RESUMEN

Prostate cancer (PC) is an aggressive cancer that can progress rapidly and eventually become castrate-resistant prostate cancer (CRPC). Stage IV metastatic castrate-resistant prostate cancer (mCRPC) is an incurable late-stage cancer type with a low 5-year overall survival rate. Targeted therapeutics such as antibody-drug conjugates (ADCs) based on high-affinity monoclonal antibodies and potent drugs conjugated via smart linkers are being developed for PC management. Conjugating further with in vitro or in vivo imaging agents, ADCs can be used as antibody-theranostic conjugates (ATCs) for diagnostic and image-guided drug delivery. In this study, we have developed a novel ATC for PSMA (+) PC therapy utilizing (a) anti-PSMA 5D3 mAb, (b) Aurora A kinase inhibitor, MLN8237, and (c) for the first time using tetrazine (Tz) and trans-cyclooctene (TCO) click chemistry-based conjugation linker (CC linker) in ADC development. The resulting 5D3(CC-MLN8237)3.2 was labeled with suitable fluorophores for in vitro and in vivo imaging. The products were characterized by SDS-PAGE, MALDI-TOF, and DLS and evaluated in vitro by optical imaging, flow cytometry, and WST-8 assay for cytotoxicity in PSMA (+/-) cells. Therapeutic efficacy was determined in human PC xenograft mouse models following a designed treatment schedule. After the treatment study animals were euthanized, and toxicological studies, complete blood count (CBC), blood clinical chemistry analysis, and H&E staining of vital organs were conducted to determine side effects and systemic toxicities. The IC50 values of 5D3(CC-MLN8237)3.2-AF488 in PSMA (+) PC3-PIP and PMSA (-) PC3-Flu cells are 8.17 nM and 161.9 nM, respectively. Pure MLN8237 shows 736.9 nM and 873.4 nM IC50 values for PC3-PIP and PC3-Flu cells, respectively. In vivo study in human xenograft mouse models confirmed high therapeutic efficacy of 5D3(CC-MLN8237)3.2-CF750 with significant control of PSMA (+) tumor growth with minimal systemic toxicity in the treated group compared to PSMA (-) treated and untreated groups. Approximately 70% of PSMA (+) PC3-PIP tumors did not exceed the threshold of the tumor size in the surrogate Kaplan-Meyer analysis. The novel ATC successfully controlled the growth of PSMA (+) tumors in preclinical settings with minimal systemic toxicities. The therapeutic efficacy and favorable safety profile of novel 5D3(CC-MLN8237)3.2 ATC demonstrates their potential use as a theranostic against aggressive PC.

RESUMEN

Nanoscale coordination polymer (NCP) is a class of hybrid materials formed by self-assembly of metal ions and organic ligands through coordination. The applications of NCP in biomedicine are quite extensive due to the diversity choice of metal ions and organic ligands. Here we designed Zr-P1 NCP based on Zr4+ selected as metal ion nodes and tetrakis(4-carboxyphenyl) ethylene as bridging ligands. Zr-P1 NCP was modified with functionalized pyrene derived polyethylene glycol (Py-PAA-PEG-Mal) on the surface and further conjugated with cRGD for active targeting of integrin αvß3 overexpressed in triple-negative breast cancer. Doxorubicin was loaded on Zr-P1 NCP with encapsulation efficiency up to 22 % for the treatment of triple negative breast cancer. 89Zr-P1 NCP can be used for in vivo tumor imaging due to the fluorescence properties resulting from the enhanced aggregation-induced Emission (AIE) behavior of P1 ligands and its positron emission tomography (PET) capability. Cellular evaluation indicated that the functionalized Zr-P1@PEG-RGD presented a good function for tumor cell targeting imaging and doxorubicin could be targeted to triple negative breast cancer when it was loaded onto Zr-P1@PEG-RGD, which corroborated with the in vivo results. In summary, 89Zr-P1@PEG-RGD can serve as a biocompatible nanoplatform for fluorescence and PET image-guided cargo delivery. STATEMENT OF SIGNIFICANCE: Nanoscale coordination polymer (NCP) is a class of hybrid materials formed by self-assembly of metal ions and organic ligands through coordination. The diversity of available metals and ligand structures upon NCP synthesis plays an advantage in establishing multimodal imaging platforms. Here we designed 89Zr-P1@PEG-RGD NCP based on Zr4+ selected as metal ion nodes and tetrakis(4-carboxyphenyl) ethylene as bridging ligands. 89Zr-P1@PEG-RGD nanomaterials have positron emission tomography (PET) capability due to the incorporation of zirconium-89, which can be used for in vivo tumor imaging with high sensitivity. The chemotherapeutic drug DOX was loaded on Zr-P1 NCP for the treatment of triple-negative breast cancer, and dual modality imaging can provide visual guidance for drug delivery.

