RESUMEN

The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.

Asunto(s)

Carcinoma Hepatocelular , Inmunoterapia , Neoplasias Hepáticas , Proteínas de la Membrana , Mitoxantrona , Nucleotidiltransferasas , Factor de Transcripción STAT3 , Mitoxantrona/farmacología , Mitoxantrona/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Animales , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Humanos , Nucleotidiltransferasas/metabolismo , Proteínas de la Membrana/metabolismo , Factor de Transcripción STAT3/metabolismo , Ratones , Inmunoterapia/métodos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Benzofuranos , Naftoquinonas

RESUMEN

Peripheral artery disease is commonly treated with balloon angioplasty, a procedure involving minimally invasive, transluminal insertion of a catheter to the site of stenosis, where a balloon is inflated to open the blockage, restoring blood flow. However, peripheral angioplasty has a high rate of restenosis, limiting long-term patency. Therefore, angioplasty is sometimes paired with delivery of cytotoxic drugs like paclitaxel to reduce neointimal tissue formation. We pursue intravascular drug delivery strategies that target the underlying cause of restenosis - intimal hyperplasia resulting from stress-induced vascular smooth muscle cell switching from the healthy contractile into a pathological synthetic phenotype. We have established MAPKAP kinase 2 (MK2) as a driver of this phenotype switch and seek to establish convective and contact transfer (coated balloon) methods for MK2 inhibitory peptide delivery to sites of angioplasty. Using a flow loop bioreactor, we showed MK2 inhibition in ex vivo arteries suppresses smooth muscle cell phenotype switching while preserving vessel contractility. A rat carotid artery balloon injury model demonstrated inhibition of intimal hyperplasia following MK2i coated balloon treatment in vivo. These studies establish both convective and drug coated balloon strategies as promising approaches for intravascular delivery of MK2 inhibitory formulations to improve efficacy of balloon angioplasty.

Asunto(s)

Péptidos y Proteínas de Señalización Intracelular , Proteínas Serina-Treonina Quinasas , Ratas Sprague-Dawley , Animales , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Péptidos/química , Péptidos/farmacología , Ratas , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/citología , Angioplastia de Balón/métodos , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Sistemas de Liberación de Medicamentos , Hiperplasia/prevención & control , Angioplastia , Neointima/prevención & control , Neointima/patología

RESUMEN

Thyroid cancer is increasing globally, with anaplastic thyroid carcinoma (ATC) being the most aggressive type and having a poor prognosis. Current clinical treatments for thyroid cancer present numerous challenges, including invasiveness and the necessity of lifelong medication. Furthermore, a significant portion of patients with ATC experience cancer recurrence and metastasis. To overcome this dilemma, we developed a pH-responsive biomimetic nanocarrier (CLP@HP-A) through the incorporation of Chlorin e6 (Ce6) and Lenvatinib (Len) within hollow polydopamine nanoparticles (HP) that were further modified with platinum nanoparticles (Pt), enabling synergistic chemotherapy and sonodynamic therapy. The CLP@HP-A nanocarriers exhibited specific binding with galectin-3 receptors, facilitating their internalization through receptor-mediated endocytosis for targeted drug delivery. Upon exposure to ultrasound (US) irradiation, Ce6 rapidly generated reactive oxygen species (ROS) to induce significant oxidative stress and trigger apoptosis in tumor cells. Additionally, Pt not only alleviated tumor hypoxia by catalyzing the conversion of H2O2 to oxygen (O2) but also augmented intracellular ROS levels through the production of hydroxyl radicals (•OH), thereby enhancing the efficacy of sonodynamic therapy. Moreover, Len demonstrated a potent cytotoxic effect on thyroid cancer cells through the induction of apoptosis. Transcriptomics analysis findings additionally corroborated that CLP@HP-A effectively triggered cancer cell apoptosis, thereby serving as a crucial mechanism for its cytotoxic effects. In conclusion, the integration of sonodynamic/chemo combination therapy with targeted drug delivery systems offers a novel approach to the management of malignant tumors.

