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This review provides an assessment of post-inhalation cough with therapeutic aerosols. Factors that increase cough may be mitigated through design of the drug, formulation, and device. The incidence of cough is typically less than 5% for drugs with a nominal dose less than 1 mg, including asthma and COPD therapeutics. Cough increases markedly as the dose approaches 100 mg. This is due to changes in the composition of epithelial lining fluid (e.g., increases in osmolality, proton concentration). Whether an individual exhibits cough depends on their degree of sensitization to mechanical and chemical stimuli. Hypersensitivity is increased when the drug, formulation or disease result in increases in lung inflammation. Cough related to changes in epithelial lining fluid composition can be limited by using insoluble neutral forms of drugs and excipients. Unlabelled Image [ABSTRACT FROM AUTHOR]

Delivery of drugs to the lungs via dry powder inhaler (DPI) is a promising approach for the treatment of both local pulmonary conditions and systemic diseases. Though DPIs are widely used for the pulmonary deposition of potent bronchodilators, anticholinergics, and corticosteroids, there is growing interest in the utilization of this delivery system for the administration of high drug doses to the lungs, as made evident by recent regulatory approvals for anti-microbial, anti-viral and osmotic agents. However, the formulation of high dose DPIs carries several challenges from both a physiological and physicochemical standpoint. This review describes the various formulation techniques utilized to overcome the barriers associated with the pulmonary delivery of high dose powders. [ABSTRACT FROM AUTHOR]

Mucus is a selective barrier to particles and molecules, preventing penetration to the epithelial surface of mucosal tissues. Significant advances in transmucosal drug delivery have recently been made and have emphasized that an understanding of the basic structure, viscoelastic properties, and interactions of mucus is of great value in the design of efficient drug delivery systems. Mucins, the primary non-aqueous component of mucus, are polymers carrying a complex and heterogeneous structure with domains that undergo a variety of molecular interactions, such as hydrophilic/hydrophobic, hydrogen bonds and electrostatic interactions. These properties are directly relevant to the numerous mucin-associated diseases, as well as delivering drugs across the mucus barrier. Therefore, in this review we discuss regional differences in mucus composition, mucus physicochemical properties, such as pore size, viscoelasticity, pH, and ionic strength. These factors are also discussed with respect to changes in mucus properties as a function of disease state. Collectively, the review seeks to provide a state of the art roadmap for researchers who must contend with this critical barrier to drug delivery. [ABSTRACT FROM AUTHOR]

Objective To investigate influences of capsule fill weight, batch size, and storage conditions on in vitro aerodynamic performance of jet-milled ibuprofen (IBU) carrier-free, dry powder inhaler formulations. Materials and methods Milled and unmilled IBU samples were characterized thermally and spectroscopically. Physicochemical characterization was performed by quantifying specific surface area, density, and angle of repose. Performance testing was conducted on IBU formulations in combination with a high resistance Monodose RS01 using Next Generation Impactor. Results and discussion There were no detectable differences between IBU samples thermally and spectroscopically. The milled IBU sample exhibited improved powder flow in comparison with the unmilled sample. The milled IBU powders possessed surprisingly high in vitro aerodynamic performance with a fine particle fraction percentage between 67 and 85%, and a minimum respirable fraction percentage of 49%. The capsule fill weights, from 10 to 50 mg, and milling batch sizes did not significantly influence performance. The importance of powder conditioning following milling was illustrated as the storage duration and temperature negatively affected performance. Conclusion In vitro aerodynamic performance of IBU is independent of capsule fill weight and batch size; however, some period of powder conditioning is recommended to reduce variability in formulation performance. [ABSTRACT FROM AUTHOR]

Objective To crystallize diclofenac (DF) from diclofenac sodium (DFNa), to micronize DF and DFNa, and to evaluate in vitro aerodynamic performance of the jet-milled formulations Materials and methods From the acidic titration of aqueous DFNa, DF crystals were formed and were identified using thermal analysis, spectroscopy, and X-ray powder diffraction. Following the micronization of the DF and DFNa powders, the recovered samples were imaged, and their particle size distributions were evaluated. Samples before and after jet millings were characterized, and in vitro aerodynamic performance testing was performed on the DF sample before jet milling and the DF and DFNa samples following jet milling. Results and discussion Hollow needles of DF were precipitated. With similar particle size distributions, the jet-milled DFNa sample from the collection bag, and the DF sample from the cyclone were used for further characterization. Despite different deposition patterns in the Next Generation Impactor, the DF hollow needles had a comparable respirable fraction percentage to the jet-milled DF and DFNa particles. However, the jet-milled DF formulation had the best in vitro aerodynamic performance. Conclusions Hollow, crystalline needles of DF were formed and possessed promising aerosol performance in comparison with the jet-milled powders. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this study was to determine the effect of both carrier particle size and surface roughness on the aerosol performance of dry powder formulations. Two morphologically distinct grades of lactose, anhydrous (AN) and granulated (GR), were fractionated into 11 discreet sizes up to 300μm, and separately employed as carriers in 2% (w/w) budesonide blends. In vitro deposition studies were performed at 60Lmin−1 with an Aerolizer® DPI. It was found that large carriers can improve dispersion performance, although the effect is more pronounced with greater surface roughness. AN carriers exhibited minimal surface roughness and generally behaved as predicted from the literature, with the smaller carriers outperforming their larger counterparts. In contrast, GR carriers had a high degree of surface roughness, and the dispersion performance of larger carriers exceeded that of the smaller size fractions. Comparing the two lactose grades, AN carriers deposited a greater fraction of the total dose up to the 90–125μm size range, when they were surpassed in performance by the GR carriers. These results suggest that the mechanism of drug detachment varies with the physical properties of the carrier particle population, where surface roughness can alter the predominant detachment mechanism to favor larger carrier particle diameters. [ABSTRACT FROM AUTHOR]

