Monitoring Of Drug Release Research Articles

Redox/ATP switchable theranostic nanoparticles for real-time fluorescence monitoring of doxorubicin delivery.

In this study, redox/ATP switchable theranostic nanoparticles (TNs) with precise specificity and controllable mobility were developed for the real-time monitoring of the release of an anticancer drug. A fluorescent probe (FAM) and a quencher (BHQ-1) were covalently conjugated to one end of an adenosine-5'-triphosphate (ATP) aptamer and its complementary DNA (cDNA), respectively. Then, doxorubicin (DOX) was intercalated within the DNA duplex to form a stable physical conjugate (FBA@DOX). Poly(ethylene glycol)-block-poly (aspartic acid-graft-cystamine) (PAS), a glutathione-sensitive cationic polymer, was synthesized and complexed with the FBA@DOX, endowing it with excellent stability in physiological solutions. Fluorescence recovery/quenching, DNase degradation, in vitro drug release, cellular uptake, and intracellular trafficking results revealed that the TNs remained in the "OFF" state, with a minimal FAM fluorescent signal and negligible DOX premature release, in low-glutathione and/or low-ATP environments. In contrast, the TNs turned "ON" and rapidly released FBA@DOX in glutathione-rich environments after internalization in cancer cells. The intracellular ATP triggered the conformational changes in FBA@DOX, thereby enabling the controlled release of DOX and simultaneous recovery of the fluorescence for monitoring the DOX release. In a cytotoxicity and apoptosis study, the redox/ATP switchable TNs demonstrated strong anticancer effects, attributable to their selective release of the drug. Overall, our findings may offer a promising strategy for developing a new generation of "smart" theranostic platforms.

Co-assembling FRET nanomedicine with self-indicating drug release

Two lipophilic fluorescent prodrugs co-assembled into nanoaggregates with the ability to release FRET-indicated drugs, which was used to investigate the role of reduction-responsive linkers on drug release kinetics in the cytoplasm and physiologically relevant media in a visualized, noninvasive manner.

A digital data acquisition scheme for SPECT and PET small animal imaging detectors for Theranostic applications

Nanoparticle based drug delivery is considered as a new, promising technology for the efficient treatment of various diseases. When nanoparticles are radiolabelled it is possible to image them, using molecular imaging techniques. The use of magnetic nanoparticles in hyperthermia is one of the most promising nanomedicine directions and requires the accurate, non-invasive, monitoring of temperature increase and drug release. The combination of imaging and therapy has opened the very promising Theranostics domain. In this work, we present a digital data acquisition scheme for nuclear medicine dedicated detectors for Theranostic applications.

Anticancer drug delivery systems based on inorganic nanocarriers with fluorescent tracers

In recent years, anticancer nanomedicines have mainly been developed for chemotherapy and combination therapy in which the main contributing anticancer drugs are delivered by deliberately designed nano drug delivery systems (nano‐DDSs). Inorganic nanocarriers equipped with fluorescent tracers have become attractive tools to monitor the whole drug delivery and release processes. The fluorescence signal of tracers could be observed concomitantly with drug release, and thus, this strategy is of great benefit to evaluate the therapeutic effects of the nano‐DDSs. This review provides a brief overview about three inorganic nanocarriers for drug delivery, including mesoporous silica, Fe3O4, and hydroxyapatite. We mainly discussed about their preparation processes, drug loading capacities, and the development of different fluorescent materials (fluorescent dyes, quantum dots, fluorescent macromolecules, and rare earth metals) hybridized to nanocarriers for real‐time monitoring of drug release both in vitro and in vivo. This review also provides some recommendations for more in‐depth research in future. © 2017 American Institute of Chemical Engineers AIChE J, 64: 835–859, 2018

Smart yolk-shell type luminescent nanocomposites based on rare-earth complex for NIR–NIR monitor of drug release in chemotherapy

Intelligent drug delivery system (IDDS), which can encapsulate and transport the drug to the nidus while monitor the pharmacokinetics behavior, greatly promote the development of tumor therapy. Herein, a smart yolk-shell type nanocomposites based on the covalent encapsulation of a Yb(III) complex in magnetism mesoporous silica nanoparticles (NPs) has been designed and assembled for IDDS. The emission peak of the Yb(III) complex in the IDDS is 980nm when excited by 850nm laser, which is essential for near-infrared excitation and near-infrared emission (NIR-NIR) and real-time drug release monitoring. The magnetism core of the IDDS is crucial for magnetic targeting therapy, while the cavity and mesoporous channel of the shell is prerequisite for high drug loading (15.9%) and encapsulation efficiency (88.5%). Additionally, when pH=5.05, 81.4% of encapsulated DOX will be released because the structure of the coated carboxymethyl chitosan changed. Simultaneously, photoluminescence intensity of the Yb(III) complex become stronger on account of the coordinated DOX leave away and the coordination sphere of the central Yb3+ ions changed. The IDDS can not only deliver the drug and monitor the process of drug release at the right spatial and temporal resolution, but also explore a path for clinical targeted therapy of tumor.