Asunto(s)

Clorofilidas , Indoles , Platino (Metal) , Polímeros , Porfirinas , Neoplasias de la Tiroides , Microambiente Tumoral , Terapia por Ultrasonido , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapia , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/metabolismo , Humanos , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Indoles/química , Terapia por Ultrasonido/métodos , Porfirinas/química , Porfirinas/farmacología , Polímeros/química , Animales , Platino (Metal)/química , Platino (Metal)/uso terapéutico , Platino (Metal)/farmacología , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Apoptosis/efectos de los fármacos , Nanopartículas/química , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Ratones , Quinolinas/farmacología , Quinolinas/química , Ratones Desnudos , Portadores de Fármacos/química

RESUMEN

Infiltration of immunosuppressive cells into the breast tumor microenvironment (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic claudin-low tumor model, limiting the efficacy of adoptive cellular therapy. However, approaches to target these cells in the TME are currently lacking. To overcome this barrier, polymeric micellular nanoparticles (PMNPs) were used for the co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta (PI3Kδ). The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor led to type 1 macrophage polarization, decreased MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the T and B cell adaptive immune responses. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic claudin-low tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant diminished the immunosuppressive TME resulting in tumor regression. These findings set the stage for clinical studies of this approach.

Asunto(s)

Nanopartículas , Receptor Toll-Like 7 , Receptor Toll-Like 8 , Microambiente Tumoral , Animales , Microambiente Tumoral/efectos de los fármacos , Receptor Toll-Like 7/agonistas , Femenino , Nanopartículas/química , Ratones , Receptor Toll-Like 8/agonistas , Inmunomodulación/efectos de los fármacos , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Ratones Endogámicos BALB C , Micelas , Humanos

RESUMEN

Controlled release or controlled drug delivery comprises the set of techniques and approaches to improve bioavailability through improved safety and/or efficacy using a carrier material for the molecule of interest. The predictability and tunability of these carriers make them ideal for protection, localization, and sustained presentation of a wide range of therapeutics, including growth factors implicated in cell survival and regeneration. Here we provide a method for encapsulating epidermal growth factor in a degradable polymer matrix for delivery to the cornea. Additional notes are included to demonstrate the wide-ranging capabilities of such methods for other materials, therapeutic agents, and sites of action within the eye.

Asunto(s)

Supervivencia Celular , Preparaciones de Acción Retardada , Supervivencia Celular/efectos de los fármacos , Humanos , Regeneración , Factor de Crecimiento Epidérmico/metabolismo , Animales , Córnea/metabolismo , Córnea/citología , Sistemas de Liberación de Medicamentos/métodos , Polímeros/química , Portadores de Fármacos/química

RESUMEN

Functional hydrogels are used for numerous biomedical applications such as tissue engineering, wound dressings, lubricants, contact lenses and advanced drug delivery systems. Most of them are based on synthetic or natural polymers forming a three-dimensional network that contains aqueous media. Among synthetic polymers, poly(meth)acrylates, polyethyleneglycols, poly(vinylalcohols), poly(vinylpyrrolidones), PLGA and poly(urethanes) are of high relevance, whereas natural polymers are mainly polysaccharides such as hyaluronic acid, alginate or chitosan and proteins such as albumin, collagen or elastin. In contrast to most synthetic polymers, natural polymers are biodegradable. Both synthetic and natural polymers are often chemically modified in order to improve or induce favorable properties and functions like high mechanical strength, stiffness, elasticity, high porosity, adhesive properties, in situ gelling properties, high water binding capacity or drug release controlling properties. Within this review we provide an overview about the broad spectrum of biomedical applications of functional hydrogels, summarize innovative approaches, discuss the concept of relevant functional hydrogels that are in clinical trials and highlight advanced products as examples for successful developments.