Abstract: In this study, carboxymethyl chitosan was prepared, characterized, and then photo-induced graft copolymerized with poly(ethylene glycol) under a nitrogen atmosphere in aqueous solution using 2,2-dimethoxy-2-phenyl acetophenone (DMPA) as the photo-initiator. The grafting copolymerization process was confirmed and the resulting copolymers were characterized using differential scanning calorimetry (DSC), FTIR spectroscopy, 2D-X ray diffraction, and elemental analysis. The kinetics of the grafting reactions was also studied. Under the applied experimental conditions, the optimum grafting values were obtained at: CMCs=0.2g, PEGA=249mM, DMPA=10.4mM at a 2h reaction time. Some of the resulting copolymers were selected and used in the presence of methylene bisacrylamide (MBA) as a crosslinking agent to develop pH-responsive hydrogel matrices. The swelling characteristics and the in vitro release profiles of 5-fluorouracil (5-FU), as a model drug, from the hydrogels were investigated. The results revealed that the hydrogel matrices developed in this study can be customized to act as good candidates in drug delivery systems. [ABSTRACT FROM AUTHOR]

Abstract: Design of appropriate inhaled carriers with adequate aerodynamic properties, drug release, biodegradation and evasion of macrophage uptake is a major challenge for controlled release pulmonary drug delivery. In this study, PEG graft copolymerized onto N-phthaloyl chitosan (NPHCs) was synthesized then characterized using FTIR, EA, DSC and 2D-XRD. The resulting PEG-g-NPHCs copolymers were self-assembled into drug-loaded nanoparticles and encapsulated in respirable/swellable sodium alginate semi-IPN hydrogel microspheres as novel biodegradable carriers for controlled release pulmonary drug delivery. The developed nano-/microspheres carrier systems were formed via spray drying followed by ionotropic crosslinking in mild aqueous medium. The size of the developed self-assembled nanoparticles and the microspheres was measured using dynamic light scattering and laser diffraction, respectively. Morphology, moisture content, in vitro biodegradation and dynamic swelling studies were also investigated for the developed carriers. A model protein was entrapped and the in vitro release profiles were determined in PBS, pH 7.4 at 37°C. A dry powder aerosolization study was conducted using a Next Generation Impactor (NGI). The developed microspheres had suitable aerodynamic diameters (1.02–2.63μm) and an excellent fine particle fraction, FPF of 31.52%. The microspheres showed also a very fast initial swelling within the first 2min and started to enzymatically degrade within the first 2h. Moreover, the microspheres entrapped up 90% of the model drug and showed promising in vitro sustained release profiles as compared to the control formulation. [Copyright &y& Elsevier]

Abstract: In the present study, carboxymethyl chitosan was prepared and characterized. Photo-induced graft copolymerization of 2-hydroxyethyl methacrylate (HEMA) onto carboxymethyl chitosan (CMCs) was then carried out under nitrogen atmosphere in aqueous solution using 2,2-dimethoxy-2-phenyl acetophenone (PI) as photo-initiator. Grafting process was confirmed and the produced copolymers were characterized with aid of elemental analysis, FTIR, 2D-X ray diffraction, differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The effects of HEMA and PI concentrations and the reaction time on the grafting yield were investigated by determining the grafting percentage and grafting efficiency. Under the applied experimental conditions, the optimum grafting conditions were obtained at: CMCs=0.2g, HEMA=0.615mol/L, PI=0.0078mol/L and reaction time=90min. The synthesized copolymers revealed a self-ability to form physically crosslinked hydrogels. The hydrogel nature of the copolymers was investigated by studying the solubility profiles and the cyclic swelling–deswelling behavior of copolymers with different grafting extents. These investigations of the photo-synthesized graft copolymers showed that they can be tailored and exploited as promising carriers for drug delivery purposes. [Copyright &y& Elsevier]

[Display omitted] • New chitosan-hyaluronic acid (CS-HA) core–shell nanoparticles (NPs) were developed. • The CS-HA NPs are the first sequential targeting delivery system of doxorubicin. • Mitotropic triphenylphosphonium-doxorubicin conjugate was synthesized. • The drug conjugate-loaded NPs were tested for sequential targeting of breast cancer. • In-vivo studies confirmed efficiency of CS-HA core–shell NPs for dual-stage delivery. Targeted therapy exploits cancerous niches' properties including acidic extracellular environment, hypoxic tumor core, and over expression of tumor-specific surface antigens. The present study aims to develop and evaluate a sequential targeted core–shell nanoparticulate (NPs) system for treatment of breast cancer. Sequential (double-stage) targeting was achieved at the cellular-level through employing the selective CD44- receptor binding hyaluronic acid (HA), followed by subcellular mitochondrial drug-delivery using the mitotropic triphenylphosphonium-conjugated doxorubicin (DOX-TPP+). NPs were prepared through incorporation of the electrostatic-complexes of DOX.HCl/DOX-TPP+ with tripolyphosphate (STPP-) into chitosan (CS) forming the core that was further coated with HA shell. Physicochemical characterization techniques namely; FTIR, DSC, DLS, morphological evaluation and spectroscopic assessments were implemented. Moreover, the drug entrapment efficiency (EE%), loading capacity (LC%), drug release profile and kinetics were investigated. Lastly, to validate the biological efficiency of the developed NPs, cytotoxic activity was evaluated as well as flow cytometric analyses to assess apoptosis induction and cell-cycle arrest were studied. Results showed that, the obtained core–shell NPs possessed a spherical shape with a mean size of 220–280 nm and attained high EE% and LC%. In-vitro cytotoxicity evaluations demonstrated successful apoptosis induction and cell-cycle abrogation. Moreover, in-vivo studies on Solid Ehrlich carcinoma (SEC)-bearing mice confirmed the efficient anticancer activity of the mitotropic DOX-TPP+-loaded NPs. Conclusively, the developed core–shell NPs proved efficient in sequential targeting of DOX to breast cancer. [ABSTRACT FROM AUTHOR]

Non-invasive delivery systems are desirable for routine administration of therapeutic protein and peptides. The large absorptive surface area of the lungs, thin alveolar epithelial barrier, and extensive vasculature makes the pulmonary route a promising option. For many years, drug delivery to the lungs has been achieved by nebulizers and metered dose inhalers. Two rapidly expanding fields of aerosol drug delivery are liquid-spray systems and dry-powder delivery systems. The selection of an aerosolization system for protein and peptide active compounds will be driven by several inter-related factors that include: physicochemical properties of the macromolecule, the principle of aerosolization of the device, and patient- and disease-related properties. Although novel liquid spray systems may have aerosol and delivery advantages over current inhalation aerosol technologies, rigorous scientific evaluation has not yet been performed due to the relatively recent introduction of these systems. Alternatively, dry-powder inhaler systems for protein and peptide therapeutics have undergone significantly more scientific evaluation. Dry-powder systems for protein and peptide therapeutics may have stability and sterility advantages. However, with currently used excipients and passive dispersion mechanisms, these devices are relatively inefficient. A convergence of improved particle manufacturing methods and technologies with active dispersion technologies may lead to more efficient delivery options. Alongside these delivery considerations, issues pertaining to economic viability, regulatory approval, and patient factors are equally important for selection of an appropriate delivery system. Thus, with our current understanding, there is no acceptable decision tree or algorithm that can be used to derive the most appropriate device technology for inhaled protein and peptide therapy. This review aims to provide guidance to select the best formulation alternative to deliver a candidate protein/peptide drug through the pulmonary route. [ABSTRACT FROM AUTHOR]

