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Nanoparticles interact with immune cells in many different ways. These interactions are crucially important for determining nanoparticles' ability to be used for cancer therapy. Traditionally, strategies such as PEGylation have been employed to reduce (the kinetics of) nanoparticle uptake by immune cells, to endow them with long circulation properties, and to enable them to exploit the Enhanced Permeability and Retention (EPR) effect to accumulate in tumors. More recently, with immunotherapy becoming an increasingly important cornerstone in the clinical management of cancer, ever more research efforts in academia and industry are focusing on specifically targeting immune cells with nanoparticles. In this chapter, we describe the barriers and opportunities of immune cell targeting with nanoparticles, and we discuss how nanoparticle-based drug delivery to specific immune cell populations in tumors as well as in secondary myeloid and lymphoid organs (such as bone marrow, lymph nodes, and spleen) can be leveraged to boost the efficacy of cancer immunotherapy.
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Nanomedicina , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Imunoterapia , Sistema ImunitárioRESUMO
Polymeric micelles are among the most extensively used drug delivery systems. Key properties of micelles, such as size, size distribution, drug loading, and drug release kinetics, are crucial for proper therapeutic performance. Whether polymers from more controlled polymerization methods produce micelles with more favorable properties remains elusive. To address this question, we synthesized methoxy poly(ethylene glycol)-b-(N-(2-benzoyloxypropyl)methacrylamide) (mPEG-b-p(HPMAm-Bz)) block copolymers of three different comparable molecular weights (â¼9, 13, and 20 kDa), via both conventional free radical (FR) and reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymers were subsequently employed to prepare empty and paclitaxel-loaded micelles. While FR polymers had relatively high dispersities (D â¼ 1.5-1.7) compared to their RAFT counterparts (D â¼ 1.1-1.3), they formed micelles with similar pharmaceutical properties (e.g., size, size distribution, critical micelle concentration, cytotoxicity, and drug loading and retention). Our findings suggest that pharmaceutical properties of mPEG-b-p(HPMAm-Bz) micelles do not depend on the synthesis route of their constituent polymers.
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Elétrons , Micelas , Polimerização , Polietilenoglicóis , Polímeros , Portadores de FármacosRESUMO
Metal complexes are extensively used for cancer therapy. The multiple variables available for tuning (metal, ligand, and metal-ligand interaction) offer unique opportunities for drug design, and have led to a vast portfolio of metallodrugs that can display a higher diversity of functions and mechanisms of action with respect to pure organic structures. Clinically approved metallodrugs, such as cisplatin, carboplatin and oxaliplatin, are used to treat many types of cancer and play prominent roles in combination regimens, including with immunotherapy. However, metallodrugs generally suffer from poor pharmacokinetics, low levels of target site accumulation, metal-mediated off-target reactivity and development of drug resistance, which can all limit their efficacy and clinical translation. Nanomedicine has arisen as a powerful tool to help overcome these shortcomings. Several nanoformulations have already significantly improved the efficacy and reduced the toxicity of (chemo-)therapeutic drugs, including some promising metallodrug-containing nanomedicines currently in clinical trials. In this critical review, we analyse the opportunities and clinical challenges of metallodrugs, and we assess the advantages and limitations of metallodrug delivery, both from a nanocarrier and from a metal-nano interaction perspective. We describe the latest and most relevant nanomedicine formulations developed for metal complexes, and we discuss how the rational combination of coordination chemistry with nanomedicine technology can assist in promoting the clinical translation of metallodrugs.
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Antineoplásicos , Complexos de Coordenação , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Humanos , Imunoterapia , Nanomedicina/métodos , Neoplasias/tratamento farmacológicoRESUMO
Superparamagnetic iron oxide nanoparticles (SPION) are extensively used for magnetic resonance imaging (MRI) and magnetic particle imaging (MPI), as well as for magnetic fluid hyperthermia (MFH). We here describe a sequential centrifugation protocol to obtain SPION with well-defined sizes from a polydisperse SPION starting formulation, synthesized using the routinely employed co-precipitation technique. Transmission electron microscopy, dynamic light scattering and nanoparticle tracking analyses show that the SPION fractions obtained upon size-isolation are well-defined and almost monodisperse. MRI, MPI and MFH analyses demonstrate improved imaging and hyperthermia performance for size-isolated SPION as compared to the polydisperse starting mixture, as well as to commercial and clinically used iron oxide nanoparticle formulations, such as Resovist® and Sinerem®. The size-isolation protocol presented here may help to identify SPION with optimal properties for diagnostic, therapeutic and theranostic applications.
