Bone-targeted erythrocyte-cancer hybrid membrane-camouflaged nanoparticles for enhancing photothermal and hypoxia-activated chemotherapy of bone invasion by OSCC.

BACKGROUND: Jaw bones are the most common organs to be invaded by oral malignancies, such as oral squamous cell carcinoma (OSCC), because of their special anatomical relationship. Various serious complications, such as pathological fractures and bone pain can significantly decrease the quality of life or even survival outcomes for a patient. Although chemotherapy is a promising strategy for bone invasion treatment, its clinical applications are limited by the lack of tumor-specific targeting and poor permeability in bone tissue. Therefore, it is necessary to develop a smart bone and cancer dual targeting drug delivery platform. RESULTS: We designed a dual targeting nano-biomimetic drug delivery vehicle Asp8[H40-TPZ/IR780@(RBC-H)] that has excellent bone and cancer targeting as well as immune escape abilities to treat malignancies in jaw bones. These nanoparticles were camouflaged with a head and neck squamous cell carcinoma WSU-HN6 cell (H) and red blood cell (RBC) hybrid membrane, which were modified by an oligopeptide of eight aspartate acid (Asp8). The spherical morphology and typical core-shell structure of biomimetic nanoparticles were observed by transmission electron microscopy. These nanoparticles exhibited the same surface proteins as those of WSU-HN6 and RBC. Flow cytometry and confocal microscopy showed a greater uptake of the biomimetic nanoparticles when compared to bare H40-PEG nanoparticles. Biodistribution of the nanoparticles in vivo revealed that they were mainly localized in the area of bone invasion by WSU-HN6 cells. Moreover, the Asp8[H40-TPZ/IR780@(RBC-H)] nanoparticles exhibited effective cancer growth inhibition properties when compared to other TPZ or IR780 formulations. CONCLUSIONS: Asp8[H40-TPZ/IR780@(RBC-H)] has bone targeting, tumor-homing and immune escape abilities, therefore, it is an efficient multi-targeting drug delivery platform for achieving precise anti-cancer therapy during bone invasion.

[Preparation, Characterization and Pharmacokinetic Study of Arginine Deiminase Lipid Nanoparticles].

OBJECTIVE: To prepare and characterize D-alpha-Tocopheryl polyethylene glycol 1000 succinate (TPGS) modified arginine deiminase (ADI) sulfobutyl-ß-Cyclodextrin liposome nanoparticles (ATCL), and to investigate the pharmacokinetic characteristics of ATCL in animals. METHODS: The reverse evaporation method was used to prepare ATCL, and the particle size and Zeta potential of ATCL were measured. Thiosemicarbazone-diacetylmonooxime colorimetric method was used to measure the activity of ADI. After intravenous administration, blood was drawn at set intervals of time and the enzyme activity in the plasma was measured. Enzyme activity-time curve was drawn subsequently and Debris Assessment Software (DAS) 2.1.1 was used to analyze the pharmacokinetic characteristics. RESULTS: The particle size and the potential of ATCL were (216.1±13.6) nm and (-19.4±2.1) mV, respectively. The optimal temperature and optimal pH for the catalytic reaction of ADI and ATCL were the same, both being 37 ℃ and pH6.5. Results of the analysis showed that the AUC (0-168 h), MRT (0-168 h), C max, T max, and t 1/2 of ATCL were 3.99, 2.56, 1.58, 3.2, and 9.88 times those of free ADI, respectively. Compared with ADI, the bioavailability of ATCL increased by 298.54%. CONCLUSION: ATCL prepared in the study can effectively improve the enzyme activity and bioavailability of ADI in Sprague-Dawley rats.

[Pharmacokinetics of Curcumin Ethosomes in Rats in vitro].

OBJECTIVES: To study the oral phamacokinetics of curcumin ethosomes in rats. METHODS: Pharmacokinetics parameters were detected by DAS 2.1.1 software analysis through data of blood concentrations harvested from HPLC after oral administration of curcumin ethosomes in rats. RESULTS: Analyzed by non-compartmental method, the area under concentration-time curve from 0 to last time [AUC(0-72h)] of curcumin ethosomes was 1.6 times larger than that of free curcumin, the peak concentration (C max) of curcumin ethosomes was 1.5 times higher than that of free curcumin, the relative bioavailability of curcumin ethosomes was 152.2%. The 90% confidential interval of AUC(0-72 h)was 102.2%-128.5%, which was not in standard interval of bioequialence. Analyzed by compartmental method, the AUC(0-72 h)of curcumin ethosomes was 1.4 times larger than that of free curcumin and the relative bioavailability of curcumin ethosomes was 128.2%. CONCLUSION: The curcumin ethosomes can enhance bioavailability, which has a bioinequivalence with free curcumin.

[The Pharmacokinetics and Pharmacodynamics of Intravenous Uricase Multivesicular Liposomes].