Ipratropium is ‘luminally recycled’ by an inter-play between apical uptake and efflux transporters in Calu-3 bronchial epithelial cell layers

The mechanism by which quaternized anticholinergic bronchodilators permeate the airway epithelium remains controversial to date. In order to elucidate the role of drug transporters, ipratropium bidirectional transport as well as accumulation and release studies were performed in layers of the broncho-epithelial cell line Calu-3 grown at an air-liquid interface, in presence or absence of a range of transporter inhibitors. Unexpectedly, a higher transepithelial permeability was observed in the secretory direction, with an apparent efflux ratio of > 4. Concentration-dependent and inhibitor studies demonstrated the drug intracellular uptake was carrier-mediated. Interestingly, monitoring drug release post cell loading revealed the presence of an efficient efflux system on the apical side of the cell layers. Acting in concert, apical transporters seem to promote the ‘luminal recycling’ of the drug and hence, limit its transcellular transport. The data are in agreement with an apical Organic Cation Transporter (OCT) being involved in this process but also suggest the participation of unknown uptake and efflux transporters sensitive to probenecid. This study suggests the absorption of ipratropium across the pulmonary barrier is primarily governed by paracellular passive diffusion but transporters might play a significant role in controlling the drug local concentrations in the lungs.

The integration of triggered drug delivery with real time quantification using FRET; creating a super ‘smart’ drug delivery system

The ability to control drug release at a specific physiological target enables the possibility of an enhanced therapeutic effect with reduced off-target toxic side effects. The discipline of controlled drug release has grown to include most areas of medicine with examples in the literature of targeted drug delivery to the majority of organs within the human body. In addition, a variety of external stimuli used to meditate the drug release process have also been investigated. Nonetheless, the concurrent real time monitoring of drug release has not been widely studied. In this manuscript, we present a novel micellar drug delivery system that is not only capable of releasing its cargo when stimulated by light but also provides a real time analysis of the amount of cargo remaining. Controlled drug release from the delivery system was mediated by physicochemical changes of a spiropyran-merocyanine photochromic dyad, while drug quantification was enabled using a Förster Resonance Energy Transfer (FRET) relationship between the photochrome and a co-encapsulated BODIPY fluorophore. The percentage of drug released from the delivery system was significantly greater (24%) when exposed to light irradiation compared to an analogous control maintained in the dark (5%). Furthermore, the fluorescence read-out capability also enabled the drug-release process to be followed in living cells with a significantly reduced fluorescence emission observed for those cells incubated with the delivery system and exposed to light irradiation compared to control cells maintained in the dark. Combined, these results highlight the utility of this approach to theranostic drug delivery with the potential of light-triggered released together with a fluorescence read-out to enable quantification of the drug release process.

PH-Responsive Nanoscale Coordination Polymer for Efficient Drug Delivery and Real-Time Release Monitoring.

Both excess dosages of drug and unwanted drug carrier can lead to severe side effects as well as the failure of tumor therapy. Here, an Fe3+ -gallic acid based drug delivery system is designed for efficient monitoring of drug release in tumor. Fe3+ and polyphenol gallic acid can form polygonal nanoscale coordination polymer in aqueous solution, which exhibits certain antitumor effect. Importantly, this coordination polymer possesses extremely high doxorubicin (DOX) loading efficacy (up to 48.3%). In vitro studies demonstrate that the fluorescence of DOX can be quenched efficiently when DOX is loaded on the coordination polymer. The acidity in lysosome also triggers the release of DOX and fluorescence recovery simultaneously, which realizes real-time monitoring of drug release in tumor cells. In vivo studies further indicate that this polyphenol-rich drug delivery system can significantly inhibit tumor growth with negligible heart toxicity of DOX. This system with minimal side effects should be a promising nanoplatform for tumor treatment.