There are a multitude of formulation factors to consider when developing a pMDI. Evaluation of each of these variables has been performed over the years, but there has been an abundance of different approaches in the determination of the effects on device performance. Thus, although much is known about pMDI on the empirical level, a systematic approach has clearly been missing. With the ratification of the Montreal Protocol and the introduction of alternative propellant systems, the opportunity to establish relationships between different levels of testing, such as in vitro measurements and in vivo outcomes, and in vivo assessments and clinical outcomes, has arrived. This review outlines research efforts that have focused on the formulation of propellant-driven metered dose inhalers using alternative propellants. These formulation factors, including device characteristics, are reviewed with respect to the performance of MDIs. [Copyright &y& Elsevier]

Nose-to-brain delivery has gained significant interest over the past several decades. This has resulted in numerous strategies described to improve the delivery of drugs to the brain directly through the olfactory epithelium of the nasal cavity. In some cases, intranasal administration may be more effective than other routes of administration in treating central nervous system and related disorders. Here, we briefly review the strategies that have been used to facilitate nose-to-brain delivery as well as approaches to block the delivery of drugs from the nose to the brain. Even though numerous strategies have already been used to increase nose-to-brain delivery, the research for strategies inhibitory of nose-to-brain delivery seems to be scarce. [ABSTRACT FROM AUTHOR]

BACKGROUND: Astaxanthin (AST) is approved by the US Food and Drug Administration (FDA) as a safe dietary supplement for humans. As a potent lipid‐soluble keto‐carotenoid, it is widely used in food, cosmetics, and the pharmaceutical industry. However, its low solubility limits its powerful biological activity and its application in these fields. This study aims to develop a delivery system to address the low solubility and bioavailability of AST and to enhance its antioxidant capacity. RESULTS: Astaxanthin‐loaded composite micelles were successfully prepared via coaxial electrospray technology. Astaxanthin existed in the amorphous state in the electro‐sprayed formulation with an approximate particle size of 186.28 nm and with a polydispersity index of 0.243. In this delivery system, Soluplus and copovidone (PVPVA 64) were the main polymeric matrix for AST, which then released the drug upon contact with aqueous media, resulting in an overall increase in drug solubility and a release rate of 94.08%. Meanwhile, lecithin, and Polyethylene glycol‐grafted Chitosan (PEG‐g‐CS) could support the absorption of AST in the gastrointestinal tract, assisting transmembrane transport. The relative bioavailability reached about 308.33% and the reactive oxygen species (ROS) scavenging efficiency of the formulation was 44.10%, which was 1.57 times higher than that of free astaxanthin (28.10%) when both were at the same concentration level based on astaxanthin. CONCLUSION: Coaxial electrospray could be applied to prepare a composite micelles system for the delivery of poorly water‐soluble active ingredients in functional food, cosmetics, and medicine. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Franz cell (FC) experiments in topical and transdermal drug development represent the gold standard in vitro method but require a relatively high quantity of human skin, are low-throughput, and are time-consuming to perform. To address these issues, we studied a micro-well plate-based screening method for permeability and retention that could enable the direct screening of large numbers of formulations simultaneously across human skin. Using freshly excised dermatomed human skin modified to reflect poor barrier function and a model hydrophilic compound, Sulforhodamine B (SRB), FC permeation and retention quantification was compared to the 96-well high-throughput system (HTS). The skin was analyzed using 2-photon microscopy to determine the drug distribution within the skin. A screen of 15 different formulations in triplicate in a single piece of human skin, using full factorial design was then conducted. Permeability of SRB across the skin as well as the drug distribution profile of SRB retained in the skin were similar for the FC and HTS system. The influence of different excipients on drug retention was observed in the full factorial formulation screen. The HTS method is promising for the investigation of large numbers of formulations and the influence of formulations changes in skin retention of drug. [ABSTRACT FROM AUTHOR]

Twin-screw continuous mixing was used to prepare aerosol powders containing 1% budesonide, 0.3% magnesium stearate, and 98.7% α -lactose monohydrate. The effect of mixing configuration was studied using three screw profiles containing either a combing element, 30° forward kneading element, or a 60° forward kneading element. The impact of screw speed, feed rate, and multiple passes through the mixer on powder quality was investigated. The impact of specific energy on aerosol performance was dependent on the mixing configuration, and high energy input was detrimental to FPF for the 30° kneading element. Control of content uniformity was demonstrated by varying the mixing element in the screw profile. Passing the material through the mixer multiple times improved the aerosol performance. The robust and tunable nature of twin-screw mixing makes it a process well suited for continuous manufacturing of aerosol powders. [Display omitted] • The mixing process is robust above a critical specific throughput. • Excessive mixing shear can reduce aerosol performance due to press on forces. • More aggressive mixing elements in the screw profile improve content uniformity. • Aerosol performance improves with multiple passes through the mixer. • Increased mixing time reduces drug agglomerates to improve FPF. [ABSTRACT FROM AUTHOR]

High-speed laser imaging (HSLI) is the preferred technique to characterize the geometry of the plume in pressurized metered dose inhalers (pMDIs). However, current methods do not allow for simulation of inhalation airflow and do not use drug mass quantification to determine plume angles. To address these limitations, a Plume Induction Port Evaluator (PIPE) was designed to characterize the plume geometry based on mass deposition patterns. The method is easily adaptable to current pMDI characterization methodologies, uses similar calculations methods, and can be used under airflow. The effect of airflow and formulation on the plume geometry were evaluated using PIPE and HSLI. Deposition patterns in PIPE were highly reproducible and log-normal distributed. Mass Median Plume Angle (MMPA) was a new characterization parameter to describe the effective angle of the droplets deposited in the induction port. Plume angles determined by mass showed a significant decrease in size as ethanol increases which correlates to the decrease on vapor pressure in the formulation. Additionally, airflow significantly decreased the angle of the plumes when cascade impactor was operated under flow. PIPE is an alternative to laser-based characterization methods to evaluate the plume angle of pMDIs based on reliable drug quantification while simulating patient inhalation. [ABSTRACT FROM AUTHOR]

