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This study describes the synthesis and characterization of triblock copolymers composed of poly[2-(methacryloyloxy)ethyl phosphorylcholine]-block-poly(propylene glycol)-block-poly[2-(methacryloyloxy)ethyl phosphorylcholine] (PMPC-b-PPG-b-PMPC) intended for, but not limited to, applications in colloidal drug delivery. Atom transfer radical polymerization led to a library of well-defined PMPC-b-PPG-b-PMPC triblock copolymers with varying overall molecular weight (ranging from ∼5 to ∼25 kDa) and composition (weight fraction of the hydrophobic PPG block ranged from ∼10 to ∼50 wt%). The properties of the synthesized triblock copolymers were linked to the PPG to bioinspired PMPC block(s) ratio, where the more hydrophilic species showed adequate aqueous solubility, surface activity and biocompatibility (non-toxicity) in in vitro cell culture. Their amphiphilic nature makes them adsorb efficiently onto polymer nanoparticles, what improves colloidal stability under stress conditions and, furthermore, depletes proteins from unwanted adsorption to the underlying surface. The current findings strengthen our insights into structure-function relationships of PMPC-based coatings leading to protecting shells on relevant polymer nanoparticle formulations. PMPC-b-PPG-b-PMPC triblock copolymers composed of a hydrophobic PPG block of 2-4 kDa flanked by two hydrophilic PMPC blocks each of 5-10 kDa seem to be most promising to enhance colloidal drug delivery vehicles., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nanotechnology-assisted RNA delivery has gotten a tremendous boost over the last decade and made a significant impact in the development of life-changing vaccines and therapeutics. With increasing numbers of emerging lipid- and polymer-based RNA nanoparticles progressing towards the clinic, it has become apparent that the safety and efficacy of these medications depend on the comprehensive understanding of their critical quality attributes (CQAs). However, despite the rapid advancements in the field, the identification and reliable quantification of CQAs remain a significant challenge. To support these efforts, this review aims to summarize the present knowledge on CQAs based on the regulatory guidelines and to provide insights into the available analytical characterization techniques for RNA-loaded nanoparticles. In this context, routine and emerging analytical techniques are categorized and discussed, focusing on the operation principle, strengths, and potential limitations. Furthermore, the importance of complementary and orthogonal techniques for the measurement of CQAs is discussed in order to ensure the quality and consistency of analytical methods used, and address potential technique-based differences., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Herein, we report the attenuated impact of bioinspired nanoparticles on the essential function of lung surfactant. Colloidal particles made from poly(lactide) caused a significant loss of surfactant protein B (and C) from a natural lung surfactant accompanied by a decline in surface activity under static conditions and surface area cycling. No such perturbation of lung surfactant composition and function was observed for polymer nanoparticles coated with bioinspired poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC). More specifically, increasing the PMPC-coating layer thickness (≥3   nm) and density (dense conformation, distance of individual polymer chains of ≤3   nm) on the polymer nanoparticle surface diminished bioadverse events. PMPC-coated poly(lactide) nanoparticles provoked a less severe perturbation of the utilized lung surfactant when compared to colloidal counterparts coated with poly(ethylene glycol). Overall, a steric shielding of colloidal drug delivery vehicles with bioinspired PMPC can be considered as a valuable approach for the rationale development of biocompatible nanomedicines intended for lung delivery.

To minimize an unwanted interference of colloidal drug delivery vehicles with the biophysical functionality of lung surfactant, the surface of polymer nanoparticles was modified with poly(ethylene glycol) (PEGylation). Plain poly(lactide) nanoparticles provoked a statistically relevant decrease in the surface activity of the naturally derived lung surfactant, Alveofact. By contrast, the extent of lung surfactant inhibition induced by PEGylated polymer nanoparticles was significantly attenuated. Here, escalations of the PEG coating layer thickness (>3 nm, with a chain-to-chain distance of ≤4 nm) on the colloidal surface were capable of circumventing bioadverse effects. Accordingly, polymer nanoparticles equipped with PEG chains with a molecular weight above 2-5 kDa were compatible with the biophysical function of Alveofact. Overall, PEGylation of polymer nanoparticles presents a promising approach for the development of inhalation nanomedicines revealing negligible effects on the surface activity of the lining layer present in the deep lungs.

Lung-delivered polymer nanoparticles provoked dysfunction of the essential lung surfactant system. A steric shielding of the nanoparticle surface with poloxamers could minimize the unwanted interference of polymer nanoparticles with the biophysical function of lung surfactant. The extent of poly(styrene) and poly(lactide) nanoparticle-induced lung surfactant inhibition could be related to the type and content of the applied poloxamer. Escalations of the adsorbed coating layer thickness (>3 nm) as well as concentration (brush- rather than mushroom-like conformation of poly(ethylene glycol), chain-to-chain distance of <5 nm) on the colloidal surface were capable of circumventing bioadverse effects. Accordingly, specific formulations (i.e., poloxamer 188, 338, and 407) avoided a perturbation of the microstructure and surface activity of Alveofact and a depletion of the content of surfactant-associated proteins. Poloxamer-modified polymer nanoparticles represent a promising nanomedicine platform intended for respiratory delivery revealing negligible effects on the biophysical functionality of the lining layer present in the deep lungs.