Acid-degradable gadolinium-based nanoscale coordination polymer: A potential platform for targeted drug delivery and potential magnetic resonance imaging

During conventional chemotherapy for cancer, nonspecific drug distribution, which causes serious side effects in normal tissues, is a serious limitation. Thus, it is desirable to develop a tumor or intracellular microenvironment-responsive nanosystem for targeted and on-demand drug release. In the present study, we engineered an intelligent pH-activatable nanosystem, in which a gadolinium-doxorubicin-loaded nanoscale coordination polymer (Gd-Dox NCPs) was the core and hyaluronic acid was the targeting shell. Taking advantage of CD44 receptor-mediated recognition, the nanoparticles were internalized selectively into human cervical carcinoma (HeLa) cells, and trapped within acidic compartments where the fluorescence of Dox recovered, along with the acid dismantling of the Gd NCPs, allowing real-time monitoring of drug release. In vitro experiments also showed that the Gd NCPs present enhanced T1 signals after acid-triggered degradation, suggesting their potential use as contrast agents for magnetic resonance imaging. Such nanocarriers, which feature high biodegradation, selective targeting ability, and rapid response to stimulus, demonstrated enhanced therapeutic efficacy in targeted cancer cells and “turned on” T1 signals in vitro, showing great promise for diagnosis and treatment.

Theranostic Prodrug Vesicles for Imaging Guided Codelivery of Camptothecin and siRNA in Synergetic Cancer Therapy.

The construction of prodrugs has been a popular strategy to overcome the limitations of chemotherapeutic drugs. However, complicated synthesis procedures and laborious purification steps make the fabrication of amphiphilic prodrugs rather difficult. By harnessing the concept of host-guest interaction, we designed and prepared a supra-amphiphile consisting of a dendritic cyclodextrin host and an adamantane/naphthalimide-modified camptothecin guest through glutathione-responsive disulfide linkage. This host-guest complex could self-assemble in aqueous solution to give nanosized vesicles. When the disulfide bond in adamantane/naphthalimide-modified camptothecin was cleaved by glutathione, the fluorescence of the freed adamantane/naphthalimide unit showed a significant red shift with enhanced intensity. Such glutathione-responsive fluorescence change allows for intracellular imaging and simultaneous monitoring of drug release in real time. On account of abundant positively charged amine groups on the supramolecular vesicle surface, siRNA (siPlK1) could be efficiently loaded on the vesicle. The gel retardation and fluorescence experiments proved that the siPlK1 was successfully bonded to the supramolecular vesicle. The vesicle with dendritic cyclodextrin ring exhibited negligible cytotoxicity even at high concentrations, avoiding the shortcoming of cytotoxicity from commonly used gene vectors. In vitro studies demonstrated that the loaded siRNA was transported into cancer cells to improve cancer therapeutic efficacy. Thus, we developed a prodrug-based supramolecular amphiphile via the host-guest interaction with better therapeutic performance than free camptothecin. The assembled system was utilized as a drug/gene vector to achieve combinational gene therapy and chemotherapy with a synergistic effect, providing an alternative strategy to deliver both prodrug and therapeutic gene.

Fabrication of Polymeric Micelles with Aggregation-Induced Emission and Forster Resonance Energy Transfer for Anticancer Drug Delivery.

With the aim of obtaining effective cancer therapy with simultaneous cellular imaging, dynamic drug-release monitoring, and chemotherapeutic treatment, a polymeric micelle with aggregation-induced emission (AIE) imaging and a Forster resonance energy transfer (FRET) effect was fabricated as the drug carrier. An amphiphilic conjugate of 1H-pyrrole-1-propanoicacid (MAL)-poly(ethylene glycol) (PEG)-Tripp-bearing AIE molecules were synthesized and self-assembled into micelles to load the anticancer drug doxorubicin (DOX). Spherical DOX-loaded micelles with the mean size of 106 nm were obtained with good physiological stability (CMC, 12.5 μg/mL), high drug-loading capacity (10.4%), and encapsulation efficiency (86%). The cellular uptake behavior of DOX-loaded MAL-PEG-Tripp micelles was visible for high-quality intracellular imaging due to the AIE property. The delivery of DOX from the drug-loaded micelles was dynamic monitored by the FRET effect between the DOX and MAL-PEG-Tripp. Both in vitro (IC50, 2.36 μg/mL) and in vivo anticancer activity tests revealed that the DOX-loaded MAL-PEG-Tripp micelles exhibited promising therapeutic efficacy to cancer with low systematic toxicity. In summary, this micelle provided an effective way to fabricate novel nanoplatform for intracellular imaging, drug-delivery tracing, and chemotherapy.

Lanthanide Complexes in Molecular Magnetic Resonance Imaging and Theranostics.

