RESUMEN
Chronic rhinosinusitis (CRS) is a chronic inflammatory condition affecting the nasal and paranasal sinuses of approximately 11.5% of the United States adult population. Oral corticosteroids are effective in controlling sinonasal inflammation in CRS, but the associated adverse effects limit their clinical use. Topical budesonide has demonstrated clinical efficacy in patients with CRS. Herein, we investigated the systemic delivery of liposomes tethered with poly(ethylene glycol) (PEG) and loaded with budesonide in a murine model of CRS. PEGylated liposomes encapsulated with budesonide phosphate (L-BudP) were administered via tail vein injection, and the feasibility of L-BudP to reduce sinonasal inflammation was compared to that of free budesonide phosphate (F-BudP) and topical budesonide phosphate (T-BudP) treatment over a 14-day study period. Compared to a single injection of F-BudP and repeat T-BudP administration, a single injection of L-BudP demonstrated increased and prolonged efficacy, resulting in the significant improvement of sinonasal tissue histopathological scores (p < 0.05) with decreased immune cell infiltration (p < 0.05). Toxicities associated with L-BudP and T-BudP treatment, assessed via body and organ weight, as well as peripheral blood liver enzyme and differential white blood cell analyses, were transient and comparable. These data suggest that systemic liposomal budesonide treatment results in improved efficacy over topical treatment.
Asunto(s)
Rinitis , Sinusitis , Adulto , Humanos , Animales , Ratones , Budesonida/uso terapéutico , Liposomas/uso terapéutico , Rinitis/tratamiento farmacológico , Rinitis/inducido químicamente , Sinusitis/tratamiento farmacológico , Sinusitis/inducido químicamente , Inflamación/tratamiento farmacológico , Enfermedad Crónica , Polietilenglicoles/uso terapéuticoRESUMEN
Osteosarcoma (OS) is the most common form of primary malignant bone cancer in adolescents. Over the years, OS prognosis has greatly improved due to adjuvant and neoadjuvant (preoperative) chemotherapeutic treatment, increasing the chances of successful surgery and reducing the need for limb amputation. However, chemotherapeutic treatment to treat OS is limited by off-target toxicities and requires improved localization at the tumor site. Collagen, the main constituent of bone tissue, is extensively degraded and remodeled in OS, leading to an increased availability of denatured (monomeric) collagen. Collagen hybridizing peptides (CHPs) comprise a class of peptides rationally designed to selectively bind to denatured collagen. In this work, we have conjugated CHPs as targeting moieties to water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers to target OS tumors. We demonstrated increased accumulation of collagen-targeted HPMA copolymer-CHP conjugates compared to nontargeted HPMA copolymers, as well as increased retention compared to both nontargeted copolymers and CHPs, in a murine intratibial OS tumor model. Furthermore, we used microcomputed tomography analysis to evaluate the bone microarchitecture and correlated bone morphometric parameters (porosity, bone volume, and surface area) with maximum accumulation (Smax) and accumulation at 168 h postinjection (S168) of the copolymers at the tumor. Our results provide the foundation for the use of HPMA copolymer-CHP conjugates as targeted drug delivery systems in OS tumors.
Asunto(s)
Neoplasias Óseas , Osteosarcoma , Ratones , Humanos , Animales , Adolescente , Microtomografía por Rayos X , Sistemas de Liberación de Medicamentos/métodos , Metacrilatos , Péptidos , Colágeno , PolímerosRESUMEN
The extracellular matrix (ECM) is dynamically involved in many aspects of cell growth and survival, and it plays an active role in cancer etiology. In comparison to healthy ECM, tumor associated ECM shows high collagen deposition and remodeling activity, which results in an increased amount of denatured collagen strands in tumor tissues. Capitalizing on this distinguishing feature, we developed tumor-localizing polymeric carriers that selectively bind to denatured collagen in the tumor ECM. We synthesized N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with their side chains conjugated to collagen hybridizing peptides (CHPs). HPMA copolymer-CHP conjugates exhibited selective affinity to denatured collagen and localized to tumors in an orthotopic MDA-MB-231 murine breast cancer model. The conjugates had increased tumor localization compared to copolymers with scrambled peptides in the side chains, as well as increased retention compared to free CHPs. Such conjugates show promise as carriers for ECM-acting drugs and imaging agents in the management of diseases characterized by high ECM remodeling activity.
Asunto(s)
Neoplasias de la Mama , Sistemas de Liberación de Medicamentos , Humanos , Animales , Ratones , Femenino , Sistemas de Liberación de Medicamentos/métodos , Metacrilatos , Péptidos , Colágeno , Matriz Extracelular , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular TumoralRESUMEN
The extracellular matrix (ECM) plays an active role in cell life through a tightly controlled reciprocal relationship maintained by several fibrous proteins, enzymes, receptors, and other components. It is also highly involved in cancer progression. Because of its role in cancer etiology, the ECM holds opportunities for cancer therapy on several fronts. There are targets in the tumor-associated ECM at the level of signaling molecules, enzyme expression, protein structure, receptor interactions, and others. In particular, the ECM is implicated in invasiveness of tumors through its signaling interactions with cells. By capitalizing on the biology of the tumor microenvironment and the opportunities it presents for intervention, the ECM has been investigated as a therapeutic target, to facilitate drug delivery, and as a prognostic or diagnostic marker for tumor progression and therapeutic intervention. This review summarizes the tumor ECM biology as it relates to drug delivery with emphasis on design parameters targeting the ECM.