Asunto(s)

Hidrogeles , Ingeniería de Tejidos , Hidrogeles/química , Humanos , Ingeniería de Tejidos/métodos , Ensayos Clínicos como Asunto , Animales , Materiales Biocompatibles/química , Sistemas de Liberación de Medicamentos/métodos , Polímeros/química

RESUMEN

Stimulator of interferon genes (STING) agonists have shown promise in cancer treatment by stimulating the innate immune response, yet their clinical potential has been limited by inefficient cytosolic entry and unsatisfactory pharmacological activities. Moreover, aggressive tumors with "cold" and immunosuppressive microenvironments may not be effectively suppressed solely through innate immunotherapy. Herein, we propose a multifaceted immunostimulating nanoparticle (Mn-MC NP), which integrates manganese II (Mn2+) coordinated photosensitizers (chlorin e6, Ce6) and STING agonists (MSA-2) within a PEGylated nanostructure. In Mn-MC NPs, Ce6 exerts potent phototherapeutic effects, facilitating tumor ablation and inducing immunogenic cell death to elicit robust adaptive antitumor immunity. MSA-2 activates the STING pathway powered by Mn2+, thereby promoting innate antitumor immunity. The Mn-MC NPs feature a high drug-loading capacity (63.42 %) and directly ablate tumor tissue while synergistically boosting both adaptive and innate immune responses. In subsutaneous tumor mouse models, the Mn-MC NPs exhibit remarkable efficacy in not only eradicating primary tumors but also impeding the progression of distal and metastatic tumors through synergistic immunotherapy. Additionally, they contribute to preventing tumor recurrence by fostering long-term immunological memory. Our multifaceted immunostimulating nanoparticle holds significant potential for overcoming limitations associated with insufficient antitumor immunity and ineffective cancer treatment.

Asunto(s)

Inmunoterapia , Manganeso , Nanopartículas , Animales , Inmunoterapia/métodos , Manganeso/química , Nanopartículas/química , Ratones , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Línea Celular Tumoral , Humanos , Porfirinas/química , Porfirinas/farmacología , Clorofilidas , Neoplasias/terapia , Neoplasias/inmunología , Fotoquimioterapia/métodos , Inmunidad Innata/efectos de los fármacos , Femenino , Ratones Endogámicos C57BL , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química

RESUMEN

Tumor immunotherapies have emerged as a promising frontier in the realm of cancer treatment. However, challenges persist in achieving localized, durable immunostimulation while counteracting the tumor's immunosuppressive environment. Here, we develop a natural mussel foot protein-based nanomedicine with spatiotemporal control for tumor immunotherapy. In this nanomedicine, an immunoadjuvant prodrug and a photosensitizer are integrated, which is driven by their dynamic bonding and non-covalent assembling with the protein carrier. Harnessing the protein carrier's bioadhesion, this nanomedicine achieves a drug co-delivery with spatiotemporal precision, by which it not only promotes tumor photothermal ablation but also broadens tumor antigen repertoire, facilitating in situ immunotherapy with durability and maintenance. This nanomedicine also modulates the tumor microenvironment to overcome immunosuppression, thereby amplifying antitumor responses against tumor progression. Our strategy underscores a mussel foot protein-derived design philosophy of drug delivery aimed at refining combinatorial immunotherapy, offering insights into leveraging natural proteins for cancer treatment.

Asunto(s)

Inmunoterapia , Nanomedicina , Animales , Inmunoterapia/métodos , Nanomedicina/métodos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/farmacología , Terapia Fototérmica/métodos , Ratones , Humanos , Microambiente Tumoral/efectos de los fármacos , Línea Celular Tumoral , Proteínas/química , Femenino , Neoplasias/terapia , Neoplasias/inmunología , Adhesivos/química , Ratones Endogámicos C57BL , Adyuvantes Inmunológicos/farmacología