Colloidal drug delivery systems often face physical and chemical instability as well as challenges with directed delivery. In order to overcome these challenges the colloidal formulations can be processed into microparticulate form (nanoembedded microparticles (NEMs)). In this study, different polymer nanocarriers (poly(lactide-co-glycolide), poly(styrene), chitosan and dendrimers) were used for preparing NEMs by spray-drying. Further, distinct matrix excipients were investigated including sugars (i.e., trehalose, sucrose, mannitol) and polymers (poly(vinyl pyrrolidone) and poly(ethylene glycol)), and the characteristics and performance of NEMs were studied in detail. It was found that with increasing hydrophilicity of the polymer nanocarriers, an increasing amount of excipient was necessary to stabilize the nanoparticles. NEMs containing polyplexes and nanogels required a matrix-to-nanoparticle (M:N) ratio of 50:1 and 10:1, respectively, whereas NEMs with poly(styrene) and poly(lactide-co-glycolide) only required an M:N ratio of 1:1 and 1:4, respectively. Investigation of different excipients demonstrated that water soluble sugars and polymers can be used to prepare NEMs and that spray-dried amorphous excipients (trehalose, sucrose, poly(vinyl pyrrolidone)) are superior to spray-dried crystalline excipients (mannitol, poly(ethylene glycol)) for stabilizing NEMs. It is therefore important to select an appropriate excipient for stabilization of a given nanoparticle system and identify a suitable level of this excipient to keep the nanoparticles viable., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Colloidal drug carriers could improve the therapy of numerous airway diseases. However, it remains unclear to what extent nanoscale particulate matter affects the biophysical function of the essential surface-active lining layer of the lungs, especially under predisposed conditions of airway diseases. Accordingly, the current study investigated the impact of defined polymer nanoparticles on impaired lung surfactants. Admixtures of plasma proteins (albumin and fibrinogen) to Curosurf led to a controllable decrease in surface activity (i.e., adsorption and minimal surface tension of >25 and >5 mN/m, respectively), which served as models for dysfunctional lung surfactants. Next, Curosurf preincubated with plasma proteins was challenged with negatively- and positively charged poly(lactide) nanoparticles. Negatively charged nanoparticles significantly perturbed the biophysical function of impaired Curosurf in a dose-dependent manner, most-likely due to a binding of essential surfactant components. By contrast, addition of positively charged nanoparticles led to no further loss of surface activity, but a remarkable depletion of plasma protein content. Once adsorbed to the surface of polymer nanoparticles, plasma proteins were hindered to displace relevant surfactant components from the air/liquid interface. Overall, the current study indicated that, depending on their physicochemical properties, colloidal drug carriers could compromise the biophysical function of impaired lung surfactants. Notably, a positive surface charge represents a parameter for the rationale design of polymer nanomedicines causing negligible adverse events on an impaired surface-active lining layer in the lungs.

The introduction of "Ouzo diagrams" has enhanced the applicability of the basic nanoprecipitation process for drug delivery research. The current study investigated the interaction of two relevant polymer/solvent systems, which is thought to impact the location of the stability-limit "Ouzo boundary". Viscosity measurements (Kurata-Stockmayer-Fixman approach) and static light scattering (Debye method) underlined a distinct interplay of the employed polymer (poly(lactide-co-glycolide)) with the utilized organic solvents (acetone and tetrahydrofuran). Both methods indicated that tetrahydrofuran was the "better" solvent for poly(lactide-co-glycolide). Thus, nanoprecipitation of this polymer/solvent composition resulted in larger nanoparticles. This observation can be attributed to the chain configuration of poly(lactide-co-glycolide) in the organic solvent, which influenced the extent of the break-up of the injected solvent layer. Accordingly, the stability-limit curve of the "Ouzo region" was shifted to lower poly(lactide-co-glycolide) fractions for tetrahydrofuran. Overall, the location of the "Ouzo region", which is an essential tool for drug delivery research, is influenced by the employed organic solvent. The current study described two distinct methods suitable to identify relevant polymer-solvent interactions, which dictate the stability-limit "Ouzo boundary" for relevant poly(lactide-co-glycolide)., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The conversion of colloidal drug carriers/polymeric nanoparticles into dry microparticulate powders (e.g., by spray-drying) is a prominent approach to overcome the aerodynamic limitations of these formulations for delivery via inhalation. However, to what extent such nano-embedded microparticles disintegrate into individual/intact nanoparticles after contacting relevant physiological media has so far not been addressed. Polymeric nanoparticles were spray-dried into nano-embedded microparticles (NEMs) using different amounts of trehalose as embedding matrix excipient. Formulations were characterized and then evaluated for their disintegration behavior after aerosolization onto model mucus. Although a rapid and complete aqueous redispersion was observed for specific excipient/nanoparticle weight ratios (i.e., greater than 1/1), the same formulations revealed no disintegration after deposition onto a static mucus layer. Double-labeled NEMs powders (i.e., dual color staining of polymeric nanoparticles and trehalose) demonstrated rapid matrix dissolution, while the nanoparticle aggregates persisted. When deposited onto agitated mucus, however, sufficient disintegration of NEMs into individual polymeric nanoparticles was observed. These findings indicate that mechanical forces are necessary to overcome the attraction between individual nanoparticles found within the NEMs. Thus, it remains questionable whether the lung mechanics (e.g., breathing, mucociliary clearance) acting on these formulations will contribute to the overall disintegration process., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Context: The process of vibrating-mesh nebulization is affected by sample physicochemical properties. Exemplary, electrolyte supplementation of diverse formulations facilitated the delivery of adequate aerosols for deep lung deposition., Objective: This study addressed the impact of storage conditions of poly(lactide-co-glycolide) nanosuspension on aerosol properties when nebulized by the eFlow®rapid., Materials and Methods: First, purified nanosuspensions were supplemented with electrolytes (i.e. sodium chloride, lactic and glycolic acid). Second, the degradable nanoparticles (NP) were incubated at different temperatures (i.e. 4, 22 and 36 °C) for up to two weeks. The effect of formulation supplementation and storage on aerosol characteristics was studied by laser diffraction and correlated with the sample conductivity., Results and Discussion: Nebulization of purified nanosuspensions resulted in droplet diameters of >7.0 µm. However, electrolyte supplementation and storage, which led to an increase in sample conductivity (>10-20 µS/cm), were capable of providing smaller droplet diameters during vibrating-mesh nebulization (≤5.0 µm). No relevant change of NP properties (i.e. size, morphology, remaining mass and molecular weight of the employed polymer) was observed when incubated at 22 °C for two weeks., Conclusion: Sample aging is an alternative to electrolyte supplementation in order to ameliorate the aerosol characteristics of degradable NP formulations when nebulized by vibrating-mesh technology.