RESUMEN
Photodynamic therapy (PDT) is a promising cancer treatment approach. However, the photosensitizers (PS) used for PDT are often limited by their poor solubility and selectivity for tumors. The goal of this study is to improve water solubility and delivery of the photosensitizer 2-[1-hexyloxyethyl]-2-divinyl pyropheophorbide-a (HPPH) to breast cancer cells. An N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-HPPH photosensitizer conjugate is synthesized with heat shock receptor glucose-regulated protein 78 (GRP78), targeting to GRP78 receptors of MCF-7 cells, which are upregulated under mild hyperthermia. It is found that the uptake of the GRP78 targeted pep-HPMA-HPPH copolymer conjugate in MCF-7 cells is improved through heat induction. Under mild hyperthermia the targeted copolymers are more effective compared to free HPPH. These results show potential for the utility of mild hyperthermia and copolymer delivery vehicles to enhance the efficacy of photodynamic therapy.
Asunto(s)
Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Endocitosis , Proteínas de Choque Térmico/metabolismo , Hipertermia Inducida , Metacrilatos/química , Fármacos Fotosensibilizantes/farmacología , Polímeros/química , Muerte Celular/efectos de los fármacos , Chaperón BiP del Retículo Endoplásmico , Femenino , Humanos , Células MCF-7 , Metacrilatos/síntesis química , Polímeros/síntesis químicaRESUMEN
Polymeric drug carriers can alter the pharmacokinetics of their drug cargoes, thereby improving drug therapeutic index and reducing side effects. Understanding and controlling polymer properties that drive tissue-specific accumulation is critical in engineering targeted drug delivery systems. For kidney disease applications, targeted drug delivery to renal cells that reside beyond the charge- and size-selective glomerular filtration barrier could have clinical potential. However, there are limited reports on polymer properties that might enhance kidney accumulation. Here, we studied the effects of molecular weight and charge on the in vivo kidney accumulation of polymers in health and disease. We synthesized a panel of well-defined polymers by atom transfer radical polymerization to answer several questions. First, the biodistribution of low molecular weight (23-27â¯kDa) polymers composed of various ratios of neutral:anionic monomers (1:0, 1:1, 1:4) in normal mice was determined. Then, highly anionic (1:4 monomer ratio) low molecular and high molecular weight (47â¯kDa) polymers were tested in both normal and experimental focal segmental glomerulosclerosis (FSGS) mice, a model that results in loss of glomerular filtration selectivity. Through these studies, we observed that kidney-specific polymer accumulation increases with anionic monomer content, but not molecular weight; experimental FSGS increases kidney accumulation of anionic polymers; and anionic polymers accumulate predominantly in proximal tubule cells, with some distribution in kidney glomeruli. These findings can be applied to the design of polymeric drug carriers to enhance or mitigate kidney accumulation.
Asunto(s)
Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Polímeros/metabolismo , Animales , Aniones , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Glomeruloesclerosis Focal y Segmentaria/patología , Humanos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Ratones , Peso Molecular , Polímeros/síntesis química , Polímeros/química , Distribución TisularRESUMEN
To further engineer dienones with optimal combinations of potency and bioavailability, thirty-four asymmetric 1,5-diarylpenta-1,4-dien-3-ones (25-58) have been designed and synthesized for the evaluation of their in vitro anti-proliferative activity in three human prostate cancer cell lines and one non-neoplastic prostate epithelial cell line. All these asymmetric dienones are sufficiently more potent than curcumin and their corresponding symmetric counterparts. The optimal dienone 58, with IC50 values in the range of 0.03-0.12 µM, is 636-, 219-, and 454-fold more potent than curcumin in three prostate cancer cell models. Dienones 28 and 49 emerged as the most promising asymmetric dienones that warrant further preclinical studies. The two lead compounds demonstrated substantially improved potency in cell models and superior bioavailability in rats, while exhibiting no acute toxicity in the animals at the dose of 10 mg/kg. Dienones 28 and 46 can induce PC-3 cell cycle regulation at the G0/G1 phase. However, dienone 28 induces PC-3 cell death in a different way from 46 even though they share the same scaffold, indicating that terminal heteroaromatic rings are critical to the action of mechanism for each specific dienone.