RESUMEN

Injuries of the respiratory system caused by viral infections (e.g., by influenza virus, respiratory syncytial virus, metapneumovirus, or coronavirus) can lead to long-term complications or even life-threatening conditions. The challenges of treatment of such diseases have become particularly pronounced during the recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One promising drug is the anti-fibrinolytic and anti-inflammatory protease inhibitor aprotinin, which has demonstrated considerable inhibition of the replication of some viruses. Encapsulation of aprotinin in liposomes can significantly improve the effectiveness of the drug, however, the use of nanoparticles as carriers of aprotinin can radically change its biodistribution in the body. Here we show that the liposomal form of aprotinin accumulates more efficiently in the lungs, heart, and kidneys than the molecular form by side-by-side comparison of the ex vivo biodistribution of these two fluorescently labeled formulations in mice using bioimaging. In particular, we synthesized liposomes of different compositions and studied their accumulation in various organs and tissues. Direct comparison of the biodistributions of liposomal and free aprotinin showed that liposomes accumulated in the lungs 1.82 times more effectively, and in the heart and kidneys - 3.56 and 2.00 times, respectively. This suggests that the liposomal formulation exhibits a longer residence time in the target organ and, thus, has the potential for a longer therapeutic effect. The results reveal the great potential of the aprotinin-loaded liposomes for the treatment of respiratory system injuries and heart- and kidney-related complications of viral infections.

RESUMEN

PURPOSE: This comprehensive review is designed to elucidate the transformative role and multifaceted applications of ocular hydrogels in contemporary ophthalmic therapeutic strategies, with a particular emphasis on their capability to revolutionize drug delivery mechanisms and optimize patient outcomes. METHODS: A systematic and structured methodology is employed, initiating with a succinct exploration of prevalent ocular pathologies and delineating the corresponding therapeutic agents. This serves as a precursor for an extensive examination of the diverse methodologies and fabrication techniques integral to the design, development, and application of hydrogels specifically tailored for ophthalmic pharmaceutical delivery. The review further scrutinizes the pivotal manufacturing processes that significantly influence hydrogel efficacy and delves into an analysis of the current spectrum of hydrogel-centric ocular formulations. RESULTS: The review yields illuminating insights into the escalating prominence of ocular hydrogels within the medical community, substantiated by a plethora of ongoing clinical investigations. It reveals the dynamic and perpetually evolving nature of hydrogel research and underscores the extensive applicability and intricate progression of transposing biologics-loaded hydrogels from theoretical frameworks to practical clinical applications. CONCLUSIONS: This review accentuates the immense potential and promising future of ocular hydrogels in the realm of ophthalmic care. It not only serves as a comprehensive guide but also as a catalyst for recognizing the transformative potential of hydrogels in augmenting drug delivery mechanisms and enhancing patient outcomes. Furthermore, it draws attention to the inherent challenges and considerations that necessitate careful navigation by researchers and clinicians in this progressive field.

RESUMEN

A common malignant bone neoplasm in teenagers is Osteosarcoma. Chemotherapy, surgical therapy, and radiation therapy together comprise the usual clinical course of treatment for Osteosarcoma. While Osteosarcoma and other bone tumors are typically treated surgically, however, surgical resection frequently fails to completely eradicate tumors, and in turn becomes the primary reason for postoperative recurrence and metastasis, ultimately leading to a high rate of mortality. Patients still require radiation and/or chemotherapy after surgery to stop the spread of the tumor and its metastases, and both treatments have an adverse influence on the body's organ systems. In the postoperative management of osteosarcoma, bone scaffolds can load cargos (growth factors or drugs) and function as drug delivery systems (DDSs). This review describes the different kinds of bone scaffolds that are currently available and highlights key studies that use scaffolds as DDSs for the treatment of osteosarcomas. The discussion also includes difficulties and perspectives regarding the use of scaffold-based DDSs. The study may serve as a source for outlining efficient and secure postoperative osteosarcoma treatment plans.