Nanoparticle-based pharmaceutical products are currently finding their way onto the market as a popular strategy to improve the therapeutic efficacy of numerous drugs, hereunder medications for a targeted treatment of severe diseases (e.g., cancer). Drug-loaded polymer and lipid nanoparticles are typically produced via solvent-based methods and result in colloidal suspensions, which often suffer from physical and chemical instability (e.g., formation of aggregates) resulting in loss of functionality. There are various ways to stabilize such nanoparticle-based formulations including addition of ionic materials to provide electrostatic repulsion or polymer materials forming a steric barrier between the particles. However, for long-term stability often water needs to be removed to obtain a dry product. For this purpose atomization-based techniques such as spray-drying and spray freeze-drying are frequently used to remove water from the nanoparticle suspensions and to form tailored powder products (e.g., nanoembedded microparticles (NEMs)). NEMs provide an excellent vehicle for both stabilization of nanoparticles and delivery of the nanoparticles to their intended site of action. Excipients such as sugars and biocompatible polymers are used to prepare the surrounding, stabilizing matrix. Further, these "Trojan" vehicles are compatible with a wide range of therapeutic molecules, nanocarriers and applications for different routes of administration. The preparation, properties and stability of these NEMs are described in this review and their application and future development are discussed.

Polymer nanoparticles (NPs) offer versatile novel biological features of interest for drug delivery applications. "Ouzo diagrams" allowed for a systematic manufacture of specified colloidal formulations by the widely used nanoprecipitation process. Surprisingly, despite the well-documented relevance of the applied organic solvent for nanoprecipitation, its effect on the actual status of the "Ouzo region" was so far not studied. Herein, investigations were undertaken to account for the potential impact of the solvent type on the "Ouzo diagrams" for poly(lactide-co-glycolide) (PLGA) and tetrahydrofuran (THF), 1,4-dioxane, acetone and dimethyl sulfoxide (DMSO). The "Ouzo region" shifted considerably to higher polymer fractions upon solvent change (rank order: THF < 1,4-dioxane < acetone < DMSO). Assuming a one-to-one transformation of detached PLGA-bearing solvent droplets (droplet diameter for THF: ∼800 nm, 1,4-dioxane: ∼700 nm, acetone: ∼500 nm and DMSO: ∼300 nm) into non-divisible polymer aggregates upon solvent displacement, facilitated to predict the size of NPs found within the "Ouzo region" (size range: 40-200 nm). In conclusion, application of "Ouzo diagrams" is a valuable tool for drug delivery research and will most-likely replace the "trial-and-error"-approach to identify the operating window for the production of stable colloidal formulations by the nanoprecipitation technique.

The current study investigated the mechanisms involved in the process of biophysical inhibition of pulmonary surfactant by polymeric nanoparticles (NP). The minimal surface tension of diverse synthetic surfactants was monitored in the presence of bare and surface-decorated (i.e. poloxamer 407) sub-100 nm poly(lactide) NP. Moreover, the influence of NP on surfactant composition (i.e. surfactant protein (SP) content) was studied. Dose-elevations of SP advanced the biophysical activity of the tested surfactant preparation. Surfactant-associated protein C supplemented phospholipid mixtures (PLM-C) were shown to be more susceptible to biophysical inactivation by bare NP than phospholipid mixture supplemented with surfactant protein B (PLM-B) and PLM-B/C. Surfactant function was hindered owing to a drastic depletion of the SP content upon contact with bare NP. By contrast, surface-modified NP were capable of circumventing unwanted surfactant inhibition. Surfactant constitution influences the extent of biophysical inhibition by polymeric NP. Steric shielding of the NP surface minimizes unwanted NP-surfactant interactions, which represents an option for the development of surfactant-compatible nanomedicines., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Reasonable suspicion has accumulated that inhaled nano-scale particulate matter influences the biophysical function of the pulmonary surfactant system. Hence, it is evident to provide novel insights into the extent and mechanisms of nanoparticle-surfactant interactions in order to facilitate the fabrication of safe nanomedicines suitable for pulmonary applications. Negatively- and positively-charged poly(styrene) nanoparticles (diameters of ~100nm) served as model carriers. Nanoparticles were incubated with several synthetic and naturally-derived pulmonary surfactants to characterize the sensitivity of each preparation to biophysical inactivation. Changes in surface properties (i.e. adsorption and dynamic surface tension behavior) were monitored in a pulsating bubble surfactometer. Both nanoparticle formulations revealed a dose-dependent influence on the biophysical behavior of all investigated pulmonary surfactants. However, the surfactant sensitivity towards inhibition depended on both the carrier type, where negatively-charged nanoparticles showed increased inactivation potency compared to their positively-charged counterparts, and surfactant composition. Among the surfactants tested, synthetic mixtures (i.e. phospholipids, phospholipids supplemented with surfactant protein B, and Venticute®) were more susceptible to surface-activity inhibition as the more complex naturally-derived preparations (i.e. Alveofact® and large surfactant aggregates isolated from rabbit bronchoalveolar lavage fluid). Overall, nanoparticle characteristics and surfactant constitution both influence the extent of biophysical inhibition of pulmonary surfactants., (© 2013.)

