RESUMO
Off-target effects of systemically administered drugs have been a major hurdle in designing therapies with desired efficacy and acceptable toxicity. Developing targeting strategies to enable site-specific drug delivery holds promise in reducing off-target effects, decreasing unwanted toxicities, and thereby enhancing a drug's therapeutic efficacy. Over the past three decades, a large body of literature has focused on understanding the biological barriers that hinder tissue-specific drug delivery and strategies to overcome them. These efforts have led to several targeting strategies that modulate drug delivery in both the preclinical and clinical settings, including small molecule-, nucleic acid-, peptide-, antibody-, and cell-based strategies. Here, we discuss key advances and emerging concepts for tissue-specific drug delivery approaches and their clinical translation.
Assuntos
Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Preparações Farmacêuticas/química , HumanosRESUMO
Erythrocytes naturally capture certain bacterial pathogens in circulation, kill them through oxidative stress, and present them to the antigen-presenting cells (APCs) in the spleen. By leveraging this innate immune function of erythrocytes, we developed erythrocyte-driven immune targeting (EDIT), which presents nanoparticles from the surface of erythrocytes to the APCs in the spleen. Antigenic nanoparticles were adsorbed on the erythrocyte surface. By engineering the number density of adsorbed nanoparticles, (i.e., the number of nanoparticles loaded per erythrocyte), they were predominantly delivered to the spleen rather than lungs, which is conventionally the target of erythrocyte-mediated delivery systems. Presentation of erythrocyte-delivered nanoparticles to the spleen led to improved antibody response against the antigen, higher central memory T cell response, and lower regulatory T cell response, compared with controls. Enhanced immune response slowed down tumor progression in a prophylaxis model. These findings suggest that EDIT is an effective strategy to enhance systemic immunity.
Assuntos
Apresentação de Antígeno/imunologia , Antígenos/imunologia , Eritrócitos/imunologia , Imunização , Animais , Formação de Anticorpos/imunologia , Antígenos/química , Biomimética , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Feminino , Humanos , Camundongos , Nanopartículas , Baço/imunologia , Vacinação , Vacinas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The succinic acid/succinate system has an excellent buffering capacity at acidic pH values (4.5-6.0), promising to be a buffer of choice for biologics having slightly acidic to basic isoelectric points (pI 6 - 9). However, its prevalence in drug products is limited due to the propensity (risk) of its components to crystallize during freezing and the consequent shift in the pH which might affect the product stability. Most of these previous assessments have been performed under operational conditions that do not simulate typical drug product processing conditions. In this work, we have characterized the physicochemical behavior of succinate formulations under representative pharmaceutical conditions. Our results indicate that the pH increases by â¼ 1.2 units in 25 mM and 250 mM succinate buffers at pharmaceutically relevant freezing conditions. X-ray diffractometry studies revealed selective crystallization of monosodium succinate, which is posed as the causative mechanism. This salt crystallization was not observed in the presence of 2% w/v sucrose, suggesting that this pH shift can be mitigated by including sucrose in the formulation. Additionally, three monoclonal antibodies (mAbs) that represent different IgG subtypes and span a range of pIs (5.9 - 8.8) were formulated with succinate and sucrose and subjected to freeze-thaw, frozen storage and lyophilization. No detrimental impact on quality attributes (QA) such as high molecular weight (HMW) species, turbidity, alteration in protein concentration and sub-visible particles, was observed of any of the mAbs tested. Lastly, drug formulations lyophilized in succinate buffer with sucrose demonstrated acceptable QA profiles upon accelerated kinetic storage stability, supporting the use of succinate buffers in mAb drug products.