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Meios de Contraste/química , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita/química , Dextranos/química , Humanos , Hipertermia Induzida , Aumento da Imagem , Tamanho da Partícula , Relação Estrutura-Atividade , Nanomedicina TeranósticaRESUMO
Objectives: RA is a chronic autoimmune disease leading to progressive destruction of cartilage and bone. RA patients show elevated IL-22 levels and the amount of IL-22-producing Th cells positively correlates with the extent of erosive disease, suggesting a role for this cytokine in RA pathogenesis. The purpose of this study was to determine the feasibility of SPECT/CT imaging with 111In-labelled anti-fibroblast activation protein antibody (28H1) to monitor the therapeutic effect of neutralizing IL-22 in experimental arthritis. Methods: Mice (six mice/group) with CIA received anti-IL-22 or isotype control antibodies. To monitor therapeutic effects after treatment, SPECT/CT images were acquired 24 h after injection of 111In-28H1. Imaging results were compared with macroscopic, histologic and radiographic arthritis scores. Results: Neutralizing IL-22 before CIA onset effectively prevented arthritis development, reaching a disease incidence of only 50%, vs 100% in the control group. SPECT imaging showed significantly lower joint tracer uptake in mice treated early with anti-IL-22 antibodies compared with the control-treated group. Reduction of disease activity in those mice was confirmed by macroscopic, histological and radiographic pathology scores. However, when treatment was initiated in a later phase of CIA, progression of joint pathology could not be prevented. Conclusion: These findings suggest that IL-22 plays an important role in CIA development, and neutralizing this cytokine seems an attractive new strategy in RA treatment. Most importantly, SPECT/CT imaging with 111In-28H1 can be used to specifically monitor therapy responses, and is potentially more sensitive in disease monitoring than the gold standard method of macroscopic arthritis scoring.
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Artrite/diagnóstico por imagem , Cartilagem Articular/diagnóstico por imagem , Gelatinases/genética , Regulação da Expressão Gênica , Interleucinas/genética , Proteínas de Membrana/genética , RNA Mensageiro/genética , Serina Endopeptidases/genética , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Artrite/tratamento farmacológico , Artrite/genética , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Colágeno/toxicidade , Modelos Animais de Doenças , Endopeptidases , Gelatinases/biossíntese , Imuno-Histoquímica , Interleucinas/biossíntese , Masculino , Proteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos DBA , Reação em Cadeia da Polimerase em Tempo Real , Serina Endopeptidases/biossíntese , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Interleucina 22RESUMO
Micelles composed of block copolymers of poly(ethylene glycol)- b-poly( N-2-benzoyloxypropyl methacrylamide) (mPEG- b-p(HPMA-Bz)) have shown great promise as drug-delivery carriers due to their excellent stability and high loading capacity. In the present study, parameters influencing micelle size were investigated to tailor sizes in the range of 25-100 nm. Micelles were prepared by a nanoprecipitation method, and their size was modulated by the block copolymer properties such as molecular weight, their hydrophilic-to-hydrophobic ratio, homopolymer content, as well as formulation and processing parameters. It was shown that the micelles have a core-shell structure using a combination of dynamic light scattering and transmission electron microscopy analysis. By varying the degree of polymerization of the hydrophobic block ( NB) between 68 and 10, at a fixed hydrophilic block mPEG5k ( NA = 114), it was shown that the hydrophobic core of the micelle was collapsed following the power law of ( NB × Nagg)1/3. Further, the calculated brush height was similar for all the micelles examined (10 nm), indicating that crew-cut micelles were made. Both addition of homopolymer and preparation of micelles at lower concentrations or lower rates of addition of the organic solvent to the aqueous phase increased the size of micelles due to partitioning of the hydrophobic homopolymer chains to the core of the micelles and lower nucleation rates, respectively. Furthermore, it was shown that by using different solvents, the size of the micelles substantially changed. The use of acetone, acetonitrile, ethanol, tetrahydrofuran, and dioxane resulted in micelles in the size range of 45-60 nm after removal of the organic solvents. The use of dimethylformamide and dimethylsulfoxide led to markedly larger sizes of 75 and 180 nm, respectively. In conclusion, the results show that by modulating polymer properties and processing conditions, micelles with tailorable sizes can be obtained.