Asunto(s)

Neoplasias Óseas , Sistemas de Liberación de Medicamentos , Osteosarcoma , Andamios del Tejido , Osteosarcoma/tratamiento farmacológico , Humanos , Sistemas de Liberación de Medicamentos/métodos , Neoplasias Óseas/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Huesos/efectos de los fármacos , Animales

RESUMEN

One of the current challenges in targeting neurological disorders is that many therapeutic molecules cannot cross the blood-brain barrier (BBB), which limits the use of natural molecules in nervous tissue regeneration. Thus, the development of new drugs to effectively treat neurological disorders would be a challenge. Natural resources are well known as a source of several therapeutic agents for the treatment of neurologic disorders. Recently, chitosan (CTS) and its derivatives from arthropod exoskeletons, have attracted much attention as a drug delivery system to transport therapeutic substances across the BBB and thanks to other neuroprotective effects including the participation to the CNS regenerations scaffolds to replicate the extracellular matrix and microenvironment of the body. This review will discuss the place of natural resource therapy in targeting neurological disorders. In particular, it will highlight recent understanding and progress in the applications of CTS as drug delivery systems and their therapeutic effects on these disorders through tissue regeneration, as well as the molecular mechanisms by which they exert these effects.

RESUMEN

Amphotericin B (AmB) is an antifungal agent administered for the management of serious systemic fungal infections. However, its clinical application is limited because of its water insolubility and side effects. Herein, to apply the minimum dose of AmB that can be used to manage fungal infections, a targeted drug delivery system was designed using lipopeptides and poly(lactide-co-glycolide) (PLGA). Lipopeptides conjugated with PEGylated distearoyl phosphoethanolamine (DSPE) and short peptides via a maleimide-thiol reaction formed nanosized micelles with PLGA and AmB. The antifungal effects of AmB-loaded micelles containing lipopeptides were remarkably enhanced both in vitro and in vivo. Moreover, the intravenous injection of these micelles demonstrated their in vivo targeting capacity of short peptides in a mouse model infected with drug-resistant Candida albicans. Our findings suggest that short antifungal peptides displayed on the surfaces of micelles represent a promising therapeutic candidate for targeting drug-resistant fungal infections.

RESUMEN

Ophthalmic diseases include a wide array of conditions, each requiring individualized treatment approaches. In ophthalmic research and as therapeutics against potential pharmacological indications, several subtypes of exosomes (EVs) have been reconnoitered, mainly for their regenerative, neuroprotective, and anti-inflammatory characteristics. EVs are recently gaining wider attention as promising vehicles for therapies because of their natural participation in communication between cells and targeted delivery. These small vesicles, derived from cells, transport numerous molecules between cells, thus contributing advantages like low immunogenicity, stability, and the ability to target cells specifically. These inherent advantages of carrying the therapeutic cargo and enabling intercellular signaling make them a captivating avenue for progressing ophthalmic disease treatment options. While research is ongoing, and clinical applications are still emerging, several EV subtypes have shown promise for possible applications in addressing several ophthalmic diseases, such as glaucoma, age-related macular degenerative disorders, retinal degenerative disorders, and ocular inflammatory conditions.

RESUMEN

INTRODUCTION: Although lignin is one of the most naturally abundant biopolymers, the overall status of its utilization has long been subpar. The ability of Lignin to readily self-assemble into nanoparticles, along with its good biocompatibility and minimal toxicity, makes it a perfect agent for nanocarriers and drug delivery. METHOD: Hence, in this study, we have attempted to examine lignin nanoparticles (LNPs) as an efficient pH-responsive nanocarrier for gastric-irritant oral NSAID, aspirin. Alkali lignin (AL) was extracted from rice straw via alkaline treatment, and the lignin nanoparticles were synthesized from lignin using the acid precipitation method. The average particle size was 201.37 ± 1.20 nm, and the synthesized LNPs exhibited a spherical shape and smooth outer surface along with high polydispersity (PDI= 0.284 ± 0.012). The LNPs showed moderate hemocompatibility during in vitro hemolysis studies. The nanoparticles presented nearly similar chemical structures to the AL from which they were developed, and the FT-IR absorption spectra confirmed the similarity of this chemical structure to the LNPs and AL. Aspirin was successfully loaded into the LNPs with a satisfactory drug loading value of 39.12 ± 1.50 and an excellent encapsulation efficiency value of 91.44 ± 0.59. RESULTS: Finally, the LNPs were capable of protecting the loaded drug at the acidic pH of the stomach (1.2) with just 29.20% release of the loaded aspirin after 10 h of observation in vitro. Contrarily, the LNPs were capable of rapidly releasing the aspirin at the basic pH of the intestine (7.4) with nearly 90% release of the loaded drug after 10 h observation in vitro. The basic pH of the intestine might lead to gradual dissociation of the LNPs followed by swift release of the loaded cargo. CONCLUSION: These findings substantiate that the LNPs carry the potential to be an apt and safe nanocarrier for oral drugs like aspirin as well as parenteral drugs, and LNPs can be utilized as an efficient alternative to enteric coating.