OBJECTIVE: To determine and compare the pharmacokinetics and pharmacodynamics of uricase-multivesicular liposomes (UOMVLs) with free uricase (UOX) in rats. METHODS: UOMVLs were prepared by the double emulsion method and confirmed with its entrapment efficiency, size and Zeta potential. Twelve healthy rats were randomly divided into two groups: one with i. v. injection of UOMVLs, and the other with i. v. injection of UOX. Their serum activity of uricase was assayed. The pharmacokinetic parameters were calculated using software DAS 2. 1. 1. Another 24 male SD rats were enrolled, the rat model of hyperuricemia was established with hypoxanthine and potassium oxonate, while normal group (n=6) was set as control. Injection of UOMVLs (1 mL, 0. 47 U/mL), UOX (1 mL, 0. 47 U/mL) and nothiy were given 1 h later in UOMVLs group (n=6), UOX group (n=6) and model group (n=6), and their serum uric acid levels were determined 1, 2, 3, 5, 7, 9, 12, 24, 36, 48 h after the establishment of hyperuricemia model. RESULTS: The entrapment efficiency of UOMVLs was (63. 75 ± 3. 65) %, with an average particle size of (22. 56 ± 1. 70) µm and Zeta potential of (-41. 81±6. 59) mV. The pharmacokinetic parameters of UOMVLs and UOX were as follows, respectively: area under time-concentration curve from 0 to infinity time (AUC0-∞) (498. 83 ± 58. 85) U/L . h and (28. 49 ± 9. 95) U/L . h; time to peak concentration (Tmax) (1. 00±0. 00) h and (0. 00±0. 00) h; peak concentration (Cmax) (73. 04±6. 35) U/L and (31. 00±6. 03) U/L; elimination half-life (t1/2) (3. 49±0. 80) h and (1. 17±0. 33) h. The relative bioavailability of UOMVLs was (1 750. 90±206. 56) %. UOMVLs decreased serum uric to normal in 9 h; whereas it took 48 h for the UOX group and the model group to return to normal. CONCLUSION: UOMVLs can prolong tmax and t1/2 and improve the relative bioavailability. UOMVLs decrease serum uric acid levels in rats with hyperuricemia more effectively than UOX.

[Pharmacokinetics and Intestinal Absorption of Curcumin Chitosan Hydrochloride Coated Liposome in Rats].

OBJECTIVE: To investigate the pharmacokinetics and intestinal absorption characteristic of curcumin chitosan hydrochloride coated liposome(CCLP) in SD rats. METHODS: Blood samples were collected after oral administration. Pharmacokinetic parameters were analyzed by DAS program. Rat single pass intestinal perfusion method was employed to investigate the absorption mechanism. RESULTS: The AUC0-t, AUC0-∞, t1/2, and Cmax of CCLP were 1. 73-fold, 1. 95-fold, 1. 56-fold and 1. 91-fold of the free drug. The intestinal absorption rate constant (Ka) of CCLP in duodenum, jejunum, ileum and colon were 1. 48, 1. 28, 1. 17 , and 4. 01 times as much as the free drug and the effective permeability(Peff) of CCLP were 1. 58, 1.-33, 1. 30 and 4. 55 times of the free drug, respectively. CONCLUSION: The bioavailability of CCLP in rats is increased remarkably and Ka is increased in various intestinal segments by CCLP, especially in colon, as well as Peff.

Understanding selective molecular recognition in integrated carbon nanotube-polymer sensors by simulating physical analyte binding on carbon nanotube-polymer scaffolds.

Macromolecular scaffolds made of polymer-wrapped single-walled carbon nanotubes (SWCNTs) have been explored recently (Zhang et al., Nature Nanotechnology, 2013) as a new class of molecular-recognition motifs. However, selective analyte recognition is still challenging and lacks the underlying fundamental understanding needed for its practical implementation in biological sensors. In this report, we combine coarse-grained molecular dynamics (CGMD) simulations, physical adsorption/binding theories, and photoluminescence (PL) experiments to provide molecular insight into the selectivity of such sensors towards a large set of biologically important analytes. We find that the physical binding affinities of the analytes on a bare SWCNT partially correlate with their distribution coefficients in a bulk water/octanol system, suggesting that the analyte hydrophobicity plays a key role in determining the binding affinities of the analytes considered, along with the various specific interactions between the analytes and the polymer anchor groups. Two distinct categories of analytes are identified to demonstrate a complex picture for the correlation between optical sensor signals and the simulated binding affinities. Specifically, a good correlation was found between the sensor signals and the physical binding affinities of the three hormones (estradiol, melatonin, and thyroxine), the neurotransmitter (dopamine), and the vitamin (riboflavin) to the SWCNT-polymer scaffold. The four amino acids (aspartate, glycine, histidine, and tryptophan) and the two monosaccharides (fructose and glucose) considered were identified as blank analytes which are unable to induce sensor signals. The results indicate great success of our physical adsorption-based model in explaining the ranking in sensor selectivities. The combined framework presented here can be used to screen and select polymers that can potentially be used for creating synthetic molecular recognition motifs.

Azithromycin cationic non-lecithoid nano/microparticles improve bioavailability and targeting efficiency.

PURPOSE: The purpose of this study was to develop and evaluate the azithromycin cationic non-lecithoid nano/microparticles with high bioavailability and lung targeting efficiency. METHODS: The cationic niosomes with different sizes (AMCNS-S and AMCNS-L) along with varied built-in characteristics were produced to achieve high bioavailability and lung targeting efficiency of azithromycin (AM) via two administration routes widely used in clinical practice, i.e., oral and intravenous routes, instead of transdermal route (by which the only marketed niosome-based drug delivery dermatologic products were given). The possible explanations for improved bioavailability and lung targeting efficacy were put forward here. RESULTS: AMCNS-S (or AMCNS