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BACKGROUND: Treatment of inflammatory kidney diseases with systemic high-dose glucocorticoids (GCs) has severe side effects. Liposomal encapsulation could facilitate local delivery of GCs to the inflamed kidney, as liposomes encapsulate their payload until extravasation at sites of inflammation, potentially resulting in local bioactivity. Our aim was to evaluate the ability of liposomes to accumulate locally after renal ischaemia-reperfusion injury in the rat and to study its effect on macrophages. METHODS: In vitro, human macrophages were incubated with fluorescent liposomes, liposomal prednisolone, prednisolone, empty liposomes or saline. Uptake was studied microscopically and treatment effect was assessed by interkeukin 6 (IL-6) enzyme-linked immunosorbent assay. The mechanism of action was evaluated by analysing GC receptor activation by microscopy and quantitative polymerase chain reaction (qPCR). In vivo, rats were subjected to ischaemia-reperfusion injury and were injected intravenously with fluorescent liposomes, liposomal prednisolone, prednisolone, empty liposomes or saline. Uptake was measured by the FLARE camera and the treatment effect by immunohistochemistry for myeloid cells and qPCR for inflammatory markers. RESULTS: In vitro, macrophages internalized liposomes after 8 hours. Prednisolone or liposomal prednisolone treatment reduced IL-6 production and both compounds induced translocation of the GC receptor to the nucleus and upregulation of PER1 messenger RNA (mRNA), indicating a similar mechanism of action. In vivo, fluorescent liposomes accumulated in the inflamed kidney. Liposomal prednisolone treatment increased the presence of ED2-positive anti-inflammatory macrophages and both prednisolone and liposomal prednisolone reduced monocyte chemoattractant protein-1 (MCP-1) mRNA production, indicating a reduced pro-inflammatory profile in the kidney. CONCLUSIONS: Liposomal encapsulation is a promising strategy for local delivery of glucocorticoids to the inflamed kidney.
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Anti-Inflamatórios/uso terapêutico , Sistemas de Liberação de Medicamentos , Mediadores da Inflamação/metabolismo , Inflamação/prevenção & controle , Lipossomos/administração & dosagem , Prednisolona/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Células Cultivadas , Humanos , Inflamação/metabolismo , Lipossomos/química , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos Lew , Traumatismo por Reperfusão/metabolismoRESUMO
Atherosclerosis is a lipid-driven inflammatory disease, for which nanomedicinal interventions are under evaluation. Previously, we showed that liposomal nanoparticles loaded with prednisolone (LN-PLP) accumulated in plaque macrophages, however, induced proatherogenic effects in patients. Here, we confirmed in low-density lipoprotein receptor knockout (LDLr(-/-)) mice that LN-PLP accumulates in plaque macrophages. Next, we found that LN-PLP infusions at 10mg/kg for 2weeks enhanced monocyte recruitment to plaques. In follow up, after 6weeks of LN-PLP exposure we observed (i) increased macrophage content, (ii) more advanced plaque stages, and (iii) larger necrotic core sizes. Finally, in vitro studies showed that macrophages become lipotoxic after LN-PLP exposure, exemplified by enhanced lipid loading, ER stress and apoptosis. These findings indicate that liposomal prednisolone may paradoxically accelerate atherosclerosis by promoting macrophage lipotoxicity. Hence, future (nanomedicinal) drug development studies are challenged by the multifactorial nature of atherosclerotic inflammation.