RESUMEN

Silica nanoparticles are increasingly considered for drug delivery applications. These applications require an understanding of their biocompatibility, including their interactions with the immune system. However, systematic studies for silica nanoparticle immunological safety profiles are lacking. To fill this gap, we conducted an in vitro study investigating various aspects of silica nanoparticles' interactions with blood and immune cells. Four types of silica nanoparticles with variations in size and porosity were studied. These included nonporous Stöber silica nanoparticles with average diameters of approximately 50 and 100 nm (SNP50 and SNP100), mesoporous silica nanoparticles of approximately 100 nm (Meso100), and hollow mesoporous silica nanoparticles of approximately 100 nm (HMSNP100) in diameter, respectively. The hematological compatibility was assessed using hemolysis, complement activation, platelet aggregation, and plasma coagulation assays. The effects of nanoparticles on immune cell function were studied using in vitro phagocytosis, chemotaxis, natural killer cell cytotoxicity, leukocyte proliferation, human lymphocyte activation, colony-forming unit granulocyte-macrophage, and leukocyte procoagulant activity assays. The in vitro findings suggest that at high concentrations, corresponding to the in vivo human dose of 40 mg/kg, silica nanoparticles demonstrated an array of immunotoxic effects that depended on their physicochemical properties. However, all types of silica nanoparticles studied were not immunotoxic at concentrations corresponding to lower doses (≤ 8 mg/kg) comparable to that of nanocarriers in other nanomedicines currently used in the clinic. These findings are promising for using silica nanoparticles for the systemic delivery of bioactive and imaging agents.

RESUMEN

INTRODUCTION: Targeted liposomal systems for cancer intention have been recognized as a specific and robust approach compared to conventional liposomal delivery systems. Cancer cells have a unique microenvironment with special over-expressed receptors on their surface, providing opportunities for discovering novel and effective drug delivery systems using active targeting. AREAS COVERED: Smartly targeted liposomes, responsive to internal or external stimulations, enhance the delivery efficiency by increasing accumulation of the encapsulated anti-cancer agent in the tumor site. The application of antibodies and aptamers against the prevalent cell surface receptors is a potent and ever-growing field. Moreover, immuno-liposomes and cancer vaccines as adjuvant chemotherapy are also amenable to favorable immune modulation. Combinational and multi-functional systems are also attractive in this regard. However, potentially active targeted liposomal drug delivery systems have a long path to clinical acceptance, chiefly due to cross-interference and biocompatibility affairs of the functionalized moieties. EXPERT OPINION: Engineered liposomal formulations have to be designed based on tissue properties, including surface chemistry, charge, and microvasculature. In this paper, we aimed to investigate the updated targeted liposomal systems for common cancer therapy worldwide.