Asunto(s)

Doxorrubicina , Tomografía de Emisión de Positrones , Radioisótopos , Neoplasias de la Mama Triple Negativas , Circonio , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Circonio/química , Animales , Tomografía de Emisión de Positrones/métodos , Humanos , Línea Celular Tumoral , Femenino , Doxorrubicina/farmacología , Doxorrubicina/química , Polímeros/química , Ratones , Sistemas de Liberación de Medicamentos , Polietilenglicoles/química , Ratones Desnudos

RESUMEN

Nowadays, polyurethanes (PUs) stand out as a promising option for drug delivery owing to their versatile properties. PUs have garnered significant attention in the biomedical sector and are extensively employed in diverse forms, including bulk devices, coatings, particles, and micelles. PUs are crucial in delivering various therapeutic agents such as antibiotics, anti-cancer medications, dermal treatments, and intravaginal rings. Effective drug release management is essential to ensure the intended therapeutic impact of PUs. Commercially available PU-based drug delivery products exemplify the adaptability of PUs in drug delivery, enabling researchers to tailor the polymer properties for specific drug release patterns. This review primarily focuses on the preparation of PU nanoparticles and their physiochemical properties for drug delivery applications, emphasizing how the formation of PUs affects the efficiency of drug delivery systems. Additionally, cutting-edge applications in drug delivery using PU nanoparticle systems, micelles, targeted, activatable, and fluorescence imaging-guided drug delivery applications are explored. Finally, the role of artificial intelligence and machine learning in drug design and delivery is discussed. The review concludes by addressing the challenges and providing perspectives on the future of PUs in drug delivery, aiming to inspire the design of more innovative solutions in this field.

RESUMEN

Fluorescence imaging in the second near-infrared window (NIR-II) has become a prevalent choice owing to its appealing advantages like deep penetration depth, low autofluorescence, decent spatiotemporal resolution, and a high signal-to-background ratio. This would expedite the innovation of NIR-II imaging-guided drug delivery (IGDD) paradigms for the improvement of the prognosis of patients with tumors. This work systematically reviews the recent progress of such NIR-II IGDD-mediated cancer therapeutics and collectively brings its essence to the readers. Special care has been taken to assess their performances based on their design approach, such as enhancing their drug loading and triggering release, designing intrinsic and extrinsic fluorophores, and/ or overcoming biological barriers. Besides, the state-of-the-art NIR-II IGDD platforms for different therapies like chemo-, photodynamic, photothermal, chemodynamic, immuno-, ion channel, gas-therapies, and multiple functions such as stimulus-responsive imaging and therapy, and monitoring of drug release and therapeutic response, have been updated. In addition, for boosting theranostic outcomes and clinical translation, the innovation directions of NIR-II IGDD platforms are summarized, including renal-clearable, biodegradable, sub-cellular targeting, and/or afterglow, chemiluminescence, X-ray excitable NIR-IGDD, and even cell therapy. This review will propel new directions for safe and efficient NIR-II fluorescence-mediated anticancer drug delivery.

Asunto(s)

Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Medicina de Precisión , Nanomedicina Teranóstica/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos/uso terapéutico , Imagen Óptica/métodos , Nanopartículas/uso terapéutico

RESUMEN

BACKGROUND: Tumor-derived exosomes (TEX) have shown great potential for drug delivery and tumor targeting. Here, we developed a novel multi-drug loaded exosomes nanoprobe for combined antitumor chemotherapy and photodynamic therapy, and monitoring the drug delivery capabilities with pre-targeting technique. METHODS: TEX of human colorectal cancer HCT116 was prepared, and Doxorubicin and the photodynamic therapy agent 5-aminolevulinic acid (ALA) were loaded and named as TEX@DOX@ALA. Tumor uptake was first examined using fluorescence imaging of the fluorescent dye Cy5 (TEX@DOX@ALA@Cy5). Visualization of exosome aggregation in tumor were realized by positron-emission tomography/computed tomography (PET/CT) with pre-targeting technique. Tumor-bearing mice were first injected with TEX@DOX@ALA labeled with azide (N3) (TEX@DOX@ALA@N3), and then 68Ga-(2,2'-((6-amino-1-(4,7-bis (carboxymethyl)-1,4,7-triazonan-1-yl) hexan-2-yl) azanediyl) diacetic acid-dibenzocyclooctyne (68Ga-L-NETA-DBCO) was injected after 24 h for PET/CT imaging via in vivo click chemistry. For the antitumor therapy with photodynamic and/or chemotherapy, seven groups of tumor-bearing mice with different therapy were monitored, and the tumor size, animal weight and the survival time were recorded. Furthermore, the samples of blood and interested tissues (heart, lung, liver, kidney, and spleen) were harvested for hematological analysis and H&E staining. RESULTS: The drug loading process did not influence the structure or the function of the HCT116 TEX membranes. In a fluorescence imaging experiment, higher fluorescence could be seen in tumor after TEX@DOX@ALA@Cy5 injected, and reached the highest signal at 24 h. From PET/CT images with subcutaneous and orthotopic colon tumor-bearing mice, clear radioactivity could be seen in tumors, which suggested the successes of TEX accumulation in tumors. TEX@DOX@ALA group with photodynamic therapy and chemotherapy had the best tumor inhibition effect compared with the other groups, with the longest survival time (36 days, 37.5%). No significant damage was found on histological observation and the blood biochemical analysis, which suggested the safety of the multi-drug loaded exosomes. CONCLUSIONS: We successfully engineered an exosome-based nanoprobe integrating PET imaging components and therapeutic drugs. This drug-loaded exosome system may effectively target tumors and enable synergistic chemotherapeutic and photodynamic antitumor effects.