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Aterosclerose/metabolismo , Aterosclerose/patologia , Prednisolona/administração & dosagem , Animais , Humanos , Lipossomos , Macrófagos/patologia , Camundongos , Placa AteroscleróticaRESUMO
BACKGROUND: The inflammatory tumor microenvironment, and more specifically the tumor-associated macrophages, plays an essential role in the development and progression of prostate cancer towards metastatic bone disease. Tumors are often characterized by a leaky vasculature, which - combined with the prolonged circulation kinetics of liposomes - leads to efficient tumor localization of these drug carriers, via the so-called enhanced permeability and retention (EPR) -effect. In this study, we evaluated the utility of targeted, liposomal drug delivery of the glucocorticoid dexamethasone in a model of prostate cancer bone metastases. METHODS: Tumor-bearing Balb-c nu/nu mice were treated intravenously with 0.2-1.0-5.0 mg/kg/week free- and liposomal DEX for 3-4 weeks and tumor growth was monitored by bioluminescent imaging. RESULTS: Intravenously administered liposomes localize efficiently to bone metastases in vivo and treatment of established bone metastases with (liposomal) dexamethasone resulted in a significant inhibition of tumor growth up to 26 days after initiation of treatment. Furthermore, 1.0 mg/kg liposomal dexamethasone significantly outperformed 1.0 mg/kg free dexamethasone, and was found to be well-tolerated at clinically-relevant dosages that display potent anti-tumor efficacy. CONCLUSIONS: Liposomal delivery of the glucocorticoid dexamethasone inhibits the growth of malignant bone lesions. We believe that liposomal encapsulation of dexamethasone offers a promising new treatment option for advanced, metastatic prostate cancer which supports further clinical evaluation.
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Antineoplásicos Hormonais/administração & dosagem , Neoplasias Ósseas/prevenção & controle , Neoplasias Ósseas/secundário , Dexametasona/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Neoplasias da Próstata/tratamento farmacológico , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Humanos , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias da Próstata/patologia , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: Here, the expression of F4/80 on the cell surface of murine macrophages was exploited to develop a novel imaging tracer that could visualize macrophages in vivo. METHODS: The immunoreactive fraction and IC50 of anti-F4/80-A3-1, conjugated with diethylenetriaminepentaacetic acid (DTPA) and radiolabelled with (111)In, were determined in vitro using murine bone marrow-derived macrophages. In vivo biodistribution studies were performed with (111)In-anti-F4/80-A3-1 and isotype-matched control antibody (111)In-rat IgG2b at 24 and 72 h post-injection (p.i.) in SCID/Beige mice bearing orthotopic MDA-MB-231 xenografts. In some studies mice were also treated with liposomal clodronate. Macrophage content in tissues was determined immunohistochemically. Micro-single photon emission computed tomography (SPECT)/CT images were also acquired. RESULTS: In vitro binding assays showed that (111)In-anti-F4/80-A3-1 specifically binds F4/80 receptor-positive macrophages. The immunoreactivity of anti-F4/80-A3-1 was 75 % and IC50 was 0.58 nM. In vivo, injection of 10 or 100 µg (111)In-anti-F4/80-A3-1 resulted in splenic uptake of 78 %ID/g and 31 %ID/g, respectively, and tumour uptake of 1.38 %ID/g and 4.08 %ID/g, respectively (72 h p.i.). Liposomal clodronate treatment reduced splenic uptake of 10 µg (111)In-anti-F4/80-A3-1 from 248 %ID/g to 114 %ID/g and reduced (111)In-anti-F4/80-A3-1 uptake in the liver and femur (24 h p.i.). Tracer retention in the blood and tumour uptake increased (24 h p.i.). Tumour uptake of (111)In-anti-F4/80-A3-1 was visualized by microSPECT/CT. Macrophage density in the spleen and liver decreased in mice treated with liposomal clodronate. Uptake of (111)In-rat IgG2b was lower in the spleen, liver and femur when compared to (111)In-anti-F4/80-A3-1. CONCLUSION: Radiolabelled anti-F4/80-A3-1 antibodies specifically localize in tissues infiltrated by macrophages in mice and can be used to visualize tumours. The liver and spleen act as antigen sink organs for macrophage-specific tracers.