Pulmonary application of drug-loaded polymeric nanosuspensions is achieved by vibrating-mesh nebulizers, which allow for an output of intact nanocarriers from the nebulizer reservoir. However, adequate aerosol droplet sizes are a prerequisite for an efficient pulmonary deposition. The current study discloses experimental findings useful to optimize the aerodynamic characteristics of formulations atomized by the vibrating-mesh nebulizers Aeroneb(®) Pro and eFlow(®)rapid. Parameters with significant influence on the aerosol droplet diameter were identified by a statistical design analysis rating size results from laser diffraction. Subsequently, the effect of selected biocompatible solutes on the aerodynamic performance of nebulized formulations was studied and correlated with their physicochemical properties. Vibrating-mesh generated aerosols were significantly affected by the dynamic viscosity and conductivity of the applied formulation. Consequently, an increase in viscosity enhancer (sucrose and poly(ethylene glycol)) or electrolyte (NaCl and CaCl2) content caused the droplet diameter to decrease. Similarly, purified nanosuspensions revealed a considerable decline in aerosol particle size upon excipient addition. However, coating of polymeric nanoparticles with poloxamer and poly(vinyl alcohol) was necessary to avoid electrolyte-induced nanoparticle aggregation. Overall, the current study emphasizes that supplementation of nanosuspensions with biocompatible solutes is an excellent means to tailor the characteristics of aerosols generated by vibrating-mesh technology., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Advances in preparation technologies for nanomedicines have provided novel formulations for pulmonary drug delivery. Application of drugs via the lungs can be considered as one of the most attractive implementations of nanoparticles for therapeutic use due to the unique anatomy and physiology of the lungs. The colloidal nature of nanoparticles provides important advantages to the formulation of drugs, which are normally difficult to administer due to poor stability or uptake, partly because nanoparticles protect the drug from the physiological milieu, facilitate transport across biological barriers and can offer controlled drug release. There are numerous methods for producing therapeutic nanoparticles, each with their own advantages and suitable application. Liquid atomization techniques such as spray drying can produce nanoparticle formulations in a dry powder form suitable for pulmonary administration in a direct one-step process. This chapter describes the different state-of-the-art techniques used to prepare drug nanoparticles (with special emphasize on spray drying techniques) and the strategies for administering such unique formulations to the pulmonary environment.

The development of novel formulations for controlled pulmonary drug delivery purposes has gained remarkable interest in medicine. Although nanomedicine represents attractive concepts for the treatment of numerous systemic diseases, scant information is available on the controlled drug release characteristics of colloidal formulations following lung administration, which might be attributed to the lack of methods to follow their absorption and distribution behavior in the pulmonary environment.In this chapter, we describe the methods of preparation and characterization of drug-loaded polymeric nanoparticles prepared from biodegradable charge-modified branched polyesters, aerosolization of the nanosuspensions using a vibrating-mesh nebulizer, and evaluation of the pulmonary pharmacokinetics (i.e., absorption and distribution characteristics) of the nanoscale drug delivery vehicles following aerosol delivery to the airspace of an isolated lung model. The disclosed methodology may contribute to the design of advanced colloids for the treatment of respiratory disorders.

Purpose: Nebulization represents one strategy to achieve pulmonary deposition of biodegradable nanoparticles. Besides stability as a key requirement to maintain functionality, the output of nanoparticles from the nebulizer needs to be considered to facilitate an efficient pulmonary therapy., Methods: Formulations nebulized by air-jet and vibrating-membrane technology were analyzed for their aerodynamic characteristics by laser diffraction. The nebulization stability of poly(D,L-lactide-co-glycolide) nanoparticles was assessed by dynamic light scattering. Moreover, several methods were employed to account for the shift in solute and NP reservoir concentration during nebulization., Results: Regardless of the formulation or nebulizer used generated aerosols all showed aerodynamic characteristics suitable for deep lung deposition. However, nanoparticles were prone to aggregation and concentrated during air-jet nebulization. The particle concentration effect was significantly pronounced in comparison to molecular solutes under the same nebulization conditions, due to nanoparticle aggregation and subsequent particle remainder in the reservoir. In contrast, vibrating-membrane technology did not affect nanoparticle integrity and reservoir concentration during nebulization, as the unaffected submicron particles passed through the tapered holes of the actuated plate., Conclusions: Aggregation and concentration effects during air-jet nebulization emphasize that nanosuspensions should preferably be delivered with a suitable vibrating-membrane device in order to ensure an effective pulmonary application.