Asunto(s)

Exosomas , Neoplasias , Animales , Línea Celular Tumoral , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Radioisótopos de Galio , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Tomografía Computarizada por Tomografía de Emisión de Positrones

RESUMEN

The use of multifunctional nanomedicines for image-guided drug delivery is currently being universally evaluated as a means of efficiently managing cancers and other diseases. In this study we evaluated the potential of an indocyanine green (ICG) and paclitaxel (PTX) loaded human serum albumin (HSA) nanoparticles that was conjugated with hyaluronic acid for use in image-guided drug delivery targeted to CD44-positive non-small cell lung cancer (NSCLC). Series of NSCLC cell lines were evaluated for the expression of CD44 using both western blot analysis and qRT-PCR and compared to a normal lung fibroblast cell line (MRC-5). Using Fluorescence microscopy and photoacoustic imaging (PA), we explored the ability of these targeted nanoparticles to selectively accumulate in NSCLC cell lines in comparison to MRC-5 and their potential for biomedical imaging towards their use for theranostic application. Results obtained suggest that these targeted nanoparticles have potential for application in both imaging and treatment of NSCLC.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Nanopartículas , Preparaciones Farmacéuticas , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Humanos , Receptores de Hialuranos , Verde de Indocianina , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/farmacología , Albúmina Sérica Humana

RESUMEN

Graphitic carbon nitride quantum dots (g-CNQDs) have shown great potential in imaging, drug delivery and photodynamic therapy (PDT). However, relevant research on g-CNQDs for PDT or drug delivery has been conducted separately. Herein, we develop a g-CNQDs-based nanoplatform (g-CPFD) to achieve simultaneously imaging and chemo-photodynamic combination therapy in one system. A g-CNQDs-based nanocarrier (g-CPF) is first prepared by successively introducing carboxyamino-terminated oligomeric polyethylene glycol and folic acid onto the surface of g-CNQDs via two-step amidation. The resultant g-CPF possesses good physiological stability, strong blue fluorescence, desirable biocompatibility, and visible light-stimulated reactive oxygen species generating ability. Further non-covalently loaded doxorubicin enables the system with chemotherapy function. Compared with free doxorubicin, g-CPFD expresses more efficient chemotherapy to HeLa cells due to improved folate receptor-mediated cellular uptake and intracellular pH-triggered drug release. Furthermore, g-CPFD under visible light irradiation shows enhanced inhibition on the growth of cancer cells compared to sole chemotherapy or PDT. Thus, g-CPFD exhibits exceptional anti-tumor efficiency due to folate receptor-mediated targeting ability, intracellular pH-triggered drug release and a combined treatment effect arising from PDT and chemotherapy. Moreover, this nanoplatform benefits imaging-guided drug delivery because of inherent fluorescent properties of doxorubicin and g-CPF, hence achieving the goal of imaging-guided chemo-photodynamic combination treatments.