RESUMEN

Pancreatic ductal adenocarcinoma remains a highly aggressive and untreatable cancer. There is a need to develop a new PDAC-associated antigen-targeting drug delivery system to tackle this disease. We validated choosing ZIP4 as a putative target in PDAC theranostics. We developed a nanosystem composed of a fluorescent polystyrene core coated with gold nanoparticles onto which a ZIP4-specific polyclonal antibody is attached. The polystyrene core's fluorescence properties allow the nanosystem tracking by intravital imaging. We also developed two ZIP4-expressing cell lines by stably transfecting HEK293 and RWP1 cells with a ZIP4-coding plasmid that simultaneously provides cells with puromycin resistance. We studied the cell internalization of the as-synthesized nanoparticles and demonstrated that ZIP4-expressing HEK293 and ZIP4-expressing RWP1 cells tended to take up more ZIP4-targeting nanoparticles. Moreover, we observed that ZIP4-targeting nanoparticles accumulated more in ZIP4-expressing HEK293 and RWP1 tumors when injected intravenously in a subcutaneous xenograft and an orthotopic in vivo model, respectively. Furthermore, the administration of these nanoparticles did not induce any significant systemic toxicity as determined by histological analysis of all organs. Altogether, these results provide the first evidence of the feasibility of using a ZIP4-targeting nanosystem further to design efficient therapeutic and diagnostic tools for PDAC.

RESUMEN

BACKGROUND: Adrenal insufficiency is usually diagnosed in children who will need lifelong hydrocortisone therapy. However, medicines for pediatrics, in terms of dosage and acceptability, are currently unavailable. RESEARCH DESIGN AND METHODS: Semi-solid extrusion (SSE) 3D printing (3DP) was utilized for manufacturing of personalized and chewable hydrocortisone formulations (printlets) for an upcoming clinical study in children at Vall d'Hebron University Hospital in Barcelona, Spain. The 3DP process was validated using a specific software for dynamic dose modulation. RESULTS: The printlets contained doses ranging from 1 to 6 mg hydrocortisone in three different flavor and color combinations to aid adherence among the pediatric patients. The pharma-ink (mixture of drugs and excipients) was assessed for its rheological behavior to ensure reproducibility of printlets through repeated printing cycles. The printlets showed immediate hydrocortisone release and were stable for 1 month of storage, adequate for prescribing instructions during the clinical trial. CONCLUSIONS: The results confirm the suitability and safety of the developed printlets for use in the clinical trial. The required technical information from The Spanish Medicines Agency for this clinical trial application was compiled to serve as guidelines for healthcare professionals seeking to apply for and conduct clinical trials on 3DP oral dosage forms.

RESUMEN

BACKGROUND: The clinical efficacy of cancer treatment protocols remains unsatisfactory; however, the emergence of ferroptosis-driven therapy strategies has renewed hope for tumor treatment, owing to their remarkable tumor suppression effects. Biologically based small-molecule inducers are used in conventional method to induce ferroptosis. Nevertheless, some molecular drugs have limited solubility, poor ability to target cells, and fast metabolism, which hinder their ability to induce ferroptosis over a prolonged period. Fortunately, further investigations of ferroptosis and the development of nanotechnology have demonstrated that nanoparticles (NPs) are more efficient in inducing ferroptosis than drugs alone, which opens up new perspectives for cancer therapy. OBJECTIVE: In order to organize a profile of recent advance in NPs for inducing ferroptosis in cancer therapy, and NPs were comprehensively classified in a new light.Materials and methods: We comprehensively searched the databases such as PubMed and Embase. The time limit for searching was from the establishment of the database to 2023.11. All literatures were related to "ferroptosis", "nanoparticles", "nanodelivery systems", "tumors", "cancer". RESULTS: We summarized and classified the available NPs from a new perspective. The NPs were classified into six categories based on their properties: (1) iron oxide NPs (2) iron - based conversion NPs (3) core-shell structure (4) organic framework (5) silica NPs (6) lipoprotein NPs. According to the therapeutic types of NPs, they can be divided into categories: (1) NPs induced ferroptosis-related immunotherapy (2) NPs loaded with drugs (3) targeted therapy of NPs (4) multidrug resistance therapy (5) gene therapy with NPs (6) energy conversion therapy. CONCLUSIONS: The insights gained from this review can provide ideas for the development of original NPs and nanodelivery systems, pave the way for related nanomaterials application in clinical cancer therapy, and advance the application and development of nanotechnology in the medical field.

Asunto(s)

Ferroptosis , Nanopartículas , Neoplasias , Ferroptosis/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Nanopartículas/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Animales