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Anticorpos Monoclonais/imunologia , Antígenos de Diferenciação/imunologia , Radioisótopos de Índio , Macrófagos/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Anticorpos Monoclonais/farmacocinética , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Traçadores Radioativos , Ratos , Distribuição TecidualRESUMO
The present study describes the development of a good manufacturing practice (GMP)-grade liposomal nanotherapy containing prednisolone phosphate for the treatment of inflammatory diseases. After formulation design, GMP production was commenced which yielded consistent, stable liposomes sized 100nm±10nm, with a prednisolone phosphate (PLP) incorporation efficiency of 3%-5%. Pharmacokinetics and toxicokinetics of GMP-grade liposomal nanoparticles were evaluated in healthy rats, which were compared to daily and weekly administration of free prednisolone phosphate, revealing a long circulatory half-life with minimal side effects. Subsequently, non-invasive multimodal clinical imaging after liposomal nanotherapy's intravenous administration revealed anti-inflammatory effects on the vessel wall of atherosclerotic rabbits. The present program led to institutional review board approval for two clinical trials with patients with atherosclerosis. FROM THE CLINICAL EDITOR: In drug discovery, bringing production to industrial scale is an essential process. In this article the authors describe the development of an anti-inflammatory nanoparticle according to good manufacturing practice. As a result, this paves the way for translating laboratory studies to clinical trials in humans.
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Anti-Inflamatórios/administração & dosagem , Aterosclerose/tratamento farmacológico , Química Farmacêutica/métodos , Glucocorticoides/administração & dosagem , Prednisolona/análogos & derivados , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/toxicidade , Aorta/efeitos dos fármacos , Aorta/patologia , Aterosclerose/patologia , Glucocorticoides/farmacocinética , Glucocorticoides/uso terapêutico , Glucocorticoides/toxicidade , Meia-Vida , Humanos , Lipossomos , Masculino , Prednisolona/administração & dosagem , Prednisolona/farmacocinética , Prednisolona/uso terapêutico , Prednisolona/toxicidade , Coelhos , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents' risk-benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP's liposomal encapsulation improved its pharmacokinetic profile in humans (n=13) as attested by an increased plasma half-life of 63h (LN-PLP 1.5mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n=14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n=30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis. FROM THE CLINICAL EDITOR: In this study, the authors undertook the first clinical trial using long-circulating liposomal nanoparticle encapsulating prednisolone in patients with atherosclerosis, based on previous animal studies. Despite little evidence of anti-inflammatory effect, the results have provided a starting point for future development of nanomedicine in cardiovascular diseases.
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Anti-Inflamatórios/administração & dosagem , Aterosclerose/tratamento farmacológico , Glucocorticoides/administração & dosagem , Macrófagos/efeitos dos fármacos , Placa Aterosclerótica/tratamento farmacológico , Prednisolona/administração & dosagem , Administração Intravenosa , Adulto , Idoso , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Artérias/efeitos dos fármacos , Artérias/patologia , Aterosclerose/patologia , Feminino , Glucocorticoides/farmacocinética , Glucocorticoides/uso terapêutico , Humanos , Lipossomos , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/patologia , Prednisolona/farmacocinética , Prednisolona/uso terapêuticoRESUMO
Glucocorticoids (GCs) are widely used to treat acute relapses of multiple sclerosis (MS). In this study, we demonstrate that liposomal encapsulation augments the therapeutic potency of GCs as they ameliorate experimental autoimmune encephalomyelitis (EAE) to the same extent as free GC, but at strongly reduced dosage and application frequency. Importantly, this is accompanied by an altered mode of action. Unlike free GCs, which mainly target T lymphocytes during EAE therapy, liposomal GCs only marginally affect T cell apoptosis and function. In contrast, liposomal GCs efficiently repress proinflammatory macrophage functions and upregulate anti-inflammatory genes associated with the alternatively activated M2 phenotype. The GC receptor (GR) per se is indispensable for the therapeutic efficacy of liposomal GC. In contrast to free GCs, however, the individual deletion of the GR either in T cells or myeloid cells has little effect on the efficacy of liposomal GCs in the treatment of EAE. Only the combined deletion of the GR in both cellular compartments markedly compromises the therapeutic effect of liposomal GCs on disease progression. In conclusion, encapsulation of GC does not only enhance their efficacy in the treatment of EAE but also alters their target cell specificity and their mode of action compared with free GCs.