Asunto(s)

Grafito , Nanopartículas , Fotoquimioterapia , Puntos Cuánticos , Doxorrubicina/farmacología , Células HeLa , Humanos , Compuestos de Nitrógeno

RESUMEN

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, and imposes significant morbidity and mortality in this population. The aggressive chemoradiotherapy required to treat high-risk NB results in survival of less than 50%, yet is associated with significant long-term adverse effects in survivors. Boosting efficacy and reducing morbidity are therefore key goals of treatment for affected children. We hypothesize that these may be achieved by developing strategies that both focus and limit toxic therapies to the region of the tumor. One such strategy is the use of targeted image-guided drug delivery (IGDD), which is growing in popularity in personalized therapy to simultaneously improve on-target drug deposition and assess drug pharmacodynamics in individual patients. IGDD strategies can utilize a variety of imaging modalities and methods of actively targeting pharmaceutical drugs, however in vivo imaging in combination with focused ultrasound is one of the most promising approaches already being deployed for clinical applications. Over the last two decades, IGDD using focused ultrasound with "microbubble" ultrasound contrast agents (UCAs) has been increasingly explored as a method of targeting a wide variety of diseases, including cancer. This technique, known as sonopermeation, mechanically augments vascular permeability, enabling increased penetration of drugs into target tissue. However, to date, methods of monitoring the vascular bioeffects of sonopermeation in vivo are lacking. UCAs are excellent vascular probes in contrast-enhanced ultrasound (CEUS) imaging, and are thus uniquely suited for monitoring the effects of sonopermeation in tumors. Methods: To monitor the therapeutic efficacy of sonopermeation in vivo, we developed a novel system using 2D and 3D quantitative contrast-enhanced ultrasound imaging (qCEUS). 3D tumor volume and contrast enhancement was used to evaluate changes in blood volume during sonopermeation. 2D qCEUS-derived time-intensity curves (TICs) were used to assess reperfusion rates following sonopermeation therapy. Intratumoral doxorubicin (and liposome) uptake in NB was evalauted ex vivo along with associated vascular changes. Results: In this study, we demonstrate that combining focused ultrasound therapy with UCAs can significantly enhance chemotherapeutic payload to NB in an orthotopic xenograft model, by improving delivery and tumoral uptake of long-circulating liposomal doxorubicin (L-DOX) nanoparticles. qCEUS imaging suggests that changes in flow rates are highly sensitive to sonopermeation and could be used to monitor the efficacy of treatment in vivo. Additionally, initial tumor perfusion may be a good predictor of drug uptake during sonopermeation. Following sonopermeation treatment, vascular biomarkers show increased permeability due to reduced pericyte coverage and rapid onset of doxorubicin-induced apoptosis of NB cells but without damage to blood vessels. Conclusion: Our results suggest that significant L-DOX uptake can occur by increasing tumor vascular permeability with microbubble sonopermeation without otherwise damaging the vasculature, as confirmed by in vivo qCEUS imaging and ex vivo analysis. The use of qCEUS imaging to monitor sonopermeation efficiency and predict drug uptake could potentially provide real-time feedback to clinicians for determining treatment efficacy in tumors, leading to better and more efficient personalized therapies. Finally, we demonstrate how the IGDD strategy outlined in this study could be implemented in human patients using a single case study.

Asunto(s)

Doxorrubicina/análogos & derivados , Microburbujas , Neuroblastoma/tratamiento farmacológico , Imagen de Perfusión/métodos , Ultrasonografía Intervencional/métodos , Animales , Apoptosis/efectos de los fármacos , Determinación del Volumen Sanguíneo/instrumentación , Determinación del Volumen Sanguíneo/métodos , Permeabilidad Capilar/efectos de la radiación , Línea Celular Tumoral , Medios de Contraste/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Estudios de Factibilidad , Humanos , Ratones , Neuroblastoma/irrigación sanguínea , Neuroblastoma/diagnóstico por imagen , Técnicas Fotoacústicas/instrumentación , Técnicas Fotoacústicas/métodos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Estudios de Casos Únicos como Asunto , Ondas Ultrasónicas , Ultrasonografía Intervencional/instrumentación , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

There is an ongoing need for noninvasive tools to manipulate brain activity with molecular, spatial and temporal specificity. Here we have investigated the use of MRI-visible, albumin-based nanoclusters for noninvasive, localized and temporally specific drug delivery to the rat brain. We demonstrated that IV injected nanoclusters could be deposited into target brain regions via focused ultrasound facilitated blood brain barrier opening. We showed that nanocluster location could be confirmed in vivo with MRI. Additionally, following confirmation of nanocluster delivery, release of the nanocluster payload into brain tissue can be triggered by a second focused ultrasound treatment performed without circulating microbubbles. Release of glutamate from nanoclusters in vivo caused enhanced c-Fos expression, indicating that the loading capacity of the nanoclusters is sufficient to induce neuronal activation. This novel technique for noninvasive stereotactic drug delivery to the brain with temporal specificity could provide a new way to study brain circuits in vivo preclinically with high relevance for clinical translation.