Assuntos
Produtos Biológicos , Ácido Succínico , Ácido Succínico/química , Soluções Tampão , Concentração de Íons de Hidrogênio , Liofilização/métodos , Succinatos , Sacarose/química , Estabilidade de MedicamentosRESUMO
Antiproliferative chemotherapeutic agents offer a potential effective treatment for inflammatory arthritis. However, their clinical application is limited by high systemic toxicity, low joint bioavailability as well as formulation challenges. Here, we report an intra-articular drug delivery system combining hyaluronic acid hydrogels and drug nanocrystals to achieve localized and sustained delivery of an antiproliferative chemotherapeutic agent camptothecin for long-term treatment of inflammatory arthritis. We synthesized a biocompatible, in situ-forming injectable hyaluronic acid hydrogel using a naturally occurring click chemistry: cyanobenzothiazole/cysteine reaction, which is the last step reaction in synthesizing D-luciferin in fireflies. This hydrogel was used to encapsulate camptothecin nanocrystals (size of 160-560 nm) which released free camptothecin in a sustained manner for 4 weeks. In vivo studies confirmed that the hydrogel remained in the joint over 4 weeks. By using the collagen-induced arthritis rat model, we demonstrate that the hydrogel-camptothecin formulation could alleviate arthritis severity as indicated by the joint size and interleukin-1ß level in the harvested joints, as well as from histological and microcomputed tomography evaluation of joints. The hydrogel-nanocrystal formulation strategy described here offers a potential solution for intra-articular therapy for inflammatory arthritis.
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Cancer immunotherapy has been at the forefront of therapeutic interventions for many different tumor types over the last decade. While the discovery of immunotherapeutics continues to occur at an accelerated rate, their translation is often hindered by a lack of strategies to deliver them specifically into solid tumors. Accordingly, significant scientific efforts have been dedicated to understanding the underlying mechanisms that govern their delivery into tumors and the subsequent immune modulation. In this review, we aim to summarize the efforts focused on overcoming tumor-associated biological barriers and enhancing the potency of immunotherapy. We summarize the current understanding of biological barriers that limit the entry of intravascularly administered immunotherapies into the tumors, in vitro techniques developed to investigate the underlying transport processes, and delivery strategies developed to overcome the barriers. Overall, we aim to provide the reader with a framework that guides the rational development of technologies for improved solid tumor immunotherapy.
Assuntos
Imunoterapia , Neoplasias , Humanos , Imunoterapia/métodos , Neoplasias/patologia , Neoplasias/terapiaRESUMO
Cancer therapy is increasingly shifting toward targeting the tumor immune microenvironment and influencing populations of tumor infiltrating lymphocytes. Breast cancer presents a unique challenge as tumors of the triple-negative breast cancer subtype employ a multitude of immunosilencing mechanisms that promote immune evasion and rapid growth. Treatment of breast cancer with chemotherapeutics has been shown to induce underlying immunostimulatory responses that can be further amplified with the addition of immune-modulating agents. Here, we investigate the effects of combining doxorubicin (DOX) and gemcitabine (GEM), two commonly used chemotherapeutics, with monophosphoryl lipid A (MPLA), a clinically used TLR4 adjuvant derived from liposaccharides. MPLA was incorporated into the lipid bilayer of liposomes loaded with a 1:1 molar ratio of DOX and GEM to create an intravenously administered treatment. In vivo studies indicated excellent efficacy of both GEM-DOX liposomes and GEM-DOX-MPLA liposomes against 4T1 tumors. In vitro and in vivo results showed increased dendritic cell expression of CD86 in the presence of liposomes containing chemotherapeutics and MPLA. Despite this, a tumor rechallenge study indicated little effect on tumor growth upon rechallenge, indicating the lack of a long-term immune response. GEM/DOX/MPLA-L displayed remarkable control of the primary tumor growth and can be further explored for the treatment of triple-negative breast cancer with other forms of immunotherapy.
RESUMO
Eliciting immune responses against primary tumours is hampered by their immunosuppressive microenvironment and by the greater inaccessibility of deeper intratumoural cells. However, metastatic tumour cells are exposed to highly perfused and immunoactive organs, such as the lungs. Here, by taking advantage of the preferential colocalization of intravenously administered erythrocytes with metastases in the lungs, we show that treatment with chemokine-encapsulating nanoparticles that are non-covalently anchored onto the surface of injected erythrocytes results in local and systemic tumour suppression in mouse models of lung metastasis. Such erythrocyte-anchored systemic immunotherapy led to the infiltration of effector immune cells into the lungs, in situ immunization without the need for exogenous antigens, inhibition of the progression of lung metastasis, and significantly extended animal survival and systemic immunity that suppressed the growth of distant tumours after rechallenge. Erythrocyte-mediated systemic immunotherapy may represent a general and potent strategy for cancer vaccination.