Asunto(s)
Alcadienos/farmacología , Antineoplásicos/farmacología , Células Epiteliales/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Alcadienos/síntesis química , Alcadienos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Epiteliales/patología , Humanos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Neoplasias de la Próstata/patología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
While commonly known for degradation of the extracellular matrix, matrix metalloproteinases (MMPs) exhibit broad potential for use in targeting of bioactive and imaging agents in cancer treatment. MMPs are upregulated at all stages of expression in cancers. A comprehensive analysis of published literature on expression of all MMP subtypes at the genetic, protein, and activity levels in normal and diseased tissues indicate targeting applicability in a variety of cancers. This expression significantly increases at advanced cancer stages, providing an improved opportunity for controlled release in higher-stage patients. Since MMPs are integral at every stage of metastasis, MMP roles in cancer are discussed with a focus on MMP distribution and mobility within cells and tumors for cancer targeting applications. Several strategies for MMP utilization in targeting - such as matrix degradation, MMP cleavage, MMP binding, and MMP-induced environmental changes - are addressed.
Asunto(s)
Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Terapia Molecular Dirigida , Neoplasias/genética , Neoplasias/metabolismo , Animales , Humanos , Regulación hacia ArribaRESUMEN
Combination of polymer therapeutics and hyperthermia has been shown to enhance accumulation in selectively heated tumor tissue. The additional use of heat shock (HS)-targeting towards tumor tissues can further enhance accumulation and retention, and improve therapeutic outcomes. In this work, high intensity focused ultrasound (HIFU) was used to generate hyperthermia in prostate tumor tissue. Upregulation of the cell surface HS receptor glucose regulated protein 78 kDa (GRP78) was observed after treatment with HIFU hyperthermia which was then targeted by specific HS-targeting peptides. We used the peptide sequence WDLAWMFRLPVG attached to the side chains of water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing docetaxel (DOC) conjugated via a lysosomally degradable linker. It was shown that HIFU-mediated HS-targeted copolymer-DOC conjugates improved treatment efficacy in a murine prostate tumor xenograft model. These results show that the use of HIFU hyperthermia in combination with HS-targeted polymer-drug conjugates has potential to improve therapeutic outcomes in prostate cancer treatment.
Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Ultrasonido Enfocado de Alta Intensidad de Ablación/métodos , Hipertermia Inducida/métodos , Neoplasias de la Próstata/terapia , Taxoides/administración & dosificación , Acrilamidas/química , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Docetaxel , Chaperón BiP del Retículo Endoplásmico , Humanos , Masculino , Ratones Desnudos , Péptidos/química , Próstata/efectos de los fármacos , Próstata/patología , Neoplasias de la Próstata/patología , Taxoides/uso terapéuticoRESUMEN
Mild hyperthermia has been used in combination with polymer therapeutics to further increase delivery to solid tumors and enhance efficacy. An attractive method for generating heat is through non-invasive high intensity focused ultrasound (HIFU). HIFU is often used for ablative therapies and must be adapted to produce uniform mild hyperthermia in a solid tumor. In this work a magnetic resonance imaging guided HIFU (MRgHIFU) controlled feedback system was developed to produce a spatially uniform 43°C heating pattern in a subcutaneous mouse tumor. MRgHIFU was employed to create hyperthermic conditions that enhance macromolecular delivery. Using a mouse model with two subcutaneous tumors, it was demonstrated that MRgHIFU enhanced delivery of both Evans blue dye (EBD) and Gadolinium-chelated N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. The EBD accumulation in the heated tumors increased by nearly 2-fold compared to unheated tumors. The Gadolinium-chelated HPMA copolymers also showed significant enhancement in accumulation over control as evaluated through MRI T1-mapping measurements. Results show the potential of HIFU-mediated hyperthermia for enhanced delivery of polymer therapeutics.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Ultrasonido Enfocado de Alta Intensidad de Ablación/métodos , Hipertermia Inducida/métodos , Sustancias Macromoleculares/administración & dosificación , Acrilamidas/administración & dosificación , Acrilamidas/metabolismo , Animales , Azul de Evans/administración & dosificación , Azul de Evans/metabolismo , Gadolinio/administración & dosificación , Gadolinio/metabolismo , Sustancias Macromoleculares/metabolismo , Imagen por Resonancia Magnética , Ratones Endogámicos , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/metabolismo , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Inspired by the synergistic effects of dietary natural products with different scaffolds on the inhibition of cancer cell proliferation, incorporation of central (1E,4E)-1,4-penta-dien-3-one linker (an optimal substitute for the central metabolically unstable diketone linker of curcumin), 1-alkyl-1H-imidazol-2-yl (a promising bioisostere of terminal aryl group in curcumin), and chromone (the common pharmacophore in genistein and quercetin) into one chemical entity resulted in ten new hybrid molecules, 3-((1E,4E)-5-(1-alkyl-1H-imidazol-2-yl)-3-oxopenta-1,4-dien-1-yl)-4H-chromen-4-ones. They were synthesized through a three-step transformation using acid-catalyzed aldol condensation as key step. The WST-1 cell proliferation assay showed that they have greater anti-proliferative potency than curcumin, quercetin, and genistein on both androgen-dependent and androgen-independent human prostate cancer cells.