Asunto(s)

Barrera Hematoencefálica , Preparaciones Farmacéuticas , Albúminas , Animales , Encéfalo/diagnóstico por imagen , Sistemas de Liberación de Medicamentos , Imagen por Resonancia Magnética , Microburbujas , Ratas

RESUMEN

Nanomedicine drug delivery systems are capable of transporting significant payloads to solid tumors. However, only a modest increase in antitumor efficacy relative to the standard of care has been observed. In this study, we demonstrate that a single dose of radiation or mild hyperthermia can substantially improve tumor uptake and distribution of nanotherapeutics, resulting in improved treatment efficacy. The delivery of nanomedicine was driven by a reduction in interstitial fluid pressure (IFP) and small perturbation of steady-state fluid flow. The transient effects on fluid dynamics in tumors with high IFP was also shown to dominate over immune cell endocytic capacity, another mechanism suspected of improving drug delivery. Furthermore, we demonstrate the specificity of this mechanism by showing that delivery of nanotherapeutics to low IFP tumors with high leukocyte infiltration does not benefit from pretreatment with radiation or heat. These results demonstrate that focusing on small perturbations to steady-state fluid dynamics, rather than large sustained effects or uncertain immune cell recruitment strategies, can impart a vulnerability to tumors with high IFP and enhance nanotherapeutic drug delivery and treatment efficacy.

Asunto(s)

Antibióticos Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/análogos & derivados , Sistemas de Liberación de Medicamentos , Líquido Extracelular/efectos de los fármacos , Calor , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Nanomedicina/métodos , Animales , Antibióticos Antineoplásicos/administración & dosificación , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Líquido Extracelular/metabolismo , Femenino , Humanos , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones SCID , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacología , Relación Estructura-Actividad , Tomografía Computarizada por Rayos X , Rayos X

RESUMEN

The goal of this study was to establish the feasibility of integrating focused ultrasound (FUS)-mediated delivery of 64Cu-integrated gold nanoclusters (64Cu-AuNCs) to the pons for in vivo quantification of the nanocluster brain uptake using positron emission tomography (PET) imaging. FUS was targeted at the pons for the blood-brain barrier (BBB) disruption in the presence of systemically injected microbubbles, followed by the intravenous injection of 64Cu-AuNCs. The spatiotemporal distribution of the 64Cu-AuNCs in the brain was quantified using in vivo microPET/CT imaging at different time points post injection. Following PET imaging, the accumulation of radioactivity in the pons was further confirmed using autoradiography and gamma counting, and the gold concentration was quantified using inductively coupled plasma-mass spectrometry (ICP-MS). We found that the noninvasive and localized BBB opening by the FUS successfully delivered the 64Cu-AuNCs to the pons. We also demonstrated that in vivo real-time microPET/CT imaging was a reliable method for monitoring and quantifying the brain uptake of 64Cu-AuNCs delivered by the FUS. This drug delivery platform that integrates FUS, radiolabeled nanoclusters, and PET imaging provides a new strategy for noninvasive and localized nanoparticle delivery to the pons with concurrent in vivo quantitative imaging to evaluate delivery efficiency. The long-term goal is to apply this drug delivery platform to the treatment of pontine gliomas.

Asunto(s)

Encéfalo/metabolismo , Radioisótopos de Cobre/administración & dosificación , Oro/administración & dosificación , Nanoestructuras/administración & dosificación , Ondas Ultrasónicas , Animales , Encéfalo/diagnóstico por imagen , Radioisótopos de Cobre/farmacocinética , Oro/farmacocinética , Masculino , Ratones Endogámicos C57BL , Microburbujas , Tomografía Computarizada por Tomografía de Emisión de Positrones

RESUMEN

Recent progress in the development of silica- and silicon-based multimodality imaging nanoprobes has advanced their use in image-guided drug delivery, and the development of novel systems for nanotheranostic and diagnostic applications. As biocompatible and flexibly tunable materials, silica and silicon provide excellent platforms with high clinical potential in nanotheranostic and diagnostic probes with well-defined morphology and surface chemistry, yielding multifunctional properties. In vivo imaging is of great value in the exploration of methods for improving site-specific nanotherapeutic delivery by silica- and silicon-based drug-delivery systems. Multimodality approaches are essential for understanding the biological interactions of nanotherapeutics in the physiological environment in vivo. The aim here is to describe recent advances in the development of in vivo imaging tools based on nanostructured silica and silicon, and their applications in single and multimodality imaging.