Nanomedicine comprises a significant potential to approach the therapy of severe diseases. Knowledge of nanoparticle behavior at the target site would contribute to the development of specialized tools for respiratory medicine. Here, we were interested in the potential of micro-computed tomography (μCT) imaging to monitor the pulmonary distribution of polymeric nanoparticles. Composite nanoparticles were analyzed for physicochemical properties, morphology and composition. μCT was employed to visualize the pulmonary distribution of composite nanoparticles in an ex vivo lung model. Employed composite nanoparticles were composed of poly(styrene) cores coated by a thin shell of colloidal iron oxide. Particles were mainly located in the interstitial space and associated with pulmonary cells, as observed by light microscopy. μCT detected enhanced X-ray opacities in the conducting (linear pattern) and respiratory airways (aciniform X-ray attenuations). In conclusion, multifunctional nanoparticles will prompt the development of novel therapeutic and diagnostic tools in respiratory medicine., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Strategies for further advancements in pulmonary drug delivery include the application of colloidal carriers. Freeze-drying in the presence of lyoprotectants is a valuable approach to improve long-term stability of biodegradable nanoparticles, but possibly constrains aerosol generation after powder rehydration, when employing traditional nebulizers. Here, we investigated the impact of lyoprotectants on both output and aerodynamic performance of air-jet, ultrasonic, and vibrating-mesh nebulization. Additionally, changes in formulation temperature and concentration were monitored, to estimate physicochemical alterations of formulations during nebulization. The stability of poly(d,l-lactide-co-glycolide) nanoparticles was maintained for lyoprotectant/nanoparticle ratios above 5/1. All nebulized formulations displayed suitable output and aerodynamic characteristics for peripheral lung deposition. Air-jet- and ultrasonic nebulization was associated with considerable temperature (~10°C) and concentration changes (up to 156%) of the reservoir fluid, which consequently, caused significant shifting of surface tension and viscosity. By contrast, vibrating-mesh nebulization caused marginal temperature increase (~5°C) with no apparent signs of concentration. Thus, the changing surface tension and viscosity were fitted employing Eötvös' rule and the Andrade equation (R(2)>0.98), allowing to predict the physicochemical properties of each formulation for prolonged nebulization periods. In particular, vibrating-mesh nebulization seems to be promising for aerosol application of rehydrated freeze-dried biodegradable nanoparticles to the respiratory tract., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Pulmonary drug and gene delivery to the lung represents a non-invasive avenue for local and systemic therapies. However, the respiratory tract provides substantial barriers that need to be overcome for successful pulmonary application. In this regard, micro- and nano-sized particles offer novel concepts for the development of optimized therapeutic tools in pulmonary research. Polymeric nano-carriers are generally preferred as controlled pulmonary delivery systems due to prolonged retention in the lung. Specific manipulation of nano-carrier characteristics enables the design of "intelligent" carriers specific for modulation of the duration and intensity of pharmacological effects. New formulations should be tested for pulmonary absorption and distribution using more advanced ex vivo and in vivo models. The delivery of nano-carriers to the air-space enables a detailed characterization of the interaction between the carrier vehicle and the natural pulmonary environment. In summary, polymeric nanoparticles seem to be especially promising as controlled delivery systems and represent a solid basis for future advancement for pulmonary delivery applications., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The aim of this study is to investigate the feasibility and efficacy of PEC nanoparticles as delivery system for cancer chemotherapy. Assembly of paclitaxel-loaded nanoparticles with high loading efficiency and narrow-size distribution is successful. For non-invasive in vivo tracing, nanoparticle blends of chelator bearing poly(lactide) with PEC and PLGA are successfully prepared. Pharmacokinetic studies in mice reveal a twofold higher circulation time of PEC as compared to PLGA. A tumor model shows an accumulation of PEC NPs in cancerous tissue and a higher anti-tumor efficiency compared to the standard Taxol™, which is reflected in a significantly slower tumor growth compared to the NaCl control group., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The purpose of the present study was to transfer aqueous PEG-PCL-PEI nano-suspensions into dry ready-to-use formulations, suitable for delivery of siRNA. Therefore, freshly prepared nano-suspensions were lyophilised with glucose as lyoprotectant. Firstly, the required glucose concentration for sufficient stabilisation of unloaded carriers was determined via dynamic light scattering. Morphology of fresh and rehydrated carriers was visualised by cryogenic scanning electron microscopy. Subsequently, the feasibility of siRNA loading before and after lyophilisation was investigated. For both strategies complex diameter and in vitro transfection efficiency were determined and correlated to freshly prepared samples. Hydrodynamic diameter (95.2 ± 1.4 nm) and size distribution (0.132 ± 0.019) of unloaded nano-suspension were restored after rehydration by addition of ≥ 1.5% of glucose before lyophilisation. Moreover, after loading of rehydrated carriers with siRNA, no significant difference in complex size was observed as compared to freshly prepared ones. Stabilisation of pre-formed carrier/siRNA complexes during lyophilisation is feasible at elevated N/P (e.g. 20) and glucose concentrations above 5%. As determined via real-time-PCR, lyophilised samples were as active as freshly prepared ones regarding transfection efficiency. In conclusion, lyophilisation is an effective technique to produce physically stable PEG-PCL-PEI formulations. These general findings may be applicable to further particulate gene delivery systems to shelf ready-to-use formulations., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Numerous studies have addressed the controlled pulmonary drug delivery properties of colloidal particles. However, only scant information on the potential of spray-drying for submicron particle preparation is available. By exploiting the advantages of spray-drying, the characteristics of submicron particles can be optimized to meet the requirements necessary for lung application. Submicron particles were prepared from organic poly(d,l-lactide-co-glycolide) (PLGA) solutions, and composite particles were spray-dried from aqueous PLGA nanosuspensions. The feed concentration, as well as the spray-mesh diameter influenced the resulting particle sizes. Nanoparticles were virtually unaffected after spray-drying. The aerodynamic characteristics of both particle species revealed aerosol particle sizes suitable for deposition in the deep lungs (≤4μm). While the entrapped drug was released within ~90min from the composite particles, extensive drug retardation (~480min) was observed for PLGA particles spray-dried from organic solution. These results suggest that nanospray-drying is a convenient method to prepare submicron, controlled drug delivery vehicles useful for pulmonary application potentially allowing access to alveolar tissue., (Copyright © 2011. Published by Elsevier B.V.)