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Encefalomielite Autoimune Experimental/tratamento farmacológico , Glucocorticoides/administração & dosagem , Lipossomos , Macrófagos/efeitos dos fármacos , Animais , Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Glucocorticoides/deficiência , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Despite the introduction of multiple new drugs and combination therapies, conventional dexamethasone remains a cornerstone in the treatment of multiple myeloma (MM). Its application is, however, limited by frequent adverse effects of which the increased infection rate may have the strongest clinical impact. The efficacy-safety ratio of dexamethasone in MM may be increased by encapsulation in long-circulating PEG-liposomes, thereby both enhancing drug delivery to MM lesions and reducing systemic corticosteroid exposure. We evaluated the preliminary safety and feasibility of a single intravenous (i.v.) infusion of pegylated liposomal dexamethasone phosphate (Dex-PL) in heavily pretreated relapsing or progressive symptomatic MM patients within a phase I open-label non-comparative interventional trial at two dose levels. In the 7 patients that were enrolled (prior to having to close the study prematurely due to slow recruitment), Dex-PL was found to be well tolerated and, as compared to conventional dexamethasone, no new or unexpected adverse events were detected. Pharmacokinetic analysis showed high and persisting concentrations of dexamethasone in the circulation for over a week after i.v. administration, likely caused by the long-circulation half-life of the liposomes that retain dexamethasone as the inactive phosphate prodrug form, something which could significantly limit systemic exposure to the active parent drug. Thus, despite the limitations of this small first-in-man trial, Dex-PL seems safe and well tolerated without severe side effects. Follow-up studies are needed to confirm this in a larger patient cohort and to evaluate if i.v. Dex-PL can provide a safer and more efficacious dexamethasone treatment option for MM.
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Mieloma Múltiplo , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona/efeitos adversos , Lipossomos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/patologia , Resultado do TratamentoRESUMO
Nanomedicine holds promise for potentiating drug combination therapies. Increasing (pre)clinical evidence is available exemplifying the value of co-formulating and co-delivering different drugs in modular nanocarriers. Taxanes like paclitaxel (PTX) are widely used anticancer agents, and commonly combined with corticosteroids like dexamethasone (DEX), which besides for suppressing inflammation and infusion reactions, are increasingly explored for modulating the tumor microenvironment towards enhanced nano-chemotherapy delivery and efficacy. We here set out to develop a size- and release rate-tunable polymeric micelle platform for co-delivery of taxanes and corticosteroids. We synthesized amphiphilic mPEG-b-p(HPMAm-Bz) block copolymers of various molecular weights and used them to prepare PTX and DEX single- and double-loaded micelles of different sizes. Both drugs could be efficiently co-encapsulated, and systematic comparison between single- and co-loaded formulations demonstrated comparable physicochemical properties, encapsulation efficiencies, and release profiles. Larger micelles showed slower drug release, and DEX release was always faster than PTX. The versatility of the platform was exemplified by co-encapsulating two additional taxane-corticosteroid combinations, demonstrating that drug hydrophobicity and molecular weight are key properties that strongly contribute to drug retention in micelles. Altogether, our work shows that mPEG-b-p(HPMAm-Bz) polymeric micelles serve as a tunable and versatile nanoparticle platform for controlled co-delivery of taxanes and corticosteroids, thereby paving the way for using these micelles as a modular carrier for multidrug nanomedicine.