The feasibility of twin-screw corotating extruder as a continuous process mixer to prepare dry powder inhalation (DPI) powders was investigated. Interactive mixtures of 1% micronized budesonide, 0.3% magnesium stearate and 98.7% alpha-lactose monohydrate were manufactured using a Leistritz Nano-16 extruder at various processing conditions. One set of GFM (grooved mixing) elements were included in the screw profile to provide distributive mixing of conveyed powders with the goal of resulting in a homogeneous mixture. Residence time in the twin-screw mixer was modelled to quantify mixing efficiency. Comparative powders were also prepared using either low or high-shear batch mixing to compare the effect of mixing methods on the properties of the budesonide dry powder inhalation formulation. Twin screw mixing results in homogeneous mixtures with aerosol performance comparable to that of high-shear batch mixing. Scanning electron microscopy confirmed that twin screw mixing produces particles with morphology like that of low and high-shear batch mixing. X-ray diffraction (XRD) analysis verified that there was no form change of the drug due to twin-screw processing. Statistical regression was used to probe the relationship between twin screw mixing process parameters such as screw speed and feed rate and aerosol performance. The twin screw mixing process was found to be robust, as no significant differences in aerosol performance were found for various processing parameters. [Display omitted] [ABSTRACT FROM AUTHOR]

In recent years, several new genome editing technologies have been developed. Of these the zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR/Cas9 RNA-guided endonuclease system are the most widely described. Each of these technologies utilizes restriction enzymes to introduce a DNA double stranded break at a targeted location with the guide of homologous binding proteins or RNA. Such targeting is viewed as a significant advancement compared to current gene therapy methods that lack such specificity. Proof-of-concept studies have been performed to treat multiple disorders, including in vivo experiments in mammals and even early phase human trials. Careful consideration and investigation of delivery strategies will be required so that the therapeutic potential for gene editing is achieved. In this review, the mechanisms of each of these gene editing technologies and evidence of therapeutic potential will be briefly described and a comprehensive list of past studies will be provided. The pharmaceutical approaches of each of these technologies are discussed along with the current delivery obstacles. The topics and information reviewed herein provide an outline of the groundbreaking research that is being performed, but also highlights the potential for progress yet to be made using these gene editing technologies. [ABSTRACT FROM AUTHOR]

[Display omitted] Twin-screw extruders are useful in tuning certain product characteristics due to the ability to greatly modify screw profiles as well as operating parameters. However, their use has not yet been applied to dry powder inhalation. In this study the feasibility of using a twin-screw extruder to blend dry powders for inhalation was assessed. Micronized rifampicin (1%) was used as a model drug with lactose carrier (median size ∼ 44 µm) and 0.4% magnesium stearate as a multi-functional ternary agent. Blend performance was compared with low shear (Turbula®) batch mixing. Similar blend uniformity and aerosol performance was observed, indicating the twin-screw extruder successfully functions as a mixer for dry powders for inhalation. The ability to utilize the twin-screw extruder as a continuous mixer leads to new opportunities in the continuous manufacturing of powders for inhalation. [ABSTRACT FROM AUTHOR]

[Display omitted] The process of solids mixing is applied across a considerable range of industries. Pharmaceutical science is one of those industries that utilizes solids mixing extensively. Specifically, solids mixing as a key factor in the preparation of dry powder inhalers using the ordered mixing process will be discussed here. This review opens with a history of dry powder mixing theory, continues to ordered mixing in the preparation for dry powder inhalers, details key interparticulate interactions, explains formulation components for dry powder blends, and finally discusses different types of mixers used in the production of dry powder blends for inhalation. Lastly, the authors offer some suggestions for future work on this topic. [ABSTRACT FROM AUTHOR]

Monoclonal antibody (mAb) based therapies may provide a valuable new treatment modality for acute and chronic lung diseases, including asthma, respiratory infections, and lung cancer. Currently mAbs are delivered via systemic administration routes, but direct delivery to the lungs via the inhaled route could provide higher concentrations at the site of disease and reduced off-target effects. Though lyophilized mAbs may be reconstituted and delivered to the lungs using nebulizers, dry powder inhalers provide a more patient-friendly delivery method based upon their fast administration time and portability. However, particle engineering processes required to prepare respirable dried powders for DPI delivery involve multiple potential stressors for mAbs, which have not been fully explored. In this study, a systematic examination of various aspects of the particle engineering process (atomization, freezing, drying, and storage) was performed to further understand their impact on mAb structure and aggregation. Using anti-streptavidin IgG1 as a model mAb, atomization settings were optimized using a design of experiments approach to elucidate the relationship between feed flow rate, formulation solid content, and atomization airflow rate and protein structural changes and aggregation. The optimized atomization conditions were then applied to spray drying and spray freezing drying particle engineering processes to determine the effects of freezing and drying on IgG1 stability and aerosol performance of the powders. IgG1 was found to be particularly susceptible to degradation induced by the expansive air-ice interface generated by spray freeze drying and this process also produced powders that exhibited decreased storage stability. This study further delineates the design space for manufacturing of respirable biologic therapies and is intended to serve as a roadmap for future development work. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] In recent years, several techniques were employed to develop a local sustained pulmonary delivery of sildenafil citrate (SC) as an alternative for the intravenous and oral treatment of pulmonary arterial hypertension (PAH). Most of these methods, however, need to be improved due to limitations of scalability, low yield production, low drug loading, and stability issues. In this study, we report the use of hot-melt extrusion (HME) as a scalable process for making Poly (lactic-co-glycolic acid) (PLGA) microparticles with high SC load. The prepared particles were tested in vitro for local drug delivery to the lungs by inhalation. Sodium bicarbonate was included as a porogen in the formulation to make the particles more brittle and to impart favorable aerodynamic properties. Six formulations were prepared with different formulation compositions. Laser diffraction analysis was used to estimate the geometric particle size distribution of the microparticles. In-vitro aerodynamic performance was evaluated by the next-generation cascade impactor (NGI). It was reported in terms of an emitted dose (ED), an emitted fraction (EF%), a respirable fraction (RF%), a fine particle fraction (FPF%), a mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD). The formulations have also been characterized for surface morphology, entrapment efficiency, drug load, and in-vitro drug release. The results demonstrated that PLGA microparticles have a mean geometric particle size between 6 and 14 µm, entrapment efficiency of 77 to 89 %, and SC load between 17 and 33 % w/w. Fifteen percent of entrapped sildenafil was released over 24 h from the PLGA microparticles, and seventy percent over 7 days. The aerodynamic properties included fine particle fraction ranging between 19 and 33 % and an average mass median aerodynamic diameter of 6–13 µm. [ABSTRACT FROM AUTHOR]

