetais/química , Adjuvantes Imunológicos/administração & dosagem , Anfotericina B/administração & dosagem , Preparações de Ação Retardada/química , Polímeros/química , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Receptores Toll-Like/agonistas , Acetais/efeitos adversos , Adjuvantes Imunológicos/efeitos adversos , Adjuvantes Imunológicos/uso terapêutico , Anfotericina B/efeitos adversos , Anfotericina B/uso terapêutico , Animais , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antifúngicos/uso terapêutico , Preparações de Ação Retardada/efeitos adversos , Feminino , Camundongos Endogâmicos BALB C , Nanopartículas/efeitos adversos , Nanopartículas/química , Polímeros/efeitos adversos , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vacinas contra Vírus Sincicial Respiratório/uso terapêutico , Temperatura , Receptores Toll-Like/imunologia , Temperatura de TransiçãoRESUMO
Degradable synthetic crosslinking is a versatile strategy to harness nanomaterials against disassembly in a complex physiological medium prompted by dilution effects or competitive interaction. In particular, chemical bonds such as ketals that are stable at physiological conditions but are cleaved in response to disease-mediated or intracellular conditions (e.g., a mildly acidic pH) are of great relevance for biomedical applications. Despite the range of spectroscopic or chromatographic analyses methods that allow chemical degradation in solution to be assessed, it is much less straightforward to interrogate synthetic nanomaterials for their degradation state when located inside a living organism. We demonstrate a method based on FRET analysis to monitor intracellular disassembly of block-copolymer-derived nanoparticles engineered with a FRET couple on separate polymer chains, which after self-assembly are covalently crosslinked with a pH-sensitive ketal-containing crosslinker.
Assuntos
Transferência Ressonante de Energia de Fluorescência , Nanopartículas/química , Animais , Carbocianinas/química , Linhagem Celular , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Difusão Dinâmica da Luz , Concentração de Íons de Hidrogênio , Hidrólise , Lisossomos/metabolismo , Camundongos , Microscopia Confocal , Nanopartículas/metabolismoRESUMO
Anisotropic nanostructures, such as nanotubes, incorporating bioactive molecules present interesting features for application as drug delivery carriers. Here, we present the synthesis of layer-by-layer (LbL) nanotubes including protein (ovalbumin) layers and go from simple to more complex synergetic combinations of synthetic and natural polyelectrolytes, leading to structures with tunable properties. The rigidity in organic and aqueous media, the stability in buffer solution and the uptake of different LbL tubes by dendritic cells (DCs) are analyzed to contrast size and chemistry. The most rigid studied systems appear as the best candidates to be internalized by cells, regardless of the chemistry of their outermost layers. The successful transport of long protein-loaded robust rigid nanotubes to the cytoplasm of DCs paves the way for their use as new cargo for the delivery of large amounts of antigen to such cells.
Assuntos
Células Dendríticas/metabolismo , Ovalbumina/química , Animais , Antígenos/química , Linhagem Celular , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Camundongos , Nanoestruturas/química , Nanotubos/química , Polieletrólitos/químicaRESUMO
Despite their great versatility and ease of functionalization, most polymer-based nanocarriers intended for use in drug delivery often face serious limitations that can prevent their clinical translation, such as uncontrolled drug release and off-target toxicity, which mainly originate from the burst release phenomenon. In addition, residual solvents from the formulation process can induce toxicity, alter the physico-chemical and biological properties and can strongly impair further pharmaceutical development. To address these issues, we report polymer prodrug nanoparticles, which are prepared without organic solvents via an all-aqueous formulation process, and provide sustained drug release. This was achieved by the "drug-initiated" synthesis of well-defined copolymer prodrugs exhibiting a lower critical solution temperature (LCST) and based on the anticancer drug gemcitabine (Gem). After screening for different structural parameters, prodrugs based on amphiphilic diblock copolymers were formulated into stable nanoparticles by all-aqueous nanoprecipitation, with rather narrow particle size distribution and average diameters in the 50-80 nm range. They exhibited sustained Gem release in human serum and acetate buffer, rapid cellular uptake and significant cytotoxicity on A549 and Mia PaCa-2 cancer cells. We also demonstrated the versatility of this approach by formulating Gem-based polymer prodrug nanoparticles loaded with doxorubicin (Dox) for combination therapy. The dual-drug nanoparticles exhibited sustained release of Gem in human serum and acidic release of Dox under accelerated pathophysiological conditions. Importantly, they also induced a synergistic effect on triple-negative breast cancer line MDA-MB-231, which is a relevant cell line to this combination.