Asunto(s)

Imagen Multimodal , Materiales Biocompatibles , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Nanopartículas , Porosidad , Silicio , Dióxido de Silicio

RESUMEN

Image-guided and target-selective modulation of drug delivery by external physical triggers at the site of pathology has the potential to enable tailored control of drug targeting. Magnetic microbubbles that are responsive to magnetic and acoustic modulation and visible to ultrasonography have been proposed as a means to realize this drug targeting strategy. To comply with this strategy in vivo, magnetic microbubbles must circulate systemically and evade deposition in pulmonary capillaries, while also preserving magnetic and acoustic activities in circulation over time. Unfortunately, challenges in fabricating magnetic microbubbles with such characteristics have limited progress in this field. In this report, we develop magnetic microbubbles (MagMB) that display strong magnetic and acoustic activities, while also preserving the ability to circulate systemically and evade pulmonary entrapment. METHODS: We systematically evaluated the characteristics of MagMB including their pharmacokinetics, biodistribution, visibility to ultrasonography and amenability to magneto-acoustic modulation in tumor-bearing mice. We further assessed the applicability of MagMB for ultrasonography-guided control of drug targeting. RESULTS: Following intravenous injection, MagMB exhibited a 17- to 90-fold lower pulmonary entrapment compared to previously reported magnetic microbubbles and mimicked circulation persistence of the clinically utilized Definity microbubbles (>10 min). In addition, MagMB could be accumulated in tumor vasculature by magnetic targeting, monitored by ultrasonography and collapsed by focused ultrasound on demand to activate drug deposition at the target. Furthermore, drug delivery to target tumors could be enhanced by adjusting the magneto-acoustic modulation based on ultrasonographic monitoring of MagMB in real-time. CONCLUSIONS: Circulating MagMB in conjunction with ultrasonography-guided magneto-acoustic modulation may provide a strategy for tailored minimally-invasive control over drug delivery to target tissues.

Asunto(s)

Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Animales , Línea Celular Tumoral , Medios de Contraste/farmacocinética , Fluorocarburos/administración & dosificación , Fluorocarburos/farmacocinética , Magnetismo/métodos , Ratones , Microburbujas , Distribución Tisular , Ultrasonografía/métodos

RESUMEN

Clinical imaging modalities have reached a prominent role in medical diagnosis and patient management in the last decades. Different image methodologies as Positron Emission Tomography, Single Photon Emission Tomography, X-Rays, or Magnetic Resonance Imaging are in continuous evolution to satisfy the increasing demands of current medical diagnosis. Progress in these methodologies has been favored by the parallel development of increasingly more powerful contrast agents. These are molecules that enhance the intrinsic contrast of the images in the tissues where they accumulate, revealing noninvasively the presence of characteristic molecular targets or differential physiopathological microenvironments. The contrast agent field is currently moving to improve the performance of these molecules by incorporating the advantages that modern nanotechnology offers. These include, mainly, the possibilities to combine imaging and therapeutic capabilities over the same theranostic platform or improve the targeting efficiency in vivo by molecular engineering of the nanostructures. In this review, we provide an introduction to multimodal imaging methods in biomedicine, the sub-nanometric imaging agents previously used and the development of advanced multimodal and theranostic imaging agents based in nanotechnology. We conclude providing some illustrative examples from our own laboratories, including recent progress in theranostic formulations of magnetoliposomes containing ω-3 poly-unsaturated fatty acids to treat inflammatory diseases, or the use of stealth liposomes engineered with a pH-sensitive nanovalve to release their cargo specifically in the acidic extracellular pH microenvironment of tumors.

Asunto(s)

Medios de Contraste/administración & dosificación , Liposomas/administración & dosificación , Imagen Multimodal/métodos , Nanopartículas/administración & dosificación , Nanotecnología/métodos , Animales , Medios de Contraste/química , Humanos , Liposomas/química , Nanopartículas/química

RESUMEN

Doxorubicin (Dox)-loaded stealth liposomes (similar to those in clinical use) can incorporate small amounts of porphyrin-phospholipid (PoP) to enable chemophototherapy (CPT). PoP is also an intrinsic and intrabilayer 64Cu chelator, although how radiolabeling impacts drug delivery has not yet been assessed. Here, we show that 64Cu can radiolabel the stable bilayer of preformed Dox-loaded PoP liposomes with inclusion of 1% ethanol without inducing drug leakage. Dox-PoP liposomes labeled with intrabilayer copper behaved nearly identically to unlabeled ones in vitro and in vivo with respect to physical parameters, pharmacokinetics, and CPT efficacy. Positron emission tomography and near-infrared fluorescence imaging visualized orthotopic mammary tumors in mice with passive liposome accumulation following administration. A single CPT treatment with 665 nm light (200 J/cm2) strongly inhibited primary tumor growth. Liposomes accumulated in lung metastases, based on NIR imaging. These results establish the feasibility of CPT interventions guided by intrinsic multimodal imaging of Dox-loaded stealth PoP liposomes.