Abstract: Batch-to-batch variability, whereby distinct batches of dry powder inhaler formulations, though manufactured with identical components and specifications, may exhibit significant variations in aerosol performance, is a major obstacle to consistent and reproducible drug delivery for inhalation therapy. This variability may arise from processing or manufacturing effects that have yet to be investigated. This study focused on the potential effects of mild compression forces experienced during powder manufacture and transport (such as during the filling of, or storage in, a hopper) on the flowability and aerosol performance of a lactose-based dry powder inhaler formulation. Different grades of inhalation lactose were subjected to typical compression forces by either placing a weight of known mass on the sample or by using a Texture Analyzer to apply a constant force while measuring the distance of compaction. Powder flowability was evaluated with a rotating drum apparatus by imaging the avalanching of the powder over time. The average avalanche angle and avalanche time were used to determine the flowability of each sample, both before and after compression treatment. Aerosol performance of treated and untreated lactose/budesonide blends (2% (w/w)) was assessed in dispersion studies using a next generation impactor. At compression forces in excess of 5kPa, the flowability of milled lactose was decreased relative to the untreated sample. Compression of lactose prior to blending caused a decrease in in vitro aerosol dispersion performance. However, dispersion performance was unchanged when compression occurred subsequent to drug blending. In contrast, inhalation grade sieved lactose, differing from the milled grade with a lower concentration of lactose fines (<10μm) and larger overall particle sizes, exhibited no statistical differences in either flowability or dispersion performance across all experimental treatments. Thus, the compression of the lactose fines onto the surfaces of the larger lactose particles due to mild processing pressures is hypothesized to be the cause of these observed performance variations. It was shown that simulations of storage and transport in an industrial scale hopper can induce significant variations in formulation performance, and it is speculated that this could be a source of batch-to-batch variations. [Copyright &y& Elsevier]

In this investigation, novel biodegradable physically crosslinked hydrogel microparticles were developed and evaluated in vitro as potential carriers for sustained pulmonary drug delivery. To facilitate sustained release in the lungs, aerosols must first navigate past efficient aerodynamic filtering to penetrate to the deep lung (requires small particle size) where they must then avoid rapid macrophage clearance (enhanced by large particle size). The strategy suggested in this study to solve this problem is to deliver drug-loaded hydrogel microparticles with aerodynamic characteristics allowing them to be respirable when dry but attain large swollen sizes once deposited on moist lung surfaces to reduce macrophage uptake rates. The microparticles are based on PEG graft copolymerized onto chitosan in combination with Pluronic® F-108 and were prepared via cryomilling. The synthesized polymers used in preparation of the microparticles were characterized using FTIR, EA, 2D-XRD, and differential scanning calorimetry (DSC). The microparticles size, morphology, moisture content, and biodegradation rates were investigated. Swelling studies and in vitro drug release profiles were determined. An aerosolization study was conducted and macrophage uptake rates were evaluated against controls. The microparticles showed a respirable fraction of approximately 15% when prepared as dry powders. Enzymatic degradation of microparticles started within the first hour and about 7–41% weights were remaining after 240 h. Microparticles showed sustained release up to 10 and 20 days in the presence and absence of lysozyme, respectively. Preliminary macrophage interaction studies indicate that the developed hydrogel microparticles significantly delayed phagocytosis and may have the potential for sustained drug delivery to the lung. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2343–2356, 2010 [ABSTRACT FROM AUTHOR]

A significant limitation of locally delivered treatments for chronic pulmonary infections is often the short residence time within the airways. Ciprofloxacin (CIP), for example, undergoes rapid absorption from the airway lumen. Previously, we demonstrated that the complexation of CIP with copper (CIP-Cu) reduces its apparent epithelial permeability and pulmonary absorption rate without affecting antimicrobial activity against Pseudomonas aeruginosa grown planktonically or as biofilms. This study aimed to evaluate the in vivo efficacy of CIP-Cu, prepared as a dry powder, in a chronic lung infection model. The powders were prepared by jet milling (CIP-HCl) and by spray drying (CIP-Cu). A bioluminescent strain of P. aeruginosa (PAO1::p16S lux) was used to prepare bacteria-loaded agar beads that were inoculated intratracheally to rats. The dynamics of the infection were monitored using luminometry. The bacteria/beads ratio was optimized to allow the highest luminescence signal and animal survival for 8 days. The efficacy of the treatment was evaluated by luminometry in addition to the end-point (Day 8) where colony counting was performed after lung harvesting. Luminescent P. aeruginosa entrapped in agar beads were useful to monitor the spatial development of the chronic lung infection in rats. The rats were treated with the dry powders in a nose-only inhalation exposure system (NOIES). CIP-Cu and CIP-HCl powders showed similar aerodynamic properties and comparable CIP lung deposition. However, treatment with CIP-Cu significantly (p < 0.01) reduced by 4-log the number of CFU of P. aeruginosa per lung in the chronic infection model, whereas CIP-HCl effect was not different from the untreated control group. [ABSTRACT FROM AUTHOR]