Assuntos
Desoxicitidina , Liberação Controlada de Fármacos , Gencitabina , Nanopartículas , Polímeros , Pró-Fármacos , Temperatura , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Humanos , Nanopartículas/química , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/química , Desoxicitidina/farmacocinética , Polímeros/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada , Portadores de Fármacos/química , Precipitação Química , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinéticaRESUMO
Current vascular grafts, primarily Gore-Tex® and Dacron®, don't integrate with the host and have low patency in small-diameter vessels (<6 mm). Biomaterials that possess appropriate viscoelasticity, compliance, and high biocompatibility are essential for their application in small blood vessels. We have developed metal ion crosslinked poly(propanediol-co-(hydroxyphenyl methylene)amino-propanediol sebacate) (M-PAS), a biodegradable elastomer with a wide range of mechanical properties. We call these materials metallo-elastomers. An initial test on Zn-, Fe-, and Cu-PAS grafts reveals that Cu-PAS is the most suitable because of its excellent elastic recoil and well-balanced polymer degradation/tissue regeneration rate. Here we report host remodeling of Cu-PAS vascular grafts in rats over one year. 76 % of the grafts remain patent and >90 % of the synthetic polymer is degraded by 12 months. Extensive cell infiltration leads to a positive host remodeling. The remodeled grafts feature a fully endothelialized lumen. Circumferentially organized smooth muscle cells, elastin fibers, and widespread mature collagen give the neoarteries mechanical properties similar to native arteries. Proteomic analysis further reveals the presence of important vascular proteins in the neoarteries. Evidence suggests that Cu-PAS is a promising material for engineering small blood vessels.
Assuntos
Prótese Vascular , Artérias Carótidas , Elastômeros , Animais , Elastômeros/química , Ratos , Masculino , Materiais Biocompatíveis/química , Ratos Sprague-Dawley , Polímeros/química , Teste de MateriaisRESUMO
Postoperative peritoneal adhesions occur in the majority of patients undergoing intra-abdominal surgery and are one of the leading causes of hospital re-admission. There is an unmet clinical need for effective anti-adhesive biomaterials, which can be applied evenly across the damaged tissues. We examined three different responsive hydrogel types, i.e. a thermosensitive PLGA-PEG-PLGA, a pH responsive UPy-PEG and a shear-thinning hexapeptide for this purpose. More specifically, their potential to be homogeneously distributed in the peritoneal cavity by high pressure nebulization and prevent peritoneal adhesions was evaluated. Solutions of each polymer type could be successfully nebulized while retaining their responsive gelation behavior in vitro and in vivo. Furthermore, none of the polymers caused in vitro toxicity on SKOV3-IP2 cells. Following intraperitoneal administration, both the PLGA-PEG-PLGA and the hexapeptide hydrogels resulted in local inflammation and fibrosis and failed in preventing peritoneal adhesions 7 days after adhesion induction. In contrast, the pH sensitive UPy-PEG formulation was well tolerated and could significantly reduce the formation of peritoneal adhesions, even outperforming the commercially available Hyalobarrier® as positive control. To conclude, local nebulization of the bioresponsive UPy-PEG hydrogel can be considered as a promising approach to prevent postsurgical peritoneal adhesions.