Biodegradable nanoparticles have gained tremendous attraction as carriers for controlled drug delivery to the lung. Despite numerous advances in the field, e.g. development of suitable methods for pulmonary administration of polymeric nanoparticles, a sufficient association of the therapeutic agent with the carrier system as well as drug release in a controlled fashion remain considerable challenges. Hence, this study examines the optimization of biodegradable sildenafil-loaded nanoparticle formulations intended for aerosol treatment of pulmonary hypertension. A factorial design analysis was employed to identify the important experimental factors involved in the preparation of nanoparticles by the solvent evaporation technique. The effect of tailored charge-modified branched polyesters on drug loading and in vitro drug release from nanoparticles was also evaluated. Moreover, colloidal stability of obtained nanoparticles was assessed, and stabilization of nanoparticles by lyophilization was accomplished without additional excipients. Essential experimental factors were identified and optimized to allow the preparation of nanoparticles composed of linear polyesters with a sildenafil content of ~5 wt.%. The in vitro drug release profile from these nanoparticles demonstrated a sustained release of sildenafil over ~90 min. Application of charge-modified branched polyesters enhanced the drug content in nanoparticles and drug release profile, according to the charge-density present in the employed polymer. Accordingly an increase in drug loading by a factor of ~1.4, a prolonged drug release profile from nanoparticles over ~240 min was achieved. Sildenafil release from nanoparticles made of linear and charge-modified branched polyesters was governed by a diffusion process. The obtained drug diffusion coefficients were decreased as the charge-density present in the applied polymer was increased, which promotes the strategy to improve drug loading and release rates by electrostatic interactions between polymer and drug. In addition, nanoparticles showed high colloidal stability in different media of importance for pulmonary application and were successfully stabilized by lyophilization. In conclusion, optimization of the nanoparticle preparation process together with the application of tailored polymeric materials facilitated the synthesis of promising drug carriers for sildenafil that permit a novel treatment modality for severe pulmonary hypertension., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Polymeric nanoparticles meet the increasing interest for drug delivery applications and hold great promise to improve controlled drug delivery to the lung. Here, we present a series of investigations that were carried out to understand the impact of formulation variables on the nebulization performance of novel biodegradable sildenafil-loaded nanoparticles designed for targeted aerosol therapy of life-threatening pulmonary arterial hypertension. Narrowly distributed poly(D,L-lactide-co-glycolide) nanoparticles (size: ∼200 nm) were prepared by a solvent evaporation technique using poly(vinyl alcohol) (PVA) as stabilizer. The aerodynamic and output characteristics using the Aeroneb Pro nebulizer correlated well with the dynamic viscosity of the employed fluids for nebulization. The nebulization performance was mainly affected by the amount of employed stabilizer, rather than by the applied nanoparticle concentration. Nanoparticles revealed physical stability against forces generated during aerosolization, what is attributed to the adsorbed PVA layer around the nanoparticles. Sildenafil was successfully encapsulated into nanoparticles (encapsulation efficiency: ∼80%). Size, size distribution and sildenafil content of nanoparticles were not affected by nebulization and the in vitro drug release profile demonstrated a sustained sildenafil release over ∼120 min. The current study suggests that the prepared sildenafil-loaded nanoparticles are a promising pharmaceutical for the therapy of pulmonary arterial hypertension., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Amphiphilic PEG-PCL-PEI triblock copolymers self-assemble into nano-scaled, positively charged, multifunctional carriers, suitable for drug and gene delivery. A set of block copolymers with varying hydrophilic/hydrophobic ratio (systematically altered at the borderline of micelle and particle forming polymers) was synthesized, characterized and assembled into carriers. A detailed structural characterization in the liquid state of these assemblies was carried out: carrier size was determined using dynamic light scattering, cryogenic scanning electron microscopy and atomic force microscopy. Nuclear magnetic resonance analyses elucidated carrier's core-shell structure. ζ-potential and thickness of the hydrophilic outer polymer shell were determined by laser Doppler anemometry. Subsequently the impact of carrier's structure on its features (stability and toxicity) was investigated. Polymers hydrophilic in nature formed small (<40 nm) micelle-like carriers, whilst hydrophobic polymers aggregated to larger particle-like assemblies (>100 nm). Monitoring carrier size as a function of initial polymer concentration clarified different assembly mechanisms. Shell thickness, colloidal stability and toxicity were found to depend on the length of the hydrophilic polymer block. Due to controllable size, charge, stability and toxicity, this class of novel carriers is a promising candidate for prospective co-delivery of drugs and nucleic acids., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Nanoparticulate drug carriers have been proposed for the targeted and controlled release of pharmaceuticals to the lung. However, inhaled particles may adversely affect the biophysical properties of pulmonary surfactant. This study examines the influence of polymeric nanoparticles with distinct physicochemical properties on the adsorption and dynamic surface tension lowering properties of pulmonary surfactant. Nanoparticles had a mean size of 100 nm with narrow size distributions. Although poly(styrene) and poly(D,L-lactide-co-glycolide) nanoparticles revealed a dose-dependent influence on biophysics of pulmonary surfactant, positively-charged nanoparticles made from poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) showed no effect. This behavior is attributed to the differences in ζ-potential and surface hydrophobicity, which in turn involves an altered adsorption pattern of the positively charged surfactant proteins to the nanoparticles. This study suggests that polymeric nanoparticles do not substantially affect the biophysical properties of pulmonary surfactant and may be a viable drug-delivery vehicle for the inhalative treatment of respiratory diseases., From the Clinical Editor: Inhaled nanoparticulate drug carriers may adversely affect the biophysical properties of pulmonary surfactant. In this study the influence of polymeric nanoparticles was characterized from this standpoint, with the conclusion that polymeric nanoparticles do not substantially affect the biophysical properties of pulmonary surfactant and may be viable drug-delivery vehicles for inhalational treatment., (Copyright © 2011 Elsevier Inc. All rights reserved.)