Therapeutic delivery of drug and gene delivery systems have to traverse multiple biological barriers to achieve efficacy. Mucosal administration, such as pulmonary delivery in cystic fibrosis (CF) disease, remains a significant challenge due to concentrated viscoelastic mucus, which prevents drugs and particles from penetrating the mucus barrier. To address this problem, we used combinatorial peptide-presenting phage libraries and next-generation sequencing (NGS) to identify hydrophilic, net-neutral charged peptide coatings that enable penetration through human CF mucus ex vivo with ~600-fold better penetration than control, improve uptake into lung epithelial cells compared to uncoated or PEGylated-nanoparticles, and exhibit enhanced uniform distribution and retention in the mouse lung airways. These peptide coatings address multiple delivery barriers and effectively serve as excellent alternatives to standard PEG surface chemistries to achieve mucus penetration and address some of the challenges encountered using these chemistries. This biomolecule-based strategy can address multiple delivery barriers and hold promise to advance efficacy of therapeutics for diseases like CF. Unlabelled Image [ABSTRACT FROM AUTHOR]

[Display omitted] • Gelatin was used to develop a swellable matrix system for inhalable dry powder formulations to increase lung retention and control the release of drugs through ionic interactions. • A Box-Behnken approach was used to optimize aerodynamic performance by testing different combinations of SD process parameters. • Cromoglicate sodium (CS) and ipratropium bromide (IBr) microspheres were highly dispersible with a respirable fraction near 50% and a fine particle fraction near 60% • Only uncrosslinked CS and IBr microspheres increased their size by swelling after 5 min (ten and four times, respectively), which could allow for increased lung retention. • The formulations are produced with an accessible manufacturing process, a safe excipient that enhances particle dispersion, and has the potential to control the release of the drugs by a matrix-based approach. Controlled-release formulations for pulmonary delivery are highly desirable for treating chronic diseases such as COPD. However, a limited number of polymers are currently approved for inhalation. The study presents a promising strategy using gelatin as a matrix for inhalable dry powders, allowing the controlled release of ionic drugs. Ionized cromoglicate sodium (CS) and ipratropium bromide (IBr) interacted in solution with charged gelatin before spray drying (SD). Calcium carbonate was used as a crosslinker. The microspheres showed remarkable aerosol performance after optimizing the SD parameters and did not cause cytotoxicity in A549 cells. The microspheres were highly dispersible with ∼ 50–60% of respirable fraction and fine particle fraction 55–70%. Uncrosslinked microspheres increased their size from four to ten times by swelling after 5 min showing potential as a strategy to avoid macrophage clearance and prolong the therapeutic effect of the drug. Crosslinkers prevented particle swelling. Ionic interaction generated a moderate reduction of the drug release. Overall, this study provides a novel approach for developing DPI formulations for treating chronic respiratory diseases using a biopolymer approved by the FDA, potentially enhancing drug activity through controlled release and avoiding macrophage clearance. [ABSTRACT FROM AUTHOR]

Clofazimine (CFZ) is an important component of the World Health Organization's (WHO) recommended all-oral drug regimen for treatment of multi-drug resistant tuberculosis (MDR-TB). However, the lack of a dividable oral dosage form has limited the use of the drug in pediatric populations, who may require lowering of the dose to reduce the likelihood of adverse drug events. In this study, pediatric-friendly CFZ mini-tablets were prepared from micronized powder via direct compression. Rapid disintegration and maximized dissolution in GI fluids was achieved using an iterative formulation design process. Pharmacokinetic (PK) parameters of the optimized mini-tablets were obtained in Sprague-Dawley rats and compared against an oral suspension of micronized CFZ particles to examine the effect of processing and formulation on the oral absorption of the drug. Differences in maximum concentration and area under the curve between the two formulations were non-significant at the highest dosing level tested. Variability between rats prevented bioequivalence from being determined according to guidelines outlined by the Food and Drug Administration (FDA). These studies provide an important proof-of-concept for an alternative, low-cost formulation and processing approach for the oral delivery of CFZ in manner that is suitable for children as young as 6 months of age. [Display omitted] [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The objective of this work is to use phage display libraries as a screening tool to identify peptides that facilitate transport across the mucus barrier. Mucus is a complex selective barrier to particles and molecules, limiting penetration to the epithelial surface of mucosal tissues. In mucus-associated diseases such as cystic fibrosis (CF), mucus has increased viscoelasticity and a higher concentration of covalent and non-covalent physical entanglements compared to healthy tissues, which greatly hinders permeability and transport of drugs and particles across the mucosae for therapeutic delivery. Treatment of CF lung diseases and associated infections must overcome this abnormal mucosal barrier. Critical bottlenecks hindering effective drug penetration remain and while recent studies have shown hydrophilic, net-neutral charge polymers can improve the transport of nanoparticles and minimize interactions with mucus, there is a dearth of alternative carriers available. We hypothesized that the screening of a phage peptide library against a CF mucus model would lead to the identification of phage-displayed peptide sequences able to improve transport in mucus. These combinatorial libraries possess a large diversity of peptide-based formulations (108–109) to achieve unprecedented screening for potential mucus-penetrating peptides. Here, phage clones displaying discovered peptides were shown to have up to 2.6-fold enhanced diffusivity in the CF mucus model. In addition, we demonstrate reduced binding affinities to mucin compared to wild-type control. These findings suggest that phage display libraries can be used as a strategy to improve transmucosal delivery. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The number of biologics in the therapeutic development pipeline is increasing including those delivered though inhalation (Morales, 2017; Fathe, 2016). Biologics comprise a broad variety of complex macromolecules with unique physicochemical characteristics. These distinctive characteristics control their pharmacological mechanisms of action, stability, and ultimately affect their processing, formulation, and delivery requirements. This review systematically covers crucial aspects of biologic powders formulations and dry powder inhalers which need to be taken into consideration to establish the drug loading and the payload to be delivered to reach the desired clinical dose. [ABSTRACT FROM AUTHOR]