RESUMO
Pharmacological strategies to activate innate immune cells are of great relevance in the context of vaccine design and anticancer immune therapy, to mount broad immune responses able to clear infection and malignant cells. Synthetic CpG oligodeoxynucleotides (CpG-ODNs) are short single-stranded DNA molecules containing unmethylated CpG dinucleotides and a phosphorothioate backbone. Class B CpG ODNs activate robust innate immune responses through a TLR9-dependent NF-κB signaling pathway. This feature is attractive to exploit in the context of vaccine design and cancer immunotherapy. Soluble CpG-ODNs cause hepatic toxicity, which reduces its therapeutic applicability. The formulation of class B CpG ODN1826 in lipid nanoparticles (LNPs) containing an ionizable cationic lipid that complexes CpG through electrostatic interaction is reported. Upon local administration, LNP-formulated CpG drains to lymph nodes and triggers robust innate immune activation. Unformulated, soluble, CpG, by contrast, is unable to induce robust innate activation in draining lymph nodes and is distributed systemically. In a vaccination setting, LNP-formulated CpG, admixed with a protein antigen, induces higher antigen-specific antibody titers and T cell responses than antigen admixed with unformulated soluble CpG.
Assuntos
Receptor Toll-Like 9 , Vacinas , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/química , Imunidade Inata , Tecido Linfoide , Oligodesoxirribonucleotídeos/farmacologia , Oligodesoxirribonucleotídeos/químicaRESUMO
In situ anti-tumor vaccination is an attractive type of cancer immunotherapy which relies on the effectiveness of dendritic cells (DCs) to engulf tumor antigens, become activated, and present antigens to T cells in lymphoid tissue. Here, a multifunctional nanocomplex based on calcium crosslinked polyaspartic acid conjugated to either a toll-like receptor (TLR)7/8 agonist or a photosensitizer is reported. Intratumoral administration of the nanocomplex followed by laser irradiation induces cell killing and hence generation of a pool of tumor-associated antigens, with concomitant promotion of DCs maturation and expansion of T cells in tumor-draining lymph nodes. Suppression of tumor growth is observed both at the primary site and at the distal site, thereby hinting at successful induction of an adaptive anti-tumor response. This strategy holds promise for therapeutic application in a pre-operative and post-operative setting to leverage to mutanome of the patient's own tumor to mount immunological memory to clear residual tumor cells and metastasis.
Assuntos
Vacinas Anticâncer , Neoplasias , Receptor 7 Toll-Like , Receptor 8 Toll-Like , Adjuvantes Imunológicos/uso terapêutico , Animais , Antígenos de Neoplasias , Cálcio , Vacinas Anticâncer/administração & dosagem , Células Dendríticas , Sistemas de Liberação de Medicamentos , Imunidade , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , VacinaçãoRESUMO
Adjuvant is an essential component in subunit vaccines. Many agonists of pathogen recognition receptors have been developed as potent adjuvants to optimize the immunogenicity and efficacy of vaccines. Recently discovered cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has attracted much attention as it is a key mediator for modulating immune responses. Vaccines adjuvanted with STING agonists are found to mediate a robust immune defense against infections and cancer. In this review, we first discuss the mechanisms of STING agonists in the context of vaccination. Next, we present recent progress in novel STING agonist discovery and the delivery strategies. We next highlight recent work in optimizing the efficacy while minimizing toxicity of STING agonist-assisted subunit vaccines for protection against infectious diseases or treatment of cancer. Finally, we share our perspectives of current issues and future directions in further developing STING agonists for adjuvanting subunit vaccines.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Proteínas de Membrana/agonistas , Proteínas de Membrana/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Humanos , Imunidade Humoral/efeitos dos fármacos , Nucleotidiltransferases/metabolismoRESUMO
Immune stimulatory antibodies and cytokines elicit potent antitumor immunity. However, the dose-limiting systemic toxicity greatly hinders their clinical applications. Here, we demonstrate a chemical approach, termed "switchable" immune modulator (Sw-IM), to limit the systemic exposure and therefore ameliorate their toxicities. Sw-IM is a biomacromolecular therapeutic reversibly masked by biocompatible polymers through chemical linkers that are responsive to tumor-specific stimuli, such as high reducing potential and acidic pH. Sw-IMs stay inert (switch off) in the circulation and healthy tissues but get reactivated (switch on) selectively in tumor via responsive removal of the polymer masks, thus focusing the immune boosting activities in the tumor microenvironment. Sw-IMs applied to anti4-1BB agonistic antibody and IL-15 cytokine led to equivalent antitumor efficacy to the parental IMs with markedly reduced toxicities. Sw-IM provides a highly modular and generic approach to improve the therapeutic window and clinical applicability of potent IMs in mono- and combinational immunotherapies.