Asunto(s)

Antibióticos Antineoplásicos/administración & dosificación , Radioisótopos de Cobre , Doxorrubicina/administración & dosificación , Liposomas/análisis , Liposomas/química , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Animales , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Microscopía Fluorescente , Imagen Óptica , Procesos Fotoquímicos , Fototerapia , Tomografía de Emisión de Positrones

RESUMEN

High Intensity Focused Ultrasound (HIFU) is an emerging noninvasive, nonionizing physical energy based modality to ablate solid tumors with high power, or increase local permeability in tissues/tumors in pulsed mode with relatively low power. Compared with traditional ablative HIFU, nondestructive pulsed HIFU (pHIFU) is present in the majority of novel applications recently developed for enhancing the delivery of drugs and genes. Previous studies have demonstrated the capability of pHIFU to change tissue local permeability for enhanced drug delivery in both mouse tumors and mouse muscle. Further study based on bulk tissues in large animals and clinical HIFU system revealed correlation between therapeutic effect and thermal parameters, which was absent in the previous mouse studies. In this study, we further investigated the relation between the therapeutic effect of pHIFU and thermal parameters in bulky normal muscle tissues based on a rabbit model and a preclinical HIFU system. Correlation between therapeutic effect and thermal parameters was confirmed in our study on the same bulk tissues although different HIFU systems were used. Following the study in bulky normal muscle tissues, we further created bulky tumor model with VX2 tumors implanted on both hind limbs of rabbits and investigated the feasibility to enhance tumor permeability in bulky VX2 tumors in a rabbit model using pHIFU technique. A radiolabeled peptidomimetic integrin antagonist, 111In-DOTA-IA, was used following pHIFU treatment in our study to target VX2 tumor and serve as the radiotracer for follow-up single-photon emission computed tomography (SPECT) scanning. The results have shown significantly elevated uptake of 111In-DOTA-IA in the area of VX2 tumors pretreated by pHIFU compared with the control VX2 tumors not being pretreated by pHIFU, and statistical analysis revealed averaged 34.5% enhancement 24h after systematic delivery of 111In-DOTA-IA in VX2 tumors pretreated by pHIFU compared with the control VX2 tumors.

Asunto(s)

Complejos de Coordinación/administración & dosificación , Sistemas de Liberación de Medicamentos , Compuestos Heterocíclicos con 1 Anillo/administración & dosificación , Ultrasonido Enfocado de Alta Intensidad de Ablación , Radioisótopos de Indio/administración & dosificación , Neoplasias de los Músculos , Animales , Nalgas/diagnóstico por imagen , Complejos de Coordinación/farmacocinética , Complejos de Coordinación/uso terapéutico , Femenino , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Radioisótopos de Indio/farmacocinética , Radioisótopos de Indio/uso terapéutico , Imagen por Resonancia Magnética , Neoplasias de los Músculos/diagnóstico por imagen , Neoplasias de los Músculos/metabolismo , Neoplasias de los Músculos/terapia , Permeabilidad , Conejos , Tomografía Computarizada de Emisión de Fotón Único

RESUMEN

Nanoscale metal-organic frameworks (nMOF) materials represent an attractive tool for various biomedical applications. Due to the chemical versatility, enormous porosity, and tunable degradability of nMOFs, they have been adopted as carriers for delivery of imaging and/or therapeutic cargos. However, the relatively low stability of most nMOFs has limited practical in vivo applications. Here we report the production and characterization of an intrinsically radioactive UiO-66 nMOF (89Zr-UiO-66) with incorporation of positron-emitting isotope zirconium-89 (89Zr). 89Zr-UiO-66 was further functionalized with pyrene-derived polyethylene glycol (Py-PGA-PEG) and conjugated with a peptide ligand (F3) to nucleolin for targeting of triple-negative breast tumors. Doxorubicin (DOX) was loaded onto UiO-66 with a relatively high loading capacity (1 mg DOX/mg UiO-66) and served as both a therapeutic cargo and a fluorescence visualizer in this study. Functionalized 89Zr-UiO-66 demonstrated strong radiochemical and material stability in different biological media. Based on the findings from cellular targeting and in vivo positron emission tomography (PET) imaging, we can conclude that 89Zr-UiO-66/Py-PGA-PEG-F3 can serve as an image-guidable, tumor-selective cargo delivery nanoplatform. In addition, toxicity evaluation confirmed that properly PEGylated UiO-66 did not impose acute or chronic toxicity to the test subjects. With selective targeting of nucleolin on both tumor vasculature and tumor cells, this intrinsically radioactive nMOF can find broad application in cancer theranostics.