Lanthanide complexes have attracted much attention in the biomedical field, and today various imaging applications make use of their versatile magnetic and luminescence properties. In this minireview, we give insight into the mechanistic aspects that allow modulation of the relaxation or chemical exchange saturation transfer (CEST) features, and thus the magnetic resonance imaging (MRI) efficiency of paramagnetic lanthanide chelates in order to create agents that are capable of providing an MRI response as a function of a specific biomarker. We focus on the detection of neurotransmitters, enzymatic activities, and amyloid peptides. We also describe two selected theranostic strategies: 1) a novel approach directed at monitoring drug release from liponanoparticles and 2) molecular or nanoparticle probes for the MRI visualization of photosensitizer delivery in photodynamic therapy.

Rethinking cancer nanotheranostics.

Advances in nanoparticle synthesis and engineering have produced nanoscale agents affording both therapeutic and diagnostic functions that are often referred to by the portmanteau 'nanotheranostics'. The field is associated with many applications in the clinic, especially in cancer management. These include patient stratification, drug-release monitoring, imaging-guided focal therapy and post-treatment response monitoring. Recent advances in nanotheranostics have expanded this notion and enabled the characterization of individual tumours, the prediction of nanoparticle-tumour interactions, and the creation of tailor-designed nanomedicines for individualized treatment. Some of these applications require breaking the dogma that a nanotheranostic must combine both therapeutic and diagnostic agents within a single, physical entity; instead, it can be a general approach in which diagnosis and therapy are interwoven to solve clinical issues and improve treatment outcomes. In this Review, we describe the evolution and state of the art of cancer nanotheranostics, with an emphasis on clinical impact and translation.

Intracellular enzyme-activatable prodrug for real-time monitoring of chlorambucil delivery and imaging

Carboxylesterase, a necessary enzyme in various mammalian cells, has been employed in various biological applications. Herein, we designed and synthesized a novel carboxylesterase-based prodrug, which can realize simultaneous drug-release imaging and cancer chemotherapy. This prodrug comprises three parts: coumarin as the fluorophore and the cleavable architecture, chlorambucil as the anticancer drug, and acetyl group as the enzyme-responsive unit. The presence of carboxylesterase leads to the activation of coumarin fluorescence, and this fluorescence serves as the reporting signal for assessing the enzyme level and drug release. Moreover, the prodrug was incorporated in liposome for monitoring drug release and chemotherapeutic effect in living cells. Upon internalization by HeLa cells, the prodrug can release chlorambucil and exhibit high cytotoxicity. This approach may provide some helpful insights for enhancing therapeutic effect and tracking the release of prodrug.

Controlled and sustained release of a corticosteroid drug from block copolymers synthetized by ATRP

During last decades, implantable drug delivery systems (DDS) have been developed to optimize therapeutic properties of drugs and ensure their release in a specific site. Acrylic polymers have obtained growing interest in biomedical applications for their biocompatibility and chemical properties that make them extremely versatile. In this work, we focused on the realization of polymeric systems for controlled and sustained release of betamethasone 17,21‐dipropionate (BDP), a corticosteroid drug, in the treatment of the posterior eye diseases (PED). The investigated DDS were made of opportunely designed methacrylic block copolymers. Different series of methylmethacrylate/2‐hydroxyethylmethacrylate (MMA/HEMA) block copolymers, with various monomeric compositions (20‐60 mol% HEMA), were synthetized by Atom Transfer Radical Polymerization to find the best hydrophilic/hydrophobic ratio, able to ensure optimal kinetic release. Copolymers were characterized by nuclear magnectic resonance, size exclusion chromatography, and differential scanning calorimetry. Monitoring of drug release from films loaded with BDP was carried out by HPLC analysis. In particular, PMMA‐b‐PHEMA with 47 mol% of HEMA showed the best release profile to achieve the therapeutic reference dose, used in the treatment of PED (1‐3 µg/day), up to four months. Additionally, intraocular inserts with different shapes were prepared using silicon molds made by means of a 3D printer. POLYM. ENG. SCI., 57:570–578, 2017. © 2017 Society of Plastics Engineers

In vivo gastrointestinal drug-release monitoring through second near-infrared window fluorescent bioimaging with orally delivered microcarriers

Non-invasive monitoring of gastrointestinal drug release in vivo is extremely challenging because of the limited spatial resolution and long scanning time of existing bioimaging modalities, such as X-ray radiation and magnetic resonance. Here, we report a novel microcarrier that can retain drugs and withstand the harsh conditions of gastrointestinal tract. Significantly, we can track the microcarrier fate and semi-quantitatively monitor the content of drug released in vivo in real time by measuring the fluorescence signals in the second near-infrared window of lanthanide-based downconversion nanoparticles with an absorption competition-induced emission bioimaging system. The microcarriers show a prolonged residence time of up to 72 h in the gastrointestinal tract, releasing up to 62% of their content. Moreover, minimal deposition of the microcarriers is found in non-target organs, such as the liver, spleen and kidney. These findings provide novel insights for the development of therapeutic and bioimaging strategies of orally administered drugs.