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For Duchenne muscular dystrophy (DMD), a common myopathy that leads to severe disability, no causal therapy is available. Glucocorticosteroids improve patients' muscle strength, but their long-term use is limited by negative side effects. Thus, pharmacological modifications of glucocorticosteroids are required to increase the efficacy by drug targeting. Liposomal encapsulation augments systemic half-life and local tissue concentrations of glucocorticosteroids and, at the same time, reduces systemic side effects. In this study, the efficacy of novel, long-circulating, polyethylene-glycol-coated liposomes encapsulating prednisolone was compared with free prednisolone in the treatment of mdx mice, a well-established animal model for DMD. Using an objective and sensitive computerized 24-hr detection system of voluntary wheel-running in single cages, we demonstrate a significant impairment of the running performance in mdx compared with black/10 control mice aged 3-6 weeks. Treatment with liposomal or free prednisolone did not improve running performance compared with saline control or empty liposomes. Histopathological parameters, including the rate of internalized nuclei and fiber size variation, and mRNA and protein expression levels of transforming growth factor (TGF)-ß and monocytes chemotactic protein (MCP)-1 also remained unchanged. Bioactivity in skeletal muscle of liposomal and free prednisolone was demonstrated by elevated mRNA expression of muscle ring finger protein 1 (MuRF1), a mediator of muscle atrophy, and its forkhead box transcription factors (Foxo1/3). Our data support the assessment of voluntary running to be a robust and reproducible outcome measure of skeletal muscle performance during the early disease course of mdx mice and suggest that liposomal encapsulation is not superior in treatment efficacy compared with conventional prednisolone. Our study helps to improve the future design of experimental treatment in animal models of neuromuscular diseases.
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Glucocorticoides/administração & dosagem , Lipossomos/uso terapêutico , Atividade Motora/efeitos dos fármacos , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/fisiopatologia , Prednisolona/administração & dosagem , Análise de Variância , Animais , Creatina Quinase/sangue , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Força Muscular/efeitos dos fármacos , Força Muscular/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/sangue , Distrofia Muscular de Duchenne/genética , Polietilenoglicóis/administração & dosagem , RNA Mensageiro/metabolismo , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Liposomes as a drug delivery system may overcome the problems associated with non-compliance to eyedrops and inadequate control of inflammation after cataract surgery. We evaluated the safety and efficacy of a single subconjunctival injection of liposomal prednisolone phosphate (LPP) for the treatment of post-cataract surgery inflammation. This is a phase I/II, open-label non-comparative interventional trial of patients undergoing cataract surgery. All patients received a single injection of subconjunctival LPP intraoperatively. The primary outcome measure was the proportion of eyes with an anterior chamber cell count of 0 at postoperative month 1. Ocular and non-ocular adverse events, including elevated intraocular pressure, rebound iritis and pseudophakic macular edema were monitored. Five patients were enrolled in this study. The mean age was 66.6 ± 6.2 and 4 (80%) were male. The proportion of patients with AC cell grading of 0 was 0%, 80%, 80%, and 100% at day 1, week 1, month 1, and month 2 after cataract surgery, respectively. Mean laser flare photometry readings were significantly elevated at week 1 after cataract surgery (48.8 ± 18.9, p = 0.03) compared with baseline, decreasing to 25.8 ± 9.2 (p = 0.04) at month 1 and returned to baseline by month 2 (10.9 ± 5.1, p = 1.0). No ocular or non-ocular adverse events were observed. Liposomal prednisolone phosphate, administered as a single subconjunctival injection intraoperatively, can be a safe and effective treatment for post-cataract surgery inflammation. The delivery of steroids with a liposomal drug delivery system could potentially replace eyedrops as anti-inflammatory therapy following cataract surgery.