There is currently no in vitro technique for assessing plume geometry of nasal sprays under airflow conditions. However, a majority of FDA approved nasal products recommend that patients inhale during actuation. Therefore, a reproducible in vitro test that measures plume angles under physiologically relevant inhalation flow rates would be useful. The purpose of this study was to adapt the recently described Plume Induction Port Evaluator (PIPE) apparatus for nasal sprays under flow and correlate these with nasal cast deposition patterns. Mass Median Plume Angles (MMPAs) of four nasal spray formulations with increasing viscosities were determined using the PIPE apparatus in the absence and presence of airflow. MMPAs were then correlated to drug deposition within 3D printed nasal casts using airflow. We evaluated different inhalation instructions obtained from the package insert of nasal products. MMPAs significantly reduced (narrower angles) when using flow for the three formulations with the lowest viscosities. An increase in the turbinate deposition was observed in the nasal casts when just one of the nostrils was closed during inhalation, except by the highest viscosity formulation. The turbinate deposition numerically correlated with changes in the plume angles observed using PIPE. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa is an opportunistic bacteria responsible for recurrent lung infections. Previously, we demonstrated that certain materials improved the activity of tobramycin (Tob) against P. aeruginosa biofilms in vitro . We aimed to develop prototype dry powder formulations comprising Tob and a mixture of excipients and test its aerodynamic properties and antimicrobial activity. First, we evaluated different combinations of excipients with Tob in solution against P. aeruginosa biofilms. We selected the compositions with the highest activity, to prepare dry powders by spray drying. The powders were characterized by morphology, bulk density, water content, and particle size distributions. Finally, the antimicrobial activity of the powders was tested. The combinations of Tob (64 μg/mL) with l -alanine and l -proline (at 10 and 20 mM; formulations 1 and 2, respectively) and with l -alanine and succinic acid (at 20 mM; formulation 3) showed the highest efficacies in vitro and were prepared as dry powders. Formulation 1 had the best aerodynamic performance as indicated by the fine particle fraction and the best in vitro activity against P. aeruginosa biofilms. Formulation 3 represents a good candidate for further optimization because it demonstrated good dispersibility potential and optimization of the particle size distribution may achieve high delivery efficiencies. [ABSTRACT FROM AUTHOR]

The RNA interference (RNAi) constitutes a conservative mechanism in eukaryotic cells that induces silencing of target genes. In mammalians, the RNAi is triggered by siRNA (small interfering RNA) molecules. Due to its potential in silencing specific genes, the siRNA has been considered a potential alternative for the treatment of genetic and acquired diseases. However, the siRNA therapy has been limited by its low stability and rapid degradation in presence of nucleases, low cellular uptake, and immune response activation. In order to overcome these drawbacks, we propose the synthesis and characterization of non-viral delivery systems using chitosan derivatives to obtain siRNA complexes (polyplexes). The non-viral delivery systems synthesized included PEG-g-OCs (oligochitosan) and PEG-g-Cs (chitosan medium molecular weight). Both systems allowed the formation of siRNA polyplexes, increased the stability of siRNA in the presence of nucleases, enhanced cellular internalization, and showed low toxicity in the A549 cell line. Finally, the complexes obtained with the PEG-g-OCs system showed silencing activity in a GFP model in the cell line A549 in comparison with naked siRNA. [ABSTRACT FROM AUTHOR]

• Around 40% of the formulation would be deposited in the alveolar membrane. • Inclusion of alginic acid confers mucoadhesive properties to the inhalatory system. • Plasmatic area under the curve is higher when the drug is combined with the polymer. • The developed material is not cytotoxic in the A-549 cell line even at high doses. • The interaction between the drug and polymer is reversible by ionic exchange. Hypertension is a chronic pathology where blood pressure levels are continuously high, causing cardiac, renal, cerebral, and vascular damage leading to early morbi-mortality. This illness is the main risk factor for cardiovascular diseases and the main cause of atrial fibrillation. Atenolol (AT) is a β-1 blocker drug useful for antihypertension and antiarrhythmic treatments. However, this drug possesses low oral bioavailability associated to its low permeability and extensive hepatic first-pass metabolism. To solve the conventional AT-administration problems, oral controlled-release and transdermal delivery have been reported. In this work, an alternative AT inhalatory system administered by nebulization is presented. This system is based on an ionic complex between acidic groups of alginic acid and cationic groups of AT (AA-AT), which was obtained by spray-drying. Pharmaceutical and biopharmaceutical properties for AA-AT inhalatory administration using a jet nebulizer were investigated. The aerodynamic performance (assayed at different cup-nebulizer loadings) of the nebulized system demonstrated that around 40% of the formulation would deposit in the respiratory membrane, with mass median aerodynamic diameters of 3.4–3.6 µm. The AT carried in the AA-AT system was released adequately by ionic exchange in saline solution by permeation through a cellulose membrane. The presence of AA as polyelectrolyte conferred mucoadhesive properties to the ionic complex. Even at high relative AA-AT concentrations, no cytotoxic effect was detected in A-549 cell line. Finally, the preliminary pharmacokinetic assay in the in vivo model confirmed that AT was absorbed from the lung to the systemic circulation, with a greater plasmatic AUC compared to the pure drug (around 50% higher). Then, the system and the nebulization administration demonstrated potential for drug cardiac targeting. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Attention has begun to focus on the pulmonary delivery of antifungal agents for invasive fungal infections as inhalation of the fungal spores is often the initial step in the pathogenesis of many of these infections, including invasive pulmonary aspergillosis (IPA). IPA in immunocompromised patients has high mortality rates despite current systemic (oral or intravenous) therapies. In this study, particulate voriconazole (VRC) formulations were designed with suitable properties for inhalation using thin film freezing (TFF), a particle engineering process capable of producing low-density porous aggregate particles. Nanostructured amorphous morphology of VRC was less favorable in vitro and in vivo than microstructured crystalline morphology, despite being a poorly water-soluble compound. Using a Handihaler® dry powder inhaler (DPI), microstructured crystalline TFF-VRC and nanostructured amorphous TFF-VRC-PVP K25 (1:3) had fine particle fractions of 37.8% and 32.4% and mass median aerodynamic diameters of 4.2 and 5.2μm, respectively. Single dose 24-h pharmacokinetic studies were conducted in ICR mice. AUC0–24h in the lung tissue and plasma was 452.6μgh/g wet lung weight and 38.4μgh/mL, respectively, following a 10mg/kg insufflated dose of TFF-VRC directly into the lungs of the mice, while AUC0–24h in the lung tissue and plasma was 232.1μgh/g wet lung weight and 18.6μgh/mL, respectively, following a 10mg/kg insufflated dose of TFF-VRC-PVP K25 (1:3). High concentrations of VRC in lung tissue coupled with clinically relevant plasma concentrations suggest that pulmonary delivery of microstructured crystalline VRC could potentially be a beneficial strategy for administration of VRC to patients with invasive pulmonary fungal infections. [Copyright &y& Elsevier]