Simultaneous monitoring of the drug release and antitumor effect of a novel drug delivery system-MWCNTs/DOX/TC

Monitoring drug release and therapeutic efficacy is crucial for developing drug delivery systems. Our preliminary study demonstrated that, as compared with pristine multiwalled carbon nanotubes (MWCNTs), transactivator of transcription (TAT)-chitosan functionalized MWCNTs (MWCNTs-TC) were a more promising candidate for drug delivery in cancer therapy. In the present study, a MWCNTs/TC-based drug delivery system was developed for an anticancer drug, doxorubicin (DOX). The drug loading and in vitro release profiles, cellular uptake and cytotoxicity were assessed. More importantly, the in vivo drug release and antitumor effect of MWCNTs/DOX/TC were evaluated by noninvasive fluorescence and bioluminescence imaging. It was demonstrated that MWCNTs/DOX/TC can be efficiently taken up by BEL-7402 hepatoma cells. The release of DOX from MWCNTs/DOX/TC was faster under lower pH condition, which was beneficial for intrcellular drug release. The in vivo release process of DOX and antitumor effect in animal model were monitored simultaneously by noninvasive fluorescence and luminescence imaging, which demonstrated the application potential of MWCNTs/DOX/TC for cancer therapy.

A two-photon-activated prodrug for therapy and drug release monitoring.

A light-activated cleavage strategy for the concomitant release of active drugs and generation of fluorescence changes is highly desirable. Herein a molecular prodrug featuring real-time monitoring of drug localization and release by manipulating fluorophores has been created by constructing a cleavable structure which comprises a photoremovable coumarinyl, an anticancer drug camptothecin, a cleavable linker and a near infrared fluorescent dye dicyanomethylene-4H-pyran (DCM). The fluorescence of coumarinyl and CPT is completely quenched by the DCM moiety via fluorescence resonance energy transfer (FRET). The internalization of the prodrug by cells and its subsequent intracellular location can be tracked by collecting the red fluorescence of DCM; while the release of active CPT as a result of one- or two-photon irradiation can be monitored by observing the newly emerged fluorescence of CPT under one- or two-photon excitation. The prodrug also shows highly controllable cytotoxicity toward HeLa cells and A549 cells, with low IC50 values of 4.01 and 2.53 μM, respectively, upon light irradiation and with much higher IC50 values (>40 μM) without light irradiation. This strategy may provide an approach for the development of light-activatable theranostic anticancer therapeutics.

Encapsulation of aggregated gold nanoclusters in a metal-organic framework for real-time monitoring of drug release.

Gold nanoclusters (AuNCs), which have stable luminescence and negligible biotoxicity, are a promising candidate in biological fields. However, their low photoluminescence (PL) efficiency is unsatisfactory. Herein, aggregated gold nanoclusters (aAuNCs) were confined in a metal-organic framework (MOF) to maintain their aggregation, restrict the rotation of their ligands, and further improve their quantum yield (QY) to 7.74%. The aAuNCs-MOF exhibited high luminescence and good biocompatibility. More importantly, in addition to its pH-dependent luminescence and external porosity, the complex was applied for the first time in real-time monitoring of drug release.

Exploiting fluorescein based drug conjugates for fluorescent monitoring in drug delivery

Anticancer drugs connected to fluorescein based chemosensors by different biodegradable linkers were investigated for fluorescent monitoring in drug delivery models. The drug release triggered by chemo- and bio-hydrolytic environments was visualized on the basis of "switch on" fluorescence of the fluorophore moiety of fluorescein-drug conjugates. The conjugation of free phenolic hydroxyl of fluorescein chemosensor to the hydroxyl group of the drugs was employed by biodegradable oxy- and amino acrylate linkers. The chemosensor also possesses a free carboxylic group for potential conjugation to a specific carrier for targeted drug delivery applications. Fluorescent monitoring of drug release, quantum yield and other spectroscopic characteristics of our novel fluorescein-drug conjugates were measured and discussed. The work offers a versatile fluorophore platform for the fluorescent observation of drug delivery.