Assuntos
Neoplasias da Mama/terapia , Quimiocina CXCL10/metabolismo , Eritrócitos/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Administração Intravenosa , Animais , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Transfusão de Eritrócitos , Feminino , Humanos , Imunoterapia , Neoplasias Pulmonares/imunologia , Camundongos , Nanopartículas , Microambiente Tumoral/efeitos dos fármacos , Vacinação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Adjuvants play a critical role in the design and development of novel vaccines. Despite extensive research, only a handful of vaccine adjuvants have been approved for human use. Currently used adjuvants are mostly composed of components that are non-native to the human body, such as aluminum salt, bacterial lipids, or foreign genomic material. Here, a new ionic-liquid-based adjuvant is explored, synthesized using two metabolites of the body, choline and lactic acid (ChoLa). ChoLa distributes the antigen efficiently upon injection, maintains antigen integrity, enhances immune infiltration at the injection site, and leads to a potent immune response against the antigen. Thus, it can serve as a promising safe adjuvant platform that can help to protect against pandemics and future infectious threats.
Assuntos
Adjuvantes Imunológicos/química , Líquidos Iônicos/química , Segurança , Adjuvantes Imunológicos/síntese química , Animais , Glicerilfosforilcolina/química , Ácido Láctico/químicaRESUMO
Uncontrolled noncompressible hemorrhage is a major cause of mortality following traumatic injuries in civilian and military populations. An injectable hemostat for point-of-care treatment of noncompressible hemorrhage represents an urgent medical need. Here, we describe an injectable hemostatic agent via polymer peptide interfusion (HAPPI), a hyaluronic acid conjugate with a collagen-binding peptide and a von Willebrand factor-binding peptide. HAPPI exhibited selective binding to activated platelets and promoted their accumulation at the wound site in vitro. In vivo studies in mouse tail vein laceration model demonstrated a reduction of >97% in both bleeding time and blood loss. A 284% improvement in the survival time was observed in the rat inferior vena cava traumatic model. Lyophilized HAPPI could be stably stored at room temperature for several months and reconstituted during therapeutic intervention. HAPPI provides a potentially clinically translatable intravenous hemostat.
Assuntos
Hemostáticos , Polímeros , Animais , Plaquetas , Modelos Animais de Doenças , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Hemostáticos/farmacologia , Hemostáticos/uso terapêutico , Camundongos , Peptídeos , RatosRESUMO
Systemic antibodies targeting tumor necrosis factor-α (TNF-α) and interleukin-17A (IL-17A) are effective in plaque psoriasis. Despite their popularity, safety concerns pose a challenge for systemic biologics. While anti-TNF-α and anti-IL-17A antibodies effectively inhibit respective proteins, we hypothesize that an approach based on local silencing of an upstream target such as NFKBIZ can be advantageous for treating psoriasis. However, effective delivery of small interfering RNA (siRNA) into the skin is a substantial hurdle due to skin's barrier function and poor stability of siRNA. Using ionic liquids as an enabling technology, we report on the effective delivery of NFKBIZ siRNA into the skin and its therapeutic efficacy in a psoriasis model. Treatment with IL-siRNA suppressed aberrant gene expression and resulted in down-regulation of psoriasis-related signals including TNF-α and IL-17A. These results provide a framework for a topical delivery platform for siRNA.
Assuntos
Líquidos Iônicos , Psoríase , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Líquidos Iônicos/uso terapêutico , Psoríase/tratamento farmacológico , Psoríase/genética , RNA Interferente Pequeno/genética , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Red blood cells (RBC) have great potential as drug delivery systems, capable of producing unprecedented changes in pharmacokinetics, pharmacodynamics, and immunogenicity. Despite this great potential and nearly 50 years of research, it is only recently that RBC-mediated drug delivery has begun to move out of the academic lab and into industrial drug development. RBC loading with drugs can be performed in several ways-either via encapsulation within the RBC or surface coupling, and either ex vivo or in vivo-depending on the intended application. In this review, we briefly summarize currently used technologies for RBC loading/coupling with an eye on how pharmacokinetics is impacted. Additionally, we provide a detailed description of key ADME (absorption, distribution, metabolism, elimination) changes that would be expected for RBC-associated drugs and address unique features of RBC pharmacokinetics. As thorough understanding of pharmacokinetics is critical in successful translation to the clinic, we expect that this review will provide a jumping off point for further investigations into this area.