Asunto(s)

Portadores de Fármacos/química , Estructuras Metalorgánicas/química , Nanopartículas/química , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Radiofármacos/química , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Línea Celular , Línea Celular Tumoral , Medios de Contraste/química , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Liberación de Fármacos , Femenino , Humanos , Estructuras Metalorgánicas/toxicidad , Ratones Endogámicos BALB C , Terapia Molecular Dirigida , Péptidos/química , Polietilenglicoles/química , Tomografía de Emisión de Positrones , Radioisótopos/química , Distribución Tisular , Circonio/química

RESUMEN

The development of new image-guided drug delivery tools to improve the therapeutic efficacy of chemotherapeutics remains an important goal in nanomedicine. Using labeling strategies that involve radioelements that have theranostic pairs of diagnostic positron-emitting isotopes and therapeutic electron-emitting isotopes has promise in achieving this goal and further enhancing drug performance through radiotherapeutic effects. The isotopes of radioarsenic offer such theranostic potential and would allow for the use of positron emission tomography (PET) for image-guided drug delivery studies of the arsenic-based chemotherapeutic arsenic trioxide (ATO). Thiolated mesoporous silica nanoparticles (MSN) are shown to effectively and stably bind cyclotron-produced radioarsenic. Labeling studies elucidate that this affinity is a result of specific binding between trivalent arsenic and nanoparticle thiol surface modification. Serial PET imaging of the in vivo murine biodistribution of radiolabeled silica nanoparticles shows very good stability toward dearsenylation that is directly proportional to silica porosity. Thiolated MSNs are found to have a macroscopic arsenic loading capacity of 20 mg of ATO per gram of MSN, sufficient for delivery of chemotherapeutic quantities of the drug. These results show the great potential of radioarsenic-labeled thiolated MSN for the preparation of theranostic radiopharmaceuticals and image-guided drug delivery of ATO-based chemotherapeutics.

Asunto(s)

Nanopartículas , Animales , Sistemas de Liberación de Medicamentos , Ratones , Porosidad , Dióxido de Silicio , Nanomedicina Teranóstica , Distribución Tisular

RESUMEN

Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ∼120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. (64)Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of (64)Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates ((64)Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers with satisfactory drug loading capacity (e.g. for doxorubicin [DOX], 756 mg/g). Enhanced drug delivery efficiency in cbgLuc-MDA-MB-231 metastatic sites was demonstrated in DOX-loaded GO-FSHR-mAb by fluorescence imaging. This FSHR-targeted, GO-based nanoplatform can serve as a useful tool for early metastasis detection and targeted delivery of therapeutics.

Asunto(s)

Neoplasias de la Mama/patología , Doxorrubicina/administración & dosificación , Grafito/química , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Nanocápsulas/química , Neovascularización Patológica/terapia , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Anticuerpos Monoclonales/administración & dosificación , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Femenino , Humanos , Neoplasias Pulmonares/irrigación sanguínea , Ratones , Ratones Desnudos , Terapia Molecular Dirigida/métodos , Nanocápsulas/administración & dosificación , Nanoconjugados/química , Neovascularización Patológica/patología , Óxidos/química , Resultado del Tratamiento

RESUMEN

New methods for creating theranostic systems with simultaneous encapsulation of therapeutic, diagnostic, and targeting agents are much sought after. This work reports for the first time the use of coaxial electrospinning to prepare such systems in the form of core-shell fibers. Eudragit S100 was used to form the shell of the fibers, while the core comprised poly(ethylene oxide) loaded with the magnetic resonance contrast agent Gd(DTPA) (Gd(III) diethylenetriaminepentaacetate hydrate) and indomethacin as a model therapeutic agent. The fibers had linear cylindrical morphologies with clear core-shell structures, as demonstrated by electron microscopy. X-ray diffraction and differential scanning calorimetry proved that both indomethacin and Gd(DTPA) were present in the fibers in the amorphous physical form. This is thought to be a result of intermolecular interactions between the different components, the presence of which was suggested by infrared spectroscopy. In vitro dissolution tests indicated that the fibers could provide targeted release of the active ingredients through a combined mechanism of erosion and diffusion. The proton relaxivities for Gd(DTPA) released from the fibers into tris buffer increased (r1 = 4.79-9.75 s(-1) mM(-1); r2 = 7.98-14.22 s(-1) mM(-1)) compared with fresh Gd(DTPA) (r1 = 4.13 s(-1) mM(-1) and r2 = 4.40 s(-1) mM(-1)), which proved that electrospinning has not diminished the contrast properties of the complex. The new systems reported herein thus offer a new platform for delivering therapeutic and imaging agents simultaneously to the colon.

Asunto(s)

Medios de Contraste/química , Diagnóstico por Imagen/métodos , Sistemas de Liberación de Medicamentos/métodos , Nanomedicina Teranóstica/métodos , Rastreo Diferencial de Calorimetría , Medios de Contraste/síntesis química , Portadores de Fármacos/química , Gadolinio DTPA/química , Lantano/química , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos X