Poly-(ethylene glycol) modified gelatin nanoparticles for sustained delivery of the anti-inflammatory drug Ibuprofen-Sodium: An in vitro and in vivo analysis

The limited bioavailability and rapid clearance of the anti-inflammatory drug Ibuprofen Sodium (IbS) necessitates repeated drug administration. To address this, injectable IbS loaded PEGylated gelatin nanoparticles (PIG NPs) of size ~ 200 nm and entrapment efficiency ~ 70%, providing sustained release in vitro were prepared by a modified two-step desolvation process. The developed nanomedicine, containing a range of IbS concentrations up to 1 mg/mL proved to be non-toxic, hemocompatible and non-immunogenic, when tested through various in vitro assays and was reaffirmed by in vivo cytokine analysis. HPLC analysis of intravenously administered PIG NPs showed a sustained release of IbS for ~ 4 days with improved bioavailability and pharmacokinetics when compared to bare IbS and IbS-loaded non-PEGylated GNPs. Histological analysis of liver and kidney revealed tissue integrity as in the control, indicating biocompatibility of PIG NPs. The results demonstrate improved plasma half-life of IbS when encapsulated within nanogelatin, thereby aiding reduction in its frequency of administration.From the Clinical EditorIn this preclinical study, improved plasma half-life of ibuprofen sodium was demonstrated when encapsulated within PEGylated gelatin nanoparticles of ~200 nm size, expected to lead to reduced frequency of administration in future clinical applications.     

Antitumoral activity of camptothecin-loaded nanoparticles in 9L rat glioma model

Camptothecin (CPT), a plant alkaloid, is a potent anticancer drug in cell culture studies but it is clinically inactive due to rapid hydrolysis under physiological conditions. The drug exists in two forms depending on the pH value, an active lactone form at pH below 5 and an inactive carboxylate form at basic pH and this is a reversible reaction. In this study, nanoparticulate delivery systems were developed with either amphiphilic cyclodextrins, poly(lactide-co-glycolide) or poly-?-caprolactone in order to maintain the active lactone form and prevent the drug from hydrolysis. All nanoparticles were prepared with nanoprecipitation technique. Mean particle sizes were 130–280 nm and surface charges were negative. The encapsulation efficiency was significantly higher for amphiphilic cyclodextrin nanoparticles when compared to polymeric nanoparticles. Nanoparticle formulations based on cyclodextrins showed a controlled release profile extended up to 12 days. 6-O-Capro-β-cyclodextrin (1.44 μg/60 μL CPT) and concentrated 6-O-Capro-β-cyclodextrin (2.88 μg/60 μL CPT) nanoparticles significantly modified the growth or lethality of the 9L gliomas, since the median survival time was 26 days for the untreated group and between 27 and 33 days for amphiphilic cyclodextrin nanoparticle groups. These results indicate that, CPT-loaded amphiphilic cyclodextrin nanoparticles may provide a promising carrier system for the effective delivery of CPT in comparison to polymeric analogues.     

The chemotherapeutic potential of doxorubicin-loaded PEG-b-PLGA nanopolymersomes in mouse breast cancer model

Vesicles of mPEG-PLGA block copolymer were developed to deliver a therapeutic quantity of doxorubicin (DOX) for breast cancer treatment. The DOX-loaded nanoparticles (NPs) were prepared by the pH-gradient method and then evaluated in terms of morphology, size, DOX encapsulation efficiency and in vitro drug release mechanism.The PEG-PLGA nanopolymersomes were 134 ± 1.2 nm spherical NPs with a narrow size distribution (PDI = 0.121). DOX was entrapped in mPEG-PLGA nanopolymersomes with an encapsulation efficiency and a loading content of 91.25 ± 4.27% and 7.3 ± 0.34%, respectively. The DOX-loaded nanopolymersomes were found to be stable, demonstrating no significant change in particle size and encapsulation efficiency (EE%) during the 6-month storage period of the lyophilized powder at 4 °C. The nanopolymersomes sustained the release of DOX. In cytotoxicity studies of 4T1 cell line samples, free DOX showed a higher cytotoxicity (IC50 = 1.76 μg/mL) than did DOX-loaded nanopolymersomes (15.82 μg/mL) in vitro. In order to evaluate the antitumor efficacy and biodistribution of DOX-loaded nanopolymersomes, murine breast tumors were established on the BALB/c mice, and in vivo studies were performed. The obtained results demonstrated that the prepared drug delivery system was highly effective against a murine breast cancer tumor model and successfully accumulated in the tumor site through an enhanced permeation and retention mechanism.In vivo studies also proved that DOX-loaded nanopolymersomes are stable in blood circulation and could be considered a promising and effective DOX delivery system for breast cancer treatment.     

Superparamagnetic iron oxide nanoparticles (SPIONs)-loaded Trojan microparticles for targeted aerosol delivery to the lung

Targeted aerosol delivery to specific regions of the lung may improve therapeutic efficiency and minimise unwanted side effects. Targeted delivery could potentially be achieved with porous microparticles loaded with superparamagnetic iron oxide nanoparticles (SPIONs)—in combination with a target-directed magnetic gradient field. The aim of this study was to formulate and evaluate the aerodynamic properties of SPIONs-loaded Trojan microparticles after delivery from a dry powder inhaler. Microparticles made of SPIONs, PEG and hydroxypropyl-β-cyclodextrin (HPβCD) were formulated by spray drying and characterised by various physicochemical methods. Aerodynamic properties were evaluated using a next generation cascade impactor (NGI), with or without a magnet positioned at stage 2. Mixing appropriate proportions of SPIONs, PEG and HPβCD allowed Trojan microparticle to be formulated. These particles had a median geometric diameter of 2.8 ± 0.3 μm and were shown to be sensitive to the magnetic field induced by a magnet having a maximum energy product of 413.8 kJ/m³. However, these particles, characterised by a mass median aerodynamic diameter (MMAD) of 10.2 ± 2.0 μm, were considered to be not inhalable. The poor aerodynamic properties resulted from aggregation of the particles. The addition of (NH₄)₂CO₃ and magnesium stearate (MgST) to the formulation improved the aerodynamic properties of the Trojan particles and resulted in a MMAD of 2.2 ± 0.8 μm. In the presence of a magnetic field on stage 2 of the NGI, the amount of particles deposited at this stage increased 4-fold from 4.8 ± 0.7% to 19.5 ± 3.3%. These Trojan particles appeared highly sensitive to the magnetic field and their deposition on most of the stages of the NGI was changed in the presence compared to the absence of the magnet. If loaded with a pharmaceutical active ingredient, these particles may be useful for treating localised lung disease such as cancer nodules or bacterial infectious foci.     

Synthesis and study of controlled release of ofloxacin from polyester conjugates

This research compares the anti-tumor efficacy of paclitaxel delivered intratumorally in PLGA nanoparticles, microparticles, or the commercial Paclitaxel Injection^®. The hypothesis of the research is that larger PLGA microparticles adhere to mucus on the cell surface, release paclitaxel locally, and enhance cellular association of paclitaxel. PLGA-paclitaxel particles of mean diameters 315 nm, 1 μm, and 10 μm were prepared and their drug content, in vitro release, and cellular association of paclitaxel into 4T1 cells quantified. These particles were injected intratumorally into tumor xenografts, and the tumor volumes monitored over 13 days. Mean tumor volumes of the groups that received placebo and the 315 nm nanoparticles increased 2 and 1.5 times, respectively. Tumor growth was arrested in groups that received 1 μm and 10 μm microparticles. Additional cell culture studies were performed to test the hypothesis. The size-dependent increase in cellular concentration of paclitaxel was independent of duration of incubation of PLGA particles with 4T1 cells, and was enhanced 1.5 times by coating the particles or 4T1 cells with mucin. These particles were not internalized by clathrin-mediated endocytosis or macropinocytosis. In conclusion, PLGA microparticles sustained drug release, increased cellular concentration, and enhanced anti-tumor efficacy of paclitaxel compared to nanoparticles and Paclitaxel Injection^®.     

Spinning Disc Processing Technology: Potential for Large-Scale Manufacture of Chitosan Nanoparticles

Mass production of nanoparticles using a reliable cost-effective approach is a challenge in the pharmaceutical industry. In this study, the spinning disc processing (SDP) technology was used to fabricate chitosan nanoparticles, with a view to commercially produce chitosan nanoparticle-based drug delivery platforms. Chitosan solution (0.25%, w/v, in dilute acid, 27.5 mL, 1.5 mL/s) was intensely mixed with sodium tripolyphosphate solution (0.10%, w/v, in water, 20mL, 1.1mL/s) on the spinning disc (1000rpm). Transmission electron microscopy and dynamic light scattering data confirmed that the nanoparticles (20 ± 3 nm) were comparable in size and shape to those synthesised using a beaker and magnetic stirrer (31 ± 13 nm). Larger nanoparticles (131 ± 5 nm) were produced by increasing the chitosan and TPP feed concentrations to 0.5% and 0.125%, respectively. Drug loading further increased the size of the nanoparticles, with N-acetyl cysteine (NAC) having a greater effect (403 ± 4 nm) than paracetamol (165 ± 4 nm). Co-loading of both drugs increased the size of the particles to the micron range. In conclusion, the SDP is a robust technology capable of expanding the production of blank and drug-loaded chitosan nanoparticles for the biomedical and pharmaceutical industries.     

New Co-Spray-Dried Tobramycin Nanoparticles-Clarithromycin Inhaled Powder Systems for Lung Infection Therapy in Cystic Fibrosis Patients

The aim of the study was to produce easily dispersible and porous agglomerates of tobramycin nanoparticles surrounded by a matrix composed of amorphous clarithromycin. Nanoparticles of tobramycin with a median particle size of about 400 nm were produced by high-pressure homogenisation. The results from the spray-dried powders showed that the presence of these nanoparticles enhanced powder dispersion during inhalation. Moreover, local drug deposition profiles were similar for the two antibiotics, allowing them to reach the target simultaneously. The dissolution-release profiles showed that tobramycin and clarithromycin might dissolve without any difficulties in the lung. The fine particle fraction increased from 35% and 31% for the physical blend for tobramycin and clarithromycin, respectively, to 63% and 62% for the spray-dried formulation containing nanoparticles. These new formulations, showing high lung deposition properties, even at sub-optimal inspiratory flow rates, represent a great possibility for advancing pulmonary drug administration and local therapy of lung infections.     

Polyelectrolyte Stabilized Drug Nanoparticles via Flash Nanoprecipitation: A Model Study With β-Carotene

Polyelectrolyte protected β-carotene nanoparticles (nanosuspensions) with average diameter of < 100 nm were achieved by turbulent mixing and flash nanoprecipitation (FNP). Three types of multi-amine functional polyelectrolytes, ε-polylysine (ε-PL), poly(ethylene imine) (PEI), and chitosan, were investigated to electrosterically protect the nanoparticles. Particle size and distribution were measured by dynamic light scattering (DLS); particles were imaged via scanning electron microscopy (SEM) and cryogenic transmission electron microscopy (cryo-TEM). Low pH and high polyelectrolyte molecular weight gave the smallest and most stable particles. High drug loading capacity, > 80 wt%, was achieved by using either PEI or chitosan. X-ray diffraction (XRD) patterns showed that β-carotene nanoparticles were amorphous. These findings open the way for utilization of FNP for preparation of nanoparticles with enhanced bioavailability for highly water insoluble drugs.     

Long-circulating self-assembled cholesteryl albumin nanoparticles enhance tumor accumulation of hydrophobic anticancer drug

The objective of this study was to develop an albumin nanoparticle with improved stability and drug loading capacity. Generation of nanomaterials having physiologically stable and high potential for drug delivery is still challenging. Herein we synthesized cholesteryl albumin conjugate using N,N-disuccinimidyl carbonate coupling reagent and prepared paclitaxel-loaded cholesteryl albumin nanoparticle (PTX-Chol-BSA) by self-assembly with the mean hydrodynamic diameter of 147.6 ± 1.6 nm and with high loading capacity. PTX-Chol-BSA nanoparticle showed much higher colloidal stability than a simple complex of PTX and BSA (PTX–BSA) and sustained release profile. PTX-Chol-BSA nanoparticles exhibited greater cellular uptake and cytotoxicity in B16F10 and MCF-7 cancer cell lines, as compared with PTX in Cremophor EL/ethanol (PTX-Cre/EtOH) and PTX–BSA formulations. A pharmacokinetic study in tumor-bearing mice showed that the area under the concentration–time curve (AUC_{0–8 h}) following the administration of PTX-Chol-BSA was 1.6–2-fold higher than those following the administration of PTX-Cre/EtOH and PTX–BSA. In addition, the tumor AUC_{0–8 h} of PTX-Chol-BSA was around 2-fold higher than that of PTX–BSA. Furthermore, in vivo antitumor efficacy results revealed that PTX-Chol-BSA nanoparticles have greater antitumor efficacy. In conclusion, we demonstrated the potential of PTX-Chol-BSA nanoparticles for anti-tumor chemotherapy, with enhanced in vitro and in vivo behaviors, as compared to PTX–BSA and PTX-Cre/EtOH.     

PHARMACEUTICAL TECHNOLOGY: Micro-CT Analysis of Matrix-Type Drug Delivery Devices and Correlation With Protein Release Behaviour

A series of matrix-type drug delivery devices comprising a continuous phase of microporous poly(ε-caprolactone) (PCL) and a dispersed phase of protein particles (gelatin) with defined size ranges (45–90, 90–125 and 125–250 μm) were produced by rapidly cooling suspensions in dry ice followed by solvent extraction from the hardened material. High protein loadings (38–44%, w/w) were achieved and highly efficient protein release (90% of the initial load) was obtained over time periods of 3–11 days depending on particle loading and size range. The duration of protein release was extended from 3 to 11 days reducing the protein load. Quantitative analysis of Micro-CT images identified a three to four times increase in the population of sub-40 mm pores in those matrices which gave rise to accelerated protein release in 24 h (40% rising to 80%) and reduced duration of protein release (11-3 days). Formation of a high density of channels and fissures (connects) between the particles is indicated, which facilitate fluid ingress and diffusion of solubilised protein molecules. Micro-CT analysis also confirmed the uniformity of particle distribution in the matrices and provided measurements of macroporosity within 530% of the theoretical value for materials displaying irregular shaped macropores larger than 90 mm. These findings demonstrate the utility of Micro-CT for optimising the formulation and performance of matrix-type delivery devices for macromolecular entities.     

Pulmonary delivery of pyrazinamide-loaded large porous particles

We have improved the aerodynamic properties of pyrazinamide loaded large porous particles (PZA-LPPs) designed for pulmonary delivery. To overcome the segregation of the different components occurring during the spray drying process and to obtain homogeneous LPPs, spray drying parameters were modified to decrease the drying speed. As a result, good aerodynamic properties for lung delivery were obtained with a fine particle fraction (FPF) of 40.1 ± 1.0%, an alveolar fraction (AF) of 29.6 ± 3.1%, a mass median aerodynamic diameter (MMAD_aer) of 4.1 ± 0.2 μm and a geometric standard deviation (GSD) of 2.16 ± 0.16. Plasma and epithelial lining fluid (ELF) concentrations of pyrazinamide were evaluated after intratracheal insufflation of PZA-LPPs (4.22 mg kg⁻¹) into rats and compared to intravenous administration (iv) of a pyrazinamide solution (5.82 mg kg⁻¹). The in vivo pharmacokinetic evaluation of PZA-LPPs in rats reveals that intratracheal insufflation of PZA-LPPs leads to a rapid absorption in plasma with an absolute bioavailability of 66%. This proves that PZA-LPPs dissolve fast upon deposition and that PZA crosses efficiently the lung barrier to reach the systemic circulation. PZA concentrations were 1.28-fold higher in ELF after intratracheal administration than after iv administration and the ratio of ELF concentrations over plasma concentrations was 2-fold greater. Although these improvements are moderate, lung delivery of PZA appears an interesting alternative to oral delivery of the molecule and should now be tested in an infected animal model to evaluate its efficacy against Mycobacterium tuberculosis.     

Efficient drug-delivery using magnetic nanoparticles — biodistribution and therapeutic effects in tumour bearing rabbits

To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug-carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial from being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterial. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter < 200 nm) accumulates the chemotherapeutic drug mitoxantrone efficiently in tumours. With MDT we observed the following drug accumulations relative to the recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (P = 0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies.From the Clinical EditorThis team of investigators studied drug carrying nanoparticles for magnetic drug targeting (MDT), demonstrating the importance of intra-arterial administration resulting in improved clinical outcomes in the studied animal model compared with intra-venous.     

Folate-mediated poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) nanoparticles for targeting drug delivery

A novel targeting drug delivery system (TDDS) has been developed. Such a TDDS was prepared by W₁/O/W₂ solvent extraction/evaporation method, adopting poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) [P(HB-HO)] as the drug carrier, folic acid (FA) as the targeting ligand, and doxorubicin (DOX) as the model anticancer drug. The average size, drug loading capacity and encapsulation efficiency of the prepared DOX-loaded, folate-mediated P(HB-HO) nanoparticles (DOX/FA–PEG–P(HB-HO) NPs) were found to be around 240 nm, 29.6% and 83.5%. The in vitro release profile displayed that nearly 50% DOX was released in the first 5 days. The intracellular uptake tests of the nanoparticles (NPs) in vitro showed that the DOX/FA–PEG–P(HB-HO) NPs were more efficiently taken up by HeLa cells compared to non-folate-mediated P(HB-HO) NPs. In addition, DOX/FA–PEG–P(HB-HO) NPs (IC₅₀ = 0.87 μM) showed greater cytotoxicity to HeLa cells than other treated groups. In vivo anti-tumor activity of the DOX/FA–PEG–P(HB-HO) NPs showed a much better therapeutic efficacy in inhibiting tumor growth, and the final mean tumor volume was 178.91 ± 17.43 mm³, significantly smaller than normal saline control group (542.58 ± 45.19 mm³). All these results have illustrated that our techniques for the preparing of DOX/FA–PEG–P(HB-HO) NPs developed in present work are feasible and these NPs are effective in selective delivery of anticancer drug to the folate receptor-overexpressed cancer cells. The new TDDS may be a competent candidate in application in targeting treatment of cancers.     

Intracellular trafficking of nuclear localization signal conjugated nanoparticles for cancer therapy

Doxorubicin (DOX) is an anticancer drug with an intracellular site of action in the nucleus. For high antitumour activity, it should be effectively internalized into the cancer cells and accumulate in the nucleus. In this study, we have prepared a nuclear localization signal conjugated doxorubicin loaded Poly (d,l-lactide-co-glycolide) nanoparticles (NPs), to deliver doxorubicin to the nucleus efficiently. Physico-chemical characterization of these NPs showed that the drug is molecularly dispersed in spherical and smooth surfaced nanoparticles. NPs (～226 nm in diameter, 46% encapsulation efficiency) under in vitro conditions exhibited sustained release of the encapsulated drug (63% release in 60 days). Cell cytotoxicity results showed that NLS conjugated NPs exhibited comparatively lower IC₅₀ value (2.3 μM/ml) than drug in solution (17.6 μM/ml) and unconjugated NPs (7.9 μM/ml) in breast cancer cell line MCF-7 as studied by MTT assay. Cellular uptake studies by confocal laser scanning microscopy (CLSM) and fluorescence spectrophotometer showed that greater amount of drug is targeted to the nucleus with NLS conjugated NPs as compared to drug in solution or unconjugated NPs. Flow cytometry experiments results showed that NLS conjugated NPs are showing greater cell cycle (G2/M phase) blocking and apoptosis than native DOX and unconjugated NPs. In conclusion, these results suggested that NLS conjugated doxorubicin loaded NPs could be potentially useful as novel drug delivery system for breast cancer therapy.     

PEGylation of cationic,shell-crosslinked-knedel-like nanoparticles modulates inflammation and enhances cellular uptake in the lung

The airway provides a direct route for administration of nanoparticles bearing therapeutic or diagnostic payloads to the lung, however optimization of nanoplatforms for intracellular delivery remains challenging. Poly(ethylene glycol) (PEG) surface modification improves systemic performance but less is known about PEGylated nanoparticles administered to the airway. To test this, we generated a library of cationic, shell crosslinked knedel-like nanoparticles (cSCKs), including PEG (1.5 kDa PEG; 2, 5, 10 molecules/polymer arm) on the outer shell. Delivery of PEGylated cSCK to the mouse airway showed significantly less inflammation in a PEG dose-dependent manner. PEGylation also enhanced the entry of cSCKs in lung alveolar epithelial cells and improved surfactant penetration. The PEGylation effect could be explained by the altered mechanism of endocytosis. While non-PEGylated cSCKs used the clathrin-dependent route for endocytosis, entry of PEGylated cSCK was clathrin-independent. Thus, nanoparticle surface modification with PEG represents an advantageous design for lung delivery.From the Clinical EditorIn this study, the effects of PEGylation were studied on cross linked knedel-like nanoparticles in drug delivery through the lungs, demonstrating less airway inflammation in the studied model than with non-PEGylated nanoparticles, which suggests an overall favorable profile of PEGylated nanoparticles for alveolar delivery.     

Towards the bioequivalence of pressurised metered dose inhalers 1: Design and characterisation of aerodynamically equivalent beclomethasone dipropionate inhalers with and without glycerol as a non-volatile excipient

A series of semi-empirical equations were utilised to design two solution based pressurised metered dose inhaler (pMDI) formulations, with equivalent aerosol performance but different physicochemical properties. Both inhaler formulations contained the drug, beclomethasone dipropionate (BDP), a volatile mixture of ethanol co-solvent and propellant (hydrofluoroalkane-HFA). However, one formulation was designed such that the emitted aerosol particles contained BDP and glycerol, a common inhalation particle modifying excipient, in a 1:1 mass ratio. By modifying the formulation parameters, including actuator orifice, HFA and metering volumes, it was possible to produce two formulations (glycerol-free and glycerol-containing) which had identical mass median aerodynamic diameters (2.4 μm ± 0.1 and 2.5 μm ± 0.2), fine particle dose (⩽5 μm; 66 μg ± 6 and 68 μg ± 2) and fine particle fractions (28% ± 2% and 30% ± 1%), respectively. These observations demonstrate that it is possible to engineer formulations that generate aerosol particles with very different compositions to have similar emitted dose and in vitro deposition profiles, thus making them equivalent in terms of aerosol performance. Analysis of the physicochemical properties of each formulation identified significant differences in terms of morphology, thermal properties and drug dissolution of emitted particles. The particles produced from both formulations were amorphous; however, the formulation containing glycerol generated particles with a porous structure, while the glycerol-free formulation generated particles with a primarily spherical morphology. Furthermore, the glycerol-containing particles had a significantly lower dissolution rate (7.8% ± 2.1%, over 180 min) compared to the glycerol-free particles (58.0% ± 2.9%, over 60 min) when measured using a Franz diffusion cell. It is hypothesised that the presence of glycerol in the emitted aerosol particles altered solubility and drug transport, which may have implications for BDP pharmacokinetics after deposition in the respiratory tract.     

Development of a nanoparticle-based influenza vaccine using the PRINT® technology

Historically it is known that presentation of vaccine antigens in particulate form, for a wide range of pathogens, has clear advantages over the presentation of soluble antigen alone [J.C. Aguilar, E.G. Rodriguez, Vaccine adjuvants revisited. Vaccine 25 (2007) 3752–3762, M. Singh, D. O'Hagan, Advances in vaccine adjuvants. Nature Biotechnology 17 (1999) 1075–1081]. Herein we describe a novel particle-based approach, which independently controls size, shape, and composition to control the delivery and presentation of vaccine antigen to the immune system. Highly uniform particles were produced using a particle molding technology called PRINT® (Particle Replication in Non-wetting Templates) which is an off-shoot of imprint lithography [J Am Chem Soc 127 (2005) 10096–10100, J Am Chem Soc 126 (2004) 2322–2323, Chem Soc Rev 35 (2006) 1095–1104, J Am Chem Soc 130 (2008) 5008–5009, J Am Chem Soc 130 (2008) 5438–5439, Polymer Reviews 47 (2007) 321–327, Acc Chem Res 41 (2008) 1685–1695, Acc Chem Res 44 (10) (2011) 990–998]. Cylindrical (diameter [d] = 80 nm, height [h] = 320 nm) poly (lactide-co-glycolide) (PLGA) based PRINT particles were designed to electrostatically bind commercial trivalent injectable influenza vaccine. In a variety of blended PLGA formulations, these particles were safe and showed enhanced responses to influenza hemagglutinin in murine models.From the Clinical EditorShape is one of the determining factors in interactions of nanoparticles with their biologic environment. PRINT technology is able to fabricate nearly uniform nanoparticles and this technology is tested here in murine models to effectively deliver influenza vaccine.     

Improved drug targeting of cancer cells by utilizing actively targetable folic acid-conjugated albumin nanospheres

Folic acid-conjugated albumin nanospheres (FA-AN) have been developed to provide an actively targetable drug delivery system for improved drug targeting of cancer cells with reduced side effects. The nanospheres were prepared by conjugating folic acid onto the surface of albumin nanospheres using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) as a catalyst. To test the efficacy of these nanospheres as a potential delivery platform, doxorubicin-loaded albumin nanospheres (DOX-AN) and doxorubicin-loaded FA-AN (FA-DOX-AN) were prepared by entrapping DOX (an anthracycline, antibiotic drug widely used in cancer chemotherapy that works by intercalating DNA) into AN and FA-AN nanoparticles. Cell uptake of the DOX was then measured. The results show that FA-AN was incorporated into HeLa cells (tumor cells) only after 2.0 h incubation, whereas HeLa cells failed to incorporate albumin nanospheres without conjugated folic acid after 4.0 h incubation. When HeLa cells were treated with the DOX-AN, FA-DOX-AN nanoparticles or free DOX, cell viability decreased with increasing culture time (i.e. cell death increases with time) over a 70 h period. Cell viability was always the lowest for free DOX followed by FA-DOX-AN4 and then DOX-AN. In a second set of experiments, HeLa cells washed to remove excess DOX after an initial incubation for 2 h were incubated for 70 h. The corresponding cell viability was slightly higher when the cells were treated with FA-DOX-AN or free DOX whilst cells treated with DOX-AN nanoparticles remained viable. The above experiments were repeated for non-cancerous, aortic smooth muscle cells (AoSMC). As expected, cell viability of the HeLa cells (with FA receptor alpha, FRα) and AoSMC cells (without FRα) decreased rapidly with time in the presence of free DOX, but treatment with FA-DOX-AN resulted in selective killing of the tumor cells. These results indicated that FA-AN may be used as a promising actively targetable drug delivery system to improve drug targeting to cancer cells.     

Fabrication of Dissolving Polymer Microneedles for Controlled Drug Encapsulation and Delivery: Bubble and Pedestal Microneedle Designs

Dissolving microneedle patches offer promise as a simple, minimally invasive method of drug and vaccine delivery to the skin that avoids the need for hypodermic needles. However, it can be difficult to control the amount and localization of drug within microneedles. In this study, we developed novel microneedle designs to improve control of drug encapsulation and delivery using dissolving microneedles by (i) localizing drug in the microneedle tip, (ii) increasing the amount of drug loaded in microneedles while minimizing wastage, and (iii) inserting microneedles more fully into the skin. Localization of our model drug, sulforhodamine B in the microneedle tip by either casting a highly concentrated polymer solution as the needle matrix or incorporating an air bubble at the base of the microneedle achieved approximately 80% delivery within 10 min compared to 20% delivery achieved by the microneedles encapsulating nonlocalized drug. As another approach, a pedestal was introduced to elevate each microneedle for more complete insertion into the skin and to increase its drug loading capacity by threefold from 0.018 to 0.053 μL per needle. Altogether, these novel microneedle designs provide a new set of tools to fabricate dissolving polymer microneedles with improved control over drug encapsulation, loading, and delivery.     

Towards the bioequivalence of pressurised metered dose inhalers 2. Aerodynamically equivalent particles (with and without glycerol) exhibit different biopharmaceutical profiles in vitro

Two solution-based pressurised metered dose inhaler (pMDI) formulations were prepared such that they delivered aerosols with identical mass median aerodynamic diameters, but contained either beclomethasone dipropionate (BDP) alone (glycerol-free formulation) or BDP and glycerol in a 1:1 mass ratio (glycerol-containing formulation). The two formulations were deposited onto Calu-3 respiratory epithelial cell layers cultured at an air interface. Equivalent drug mass (∼1000 ng or ∼2000 ng of the formulation) or equivalent particle number (1000 ng of BDP in the glycerol-containing versus 2000 ng of BDP in the glycerol-free formulation) were deposited as aerosolised particles on the air interfaced surface of the cell layers. The transfer rate of BDP across the cell layer after deposition of the glycerol-free particles was proportional to the mass deposited. In comparison, the transfer of BDP from the glycerol-containing formulation was independent of the mass deposited, suggesting that the release of BDP is modified in the presence of glycerol. The rate of BDP transfer (and the extent of metabolism) over 2 h was faster when delivered in glycerol-free particles, 465.01 ng ± 95.12 ng of the total drug (20.99 ± 4.29%; BDP plus active metabolite) transported across the cell layer, compared to 116.17 ng ± 3.07 ng (6.07 ± 0.16%) when the equivalent mass of BDP was deposited in glycerol-containing particles. These observations suggest that the presence of glycerol in the maturated aerosol particles may influence the disposition of BDP in the lungs.