As biodegradable nanoparticles meet with increasing interest for drug delivery applications, a series of investigations were carried out to understand the mechanism of the formation of drug-loaded nanoparticles using the solvent displacement method. Although previous explanations referred to Marangoni convection as the driving force for nanoprecipitation, recent publications describing the so-called "ouzo effect" sparked these current studies using a novel negatively charged polymer, poly(vinyl sulfonate-co-vinyl alcohol)-graft-poly(D,L-lactide-co-glycolide) (P(VS-VA)-g-PLGA), and a positively charged model drug, salbutamol. Interfacial tension did not influence the nanoparticle formation as would be expected if governed by Marangoni convection, but ternary phase diagrams outlined the so-called "ouzo regions" defining the polymer and solvent concentrations leading to stable nanoparticle suspensions for both this novel polymer and unmodified poly(D,L-lactide-co-glycolide) (PLGA). Physicochemical properties, morphology and drug loading of the nanoparticles were analyzed, and stable P(VS-VA)-g-PLGA nanoparticles with and without salbutamol ranged in size from 59-191nm. The "ouzo region" phase diagram boundaries shifted considerably upon drug loading, which can be explained by the increased solubility of the polymer-drug complex. This behavior necessitated a substantial adjustment of polymer concentrations required to produce drug-loaded nanoparticles with characteristics comparable to blank nanoparticles. In conclusion, the use of "ouzo diagrams" is a beneficial tool to manufacture nanoparticles with specified physicochemical properties by the solvent displacement method.

The use of colloidal carrier systems for pulmonary drug delivery is an emerging field of interest in nanomedicine. The objective of this study was to compare the pulmonary absorption and distribution characteristics of the hydrophilic model drug 5(6)-carboxyfluorescein (CF) after aerosolization as solution or entrapped into nanoparticles in an isolated rabbit lung model (IPL). CF-nanoparticles were prepared from a new class of biocompatible, fast degrading, branched polyesters by a modified solvent displacement method. Physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, stability of nanoparticles to nebulization, aerosol characteristics as well as pulmonary dye absorption and distribution profiles after nebulization in an IPL were investigated. CF-nanoparticles were spherical in shape with a mean particle size of 195.3+/-7.1nm, a polydispersity index of 0.225+/-0.017 and a zeta-potential of -28.3+/-0.3mV. Encapsulation efficiencies of CF were as high as about 60% (drug loading of 3% (w/w)); 90% of the entrapped CF were released during the first 50min in vitro. Nanoparticle characteristics were not significantly affected by the aerosolization process utilizing a vibrating mesh nebulizer. After deposition of equal amounts of CF in the IPL, less CF was detected in the perfusate for CF-nanoparticles (plateau concentration 9.2+/-2.4ng/ml) when compared to CF aerosolized from solution (17.7+/-0.8ng/ml). In conclusion, the data suggest that inhalative delivery of biodegradable nanoparticles may be a viable approach for pulmonary drug delivery. Moreover, a targeting effect to the lung tissue is claimed.

The current study describes a convenient method for a direct size classification of spray-dried powders, which is of general interest for diverse applications in drug delivery. Accordingly, the time-consuming “trial-and-error” approach to identify critical formulation and process parameters influencing the final product specifications is replaced by a final fractionation step of the dried particles by inertial impaction. When employing the “original” vibrational spray-dryer (i.e., Nano Spray-Dryer B-90, Büchi) it was evident that both the liquid feed characteristics (e.g., concentration of dissolved solids) and process parameters (e.g., nozzle type and spray-rate) significantly affected the particle size and size distribution of generated sildenafil-loaded poly(lactide- co -glycolide) microparticles (particle size: ~ 4–~ 11 μm; particle size distribution ( span ): ~ 1.3–~ 2.2). The said formulations showed prolonged in vitro drug release properties with mean dissolution times (MDTs) ranging between ~ 4 and ~ 14 h. By contrast, replacing the electrostatic particle collector of the vibrational spray-dryer by a Next Generation Impactor enabled a direct size classification of spray-dried microparticles according to their aerodynamic behavior. Formulations collected from the individual impactor stages exhibited a defined particle size (i.e., stages I, II, III and IV with 7.8, 4.5, 3.0 and 2.1 μm, respectively) and were significantly narrowly distributed ( span : ≤ 1.2) than the non-fractionated controls. Likewise, fractionated formulations were characterized by a sustained sildenafil in vitro release behavior (MDT: ~ 1.5–~ 7 h). Overall, regardless of the primary particle size and size distribution of spray-dried powders, desired size characteristics can be achieved by a terminal size classification by inertial impaction. Hence, the described approach provides spray-dried products meeting the specific requirements of the intended application (e.g., prolonged drug delivery to the lungs). [ABSTRACT FROM AUTHOR]