Abstract: This study involves the development and characterization of a series of sodium alginate-based pH-responsive hydrogel microspheres encapsulating poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). The effect of the drying technique (air- or freeze-drying) on the size of the developed particles was determined. Swelling characteristics at different pH values, in vitro biodegradation and moisture contents of both air-dried and freeze-dried hydrogel particles were investigated. The effect of drying method on the morphology of the particles was also studied using SEM and AFM. Then, the developed alginate-PLGA particles were evaluated as potential carriers, through a new approach, to improve the dissolution, bioavailability and oral sustained release of silymarin, as a model of hydrophobic natural therapeutics. The used silymarin was isolated from the seeds of some native milk thistle (Silybum marianum) ecotypes of delta Egypt and was characterized with the aid of several analytical techniques including; 1H NMR, UV and FTIR. The obtained data showed a considerable effect of the alginate content and the drying method onto the characteristics of the prepared particles. Also, the results demonstrated that the developed alginate-based hydrogel microparticles encapsulating silymarin-loaded PLGA NPs can be used as biodegradable carriers that can confer sustained oral release of silymarin in addition to enhancing its overall dissolution and oral bioavailability. [Copyright &y& Elsevier]

Abstract: The effect of device geometry and film characteristics on the performance of several passive flutter-induced dispersion DPI prototypes was investigated. Device resistance measurements indicated that the type of films, type of device geometry and specific device dimensions significantly affects the airflow resistance of the device. It was found that airflow resistance was positively correlated to the turbulence generated within the device. In addition, in vitro deposition studies indicated that the device geometry and film properties have a significant effect on aerosol dispersion performance. From these studies, selected prototypes were observed to have improved aerosolization performance without significant increases in device resistance. With further device design optimization, flutter induced dispersion DPI may be highly efficient mechanism for drug deaggregation and aerosolization. [ABSTRACT FROM AUTHOR]

[Display omitted] Gene therapy and more recently, gene editing is attractive via pulmonary delivery for enhanced regional targeting. However, processing of sensitive therapeutics into dry powders for inhalation can be problematic due to relatively stressful spraying or milling steps. Thin-film freeze-drying (TFFD) has attracted attention with its promising application in the production of DPI formulations possessing respirable particle size range (1–5 µm) particularly for thermally or shear sensitive therapeutics. In this study, gene editing dry powder formulations containing PEGylated chitosan/CRISPR-Cas9 nanocomplexes were prepared by TFFD. To evaluate stability during processing, nanocomplex size, zeta potential and transfection efficiency of reconstituted formulations were evaluated, and six potential DPI formulations were identified and characterized in terms of geometric particle size, powder surface morphology, and crystallinity. It was found that two formulations containing 3% mannitol with or without leucine were identified as suitable for inhalation with a desired aerodynamic performance. The flow rate dependency and inhaler dependency of these two formulations were also evaluated at different flow rates (60 L/min and 45 L/min) and different inhaler devices (RS01 DPI and HandiHaler) using NGI testing. This study demonstrated that TFFD processing of CRISPR-Cas9 polymer nanocomplexes resulted in a suitable dry powder for inhalation. [ABSTRACT FROM AUTHOR]

The performance of dry powder aerosols for the delivery of drugs to the lungs has been studied extensively in the last decade. The focus for different research groups has been on aspects of the powder formulation, which relate to solid state, surface and interfacial chemistry, bulk properties (static and dynamic) and measures of performance. The nature of studies in this field, tend to be complex and correlations between specific properties and performance seem to be rare. Consequently, the adoption of formulation approaches that on a predictive basis lead to desirable performance has been an elusive goal but one that many agree is worth striving towards. The purpose of this paper is to initiate a discussion of the use of a variety of techniques to elucidate dry particle behavior that might guide the data collection process. If the many researchers in this field can agree on this, or an alternative, guide then a database can be constructed that would allow predictive models to be developed. This is the first of two papers that discuss static and dynamic methods of characterizing dry powder inhaler formulations. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1282–1301, 2007 [ABSTRACT FROM AUTHOR]

Characteristics of particles included in dry powder inhalers is extended from our previous report (in this journal) to include properties related to their dynamic performance. The performance of dry powder aerosols for pulmonary delivery is known to depend on fluidization and dispersion which reflects particle interactions in static powder beds. Since the solid state, surface/interfacial chemistry and static bulk properties were assessed previously, it remains to describe dynamic performance with a view to interpreting the integrated database. These studies result in complex data matrices from which correlations between specific properties and performance may be deduced. Lactose particles were characterized in terms of their dynamic flow, powder and aerosol electrostatics, and aerodynamic performance with respect to albuterol aerosol dispersion. There were clear correlations between flow properties and aerosol dispersion that would allow selection of lactose particles for formulation. Moreover, these properties can be related to data reported earlier on the morphological and surface properties of the carrier lactose particles. The proposed series of analytical approaches to the evaluation of powders for inclusion in aerosol products has merit and may be the basis for screening and ultimately predicting particle performance with a view to formulation optimization. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1302–1319, 2007 [ABSTRACT FROM AUTHOR]

This paper describes the design of stimuli-sensitive theranostic nanoparticles, composed of reduced graphene oxide (rGO) self-assembled on thermosensitive liposomes encapsulated doxorubicin (DOX) and carbon quantum dot (CQD) (CQD-DOX-rGO-Tlip). The rGO-Tlip particles have been observed to be flower-shaped objects. The thermoresponsive and theranostic potential of CQD-DOX-rGO-Tlips have been studied using differential scanning calorimetry (DSC), ultraviolet visible spectroscopy (UV–Vis), Raman spectroscopy and photoluminescent assays. The chemo-photothermal potential of rGO–Tlip on MD-MB-231 cells during NIR laser irradiation has been examined using MTT assay. Also, the ability of rGO–Tlip to be taken up by MD-MB-231 cells has been studied using confocal microscopy and flowcytometry. The results indicate that CQD-DOX-rGO-Tlips achieve a synergistic effect between photothermal therapy and chemotherapy for cancer treatment. Furthermore, online monitoring drug release is accomplished by studying the emission intensity of CQD while DOX released. • CQD-DOX-rGO-Tlips are introduced as a theranostic nanoparticles. • CQD-DOX-rGO-Tlips have a stimuli sensitive chemo-photothermal effect. • Online monitoring drug release can be achieved by using CQD-DOX-rGO-Tlips. • Flow cytometry confirm high cellular uptake of CQD-DOX-rGO-Tlips. [ABSTRACT FROM AUTHOR]