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Adoptive cell transfers have emerged as a disruptive approach to treat disease in a manner that is more specific than using small-molecule drugs; however, unlike traditional drugs, cells are living entities that can alter their function in response to environmental cues. In the present study, we report an engineered particle referred to as a "backpack" that can robustly adhere to macrophage surfaces and regulate cellular phenotypes in vivo. Backpacks evade phagocytosis for several days and release cytokines to continuously guide the polarization of macrophages toward antitumor phenotypes. We demonstrate that these antitumor phenotypes are durable, even in the strongly immunosuppressive environment of a murine breast cancer model. Conserved phenotypes led to reduced metastatic burdens and slowed tumor growths compared with those of mice treated with an equal dose of macrophages with free cytokine. Overall, these studies highlight a new pathway to control and maintain phenotypes of adoptive cellular immunotherapies.
Assuntos
Imunoterapia , Macrófagos , Animais , Citocinas/metabolismo , Fatores Imunológicos/metabolismo , Imunoterapia Adotiva , Macrófagos/metabolismo , Camundongos , FagocitoseRESUMO
Despite being the mainstay of cancer treatment, chemotherapy has shown limited efficacy for the treatment of lung metastasis due to ineffective targeting and poor tumor accumulation. Here, we report a highly effective erythrocyte leveraged chemotherapy (ELeCt) platform, consisting of biodegradable drug nanoparticles assembled onto the surface of erythrocytes, to enable chemotherapy for lung metastasis treatment. The ELeCt platform significantly extended the circulation time of the drug nanoparticles and delivered 10-fold higher drug content to the lung compared with the free nanoparticles. In both the early- and late-stage melanoma lung metastasis models, the ELeCt platform enabled substantial inhibition of tumor growth that resulted in significant improvement of survival. Further, the ELeCt platform can be used to deliver numerous approved chemotherapeutic drugs. Together, the findings suggest that the ELeCt platform offers a versatile strategy to enable chemotherapy for effective lung metastasis treatment.
Assuntos
Doxorrubicina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Pulmonares/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Nanopartículas/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Eritrócitos/química , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Microscopia Eletrônica de Varredura , Nanopartículas/química , Nanopartículas/ultraestrutura , Resultado do TratamentoRESUMO
Over the years, a plethora of materials - natural and synthetic - have been engineered at a nanoscopic level and explored for drug delivery. Nanocarriers based on such materials could improve the payload's pharmacokinetics and achieve the desired pharmacological response at the target tissue. Despite the development of rationally designed drug nanocarriers, only a handful of such formulations have been successfully translated into the clinic. The physicochemical properties (size, shape, surface chemistry, porosity, elasticity, and many others) of these nanocarriers influence its biological identity, which in presence of biological barriers in vivo, could significantly modulate the therapeutic index of its cargo and alter the desired outcome. Further, complexities associated with developing effective drug nanocarriers have led to conflicting views of its safety, permeation of biological barriers and cellular uptake. Here, in this review, we emphasize the effect of physicochemical properties of nanocarriers on their interactions with the biological milieu. The review will discuss in depth, how modulating the physicochemical properties would influence a drug nanocarrier's behavior in vivo and the mechanisms underlying these effects. The goal of this review is to summarize the design considerations based on these properties and to provide a conceptual template for achieving improved therapeutic efficacy with enhanced patient compliance.
Assuntos
Portadores de Fármacos , Nanopartículas , Administração Intravenosa , Animais , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Humanos , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/toxicidade , Propriedades de SuperfícieRESUMO
Immunomodulation, manipulation of the immune responses towards an antigen, is a promising strategy to treat cancer, infectious diseases, allergies, and autoimmune diseases, among others. Unique features of the skin including the presence of tissue-resident immune cells, ease of access and connectivity to other organs makes it a unique target organ for immunomodulation. In this review, we summarize advances in transdermal delivery of agents for modulating the immune responses for vaccination as well as tolerization. The biological foundation of skin-based immunomodulation and challenges in its implementation are described. Technological approaches aimed at enhancing the delivery of immunomodulatory therapeutics into skin are also discussed in this review. Progress made in the treatment of several specific diseases including cancer, infections and allergy are discussed. Finally, this review discusses some practical considerations and offers some recommendations for future studies in the field of transdermal immunomodulation.