Abstract: Polymeric nanoparticles meet the increasing interest for drug delivery applications and hold great promise to improve controlled drug delivery to the lung. Here, we present a series of investigations that were carried out to understand the impact of formulation variables on the nebulization performance of novel biodegradable sildenafil-loaded nanoparticles designed for targeted aerosol therapy of life-threatening pulmonary arterial hypertension. Narrowly distributed poly(d,l-lactide-co-glycolide) nanoparticles (size: ∼200nm) were prepared by a solvent evaporation technique using poly(vinyl alcohol) (PVA) as stabilizer. The aerodynamic and output characteristics using the Aeroneb® Pro nebulizer correlated well with the dynamic viscosity of the employed fluids for nebulization. The nebulization performance was mainly affected by the amount of employed stabilizer, rather than by the applied nanoparticle concentration. Nanoparticles revealed physical stability against forces generated during aerosolization, what is attributed to the adsorbed PVA layer around the nanoparticles. Sildenafil was successfully encapsulated into nanoparticles (encapsulation efficiency: ∼80%). Size, size distribution and sildenafil content of nanoparticles were not affected by nebulization and the in vitro drug release profile demonstrated a sustained sildenafil release over ∼120min. The current study suggests that the prepared sildenafil-loaded nanoparticles are a promising pharmaceutical for the therapy of pulmonary arterial hypertension. [Copyright &y& Elsevier]

Abstract: Nanoparticulate drug carriers have been proposed for the targeted and controlled release of pharmaceuticals to the lung. However, inhaled particles may adversely affect the biophysical properties of pulmonary surfactant. This study examines the influence of polymeric nanoparticles with distinct physicochemical properties on the adsorption and dynamic surface tension lowering properties of pulmonary surfactant. Nanoparticles had a mean size of 100 nm with narrow size distributions. Although poly(styrene) and poly(D,L-lactide-co-glycolide) nanoparticles revealed a dose-dependent influence on biophysics of pulmonary surfactant, positively-charged nanoparticles made from poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) showed no effect. This behavior is attributed to the differences in ζ-potential and surface hydrophobicity, which in turn involves an altered adsorption pattern of the positively charged surfactant proteins to the nanoparticles. This study suggests that polymeric nanoparticles do not substantially affect the biophysical properties of pulmonary surfactant and may be a viable drug-delivery vehicle for the inhalative treatment of respiratory diseases. From the Clinical Editor: Inhaled nanoparticulate drug carriers may adversely affect the biophysical properties of pulmonary surfactant. In this study the influence of polymeric nanoparticles was characterized from this standpoint, with the conclusion that polymeric nanoparticles do not substantially affect the biophysical properties of pulmonary surfactant and may be viable drug-delivery vehicles for inhalational treatment. [Copyright &y& Elsevier]

Polymeric nanoparticles meet the increasing interest for inhalation therapy and hold great promise to improve controlled drug delivery to the lung. The synthesis of tailored polymeric materials and the improvement of nanoparticle preparation techniques facilitate new perspectives for the treatment of severe pulmonary diseases. The physicochemical properties of such drug delivery systems can be investigated using conventional analytical procedures. However, the assessment of the controlled drug release properties of polymeric nanoparticles in the lung remains a considerable challenge. In this context, the isolated lung technique is a promising tool to evaluate the drug release characteristics of nanoparticles intended for pulmonary application. It allows measurements of lung-specific effects on the drug-release properties of pulmonary delivery systems. Ex vivo models are thought to overcome the common obstacles of in vitro tests and offer more reliable drug release and distribution data that are closer to the in vivo situation. [ABSTRACT FROM AUTHOR]

3D printing allows a rapid and inexpensive manufacturing of custom made and prototype devices. Micromixers are used for rapid and controlled production of nanoparticles intended for therapeutic delivery. In this study, we demonstrate the fabrication of micromixers using computational design and 3D printing, which enable a continuous and industrial scale production of nanocomplexes formed by electrostatic complexation, using the polymers poly(diallyldimethylammonium chloride) and poly(sodium 4-styrenesulfonate). Several parameters including polymer concentration, flow rate, and flow ratio were systematically varied and their effect on the properties of nanocomplexes was studied and compared with nanocomplexes prepared by bulk mixing. Particles fabricated using this cost effective device were equally small and homogenous but more consistent and controllable in size compared with those prepared manually via bulk mixing. Moreover, each micromixer could process more than 2 liters per hour with unaffected performance and the setup could easily be scaled-up by aligning several micromixers in parallel. This demonstrates that 3D printing can be used to prepare disposable high-throughput micromixers for production of therapeutic nanoparticles. [ABSTRACT FROM AUTHOR]

The present study was conducted to examine the feasibility of nimodipine-loaded PLGA microparticles suspended in Tisseel™ fibrin sealant as an in situ forming depot system. This device locally placed can be used for the treatment of vasospasm after a subarachnoid hemorrhage. Microparticles were prepared via spray-drying by using the vibration mesh spray technology of Nano Spray Dryer B-90. Spherically shaped microparticles with different loadings and high encapsulation efficiencies of 93.3–97.8% were obtained. Depending on nimodipine loading (10–40%), the particle diameter ranged from 1.9±1.2μm to 2.4±1.3μm. Thermal analyses using DSC revealed that nimodipine is dissolved in the PLGA matrix. Also, fluorescent dye loaded microparticles were encapsulated in Tisseel™ to examine the homogeneity of particles. 3D-pictures of the in situ forming devices displayed uniform particle homogeneity in the sealant matrix. Drug release was examined by fluorescence spectrophotometry which demonstrated a drug release proportional to the square root of time. A prolonged drug release of 19.5h was demonstrated under in vitro conditions. Overall, the nimodipine in situ forming device could be a promising candidate for the local treatment of vasospasm after a subarachnoid hemorrhage. [ABSTRACT FROM AUTHOR]