Assuntos
Catarata , Idoso , Anti-Inflamatórios/uso terapêutico , Catarata/induzido quimicamente , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Lipossomos , Masculino , Pessoa de Meia-IdadeRESUMO
Ischemia and reperfusion injury (IRI) is a common complication caused by inflammation and oxidative stress resulting from liver surgery. Current therapeutic strategies do not present the desirable efficacy, and severe side effects can occur. To overcome these drawbacks, new therapeutic alternatives are necessary. Drug delivery nanosystems have been explored due to their capacity to improve the therapeutic index of conventional drugs. Within nanocarriers, liposomes are one of the most successful, with several formulations currently in the market. As improved therapeutic outcomes have been demonstrated by using liposomes as drug carriers, this nanosystem was used to deliver quercetin, a flavonoid with anti-inflammatory and antioxidant properties, in hepatic IRI treatment. In the present work, a stable quercetin liposomal formulation was developed and characterized. Additionally, an in vitro model of ischemia and reperfusion was developed with a hypoxia chamber, where the anti-inflammatory potential of liposomal quercetin was evaluated, revealing the downregulation of pro-inflammatory markers. The anti-inflammatory effect of quercetin liposomes was also assessed in vivo in a rat model of hepatic IRI, in which a decrease in inflammation markers and enhanced recovery were observed. These results demonstrate that quercetin liposomes may provide a significant tool for addressing the current bottlenecks in hepatic IRI treatment.
RESUMO
Glucocorticoids (GCs) are potent anti-inflammatory drugs but their use is limited by systemic exposure leading to toxicity. Targeted GC delivery to sites of inflammation via encapsulation in long-circulating liposomes may improve the therapeutic index. We performed a randomized, double-blind, active-controlled, multi-center study in which intravenously (i.v.) administered pegylated liposomal prednisolone sodium phosphate (Nanocort) was compared to equipotent intramuscular (i.m.) methylprednisolone acetate (Depo-Medrol®; i.e. a current standards-of-care for treating flares in rheumatoid arthritis patients). We enrolled 172 patients with active arthritis who met all eligibility criteria, eventually resulting in 150 patients randomized in three groups: (1) Nanocort 75 mg i.v. infusion plus i.m. saline injection; (2) Nanocort 150 mg i.v. infusion plus i.m. saline injection; and (3) Depo-Medrol® 120 mg i.m. injection plus i.v. saline infusion. Dosing in each group occurred at baseline and on day 15 (week 2). Study visits occurred at week 1, 2, 3, 4, 6, 8 and 12, to assess both efficacy and safety. The primary endpoint was the "European League Against Rheumatism" (EULAR) responder rate at week 1. Safety was determined by the occurrence of adverse events during treatment and 12 weeks of follow-up. Treatment with Nanocort was found to be superior to Depo-Medrol® in terms of EULAR response at week 1, with p-values of 0.007 (good response) and 0.018 (moderate response). Treatments were well tolerated with a comparable pattern of adverse events in the three treatment groups. However, the Nanocort groups had a higher incidence of hypersensitivity reactions during liposome infusion. Our results show that liposomal Nanocort is more effective than Depo-Medrol® in treating patients with rheumatoid arthritis flares and has similar safety. This is the first clinical study in a large patient population showing that i.v. administered targeted drug delivery with a nanomedicine formulation improves the therapeutic index of glucocorticoids.
Assuntos
Artrite Reumatoide , Lipossomos , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Humanos , Lipossomos/uso terapêutico , Metilprednisolona/uso terapêutico , Polietilenoglicóis/uso terapêuticoRESUMO
Continuous flow manufacturing (CFM) has shown remarkable advantages in the industrial-scale production of drug-loaded nanomedicines, including mRNA-based COVID-19 vaccines. Thus far, CFM research in nanomedicine has mainly focused on the initial particle formation step, while post-formation production steps are hardly ever integrated. The opportunity to implement in-line quality control of critical quality attributes merits closer investigation. Here, we designed and tested a CFM setup for the manufacturing of liposomal nanomedicines that can potentially encompass all manufacturing steps in an end-to-end system. Our main aim was to elucidate the key composition and process parameters that affect the physicochemical characteristics of the liposomes. Total flow rate, lipid concentration and residence time of the liposomes in a high ethanol environment (i.e., above 20% v/v) emerged as critical parameters to tailor liposome size between 80 and 150 nm. After liposome formation, the pressure and the surface area of the filter in the ultrafiltration unit were critical parameters in the process of clearing the dispersion from residual ethanol. As a final step, we integrated in-line measurement of liposome size and residual ethanol content. Such in-line measurements allow for real-time monitoring and in-process adjustment of key composition and process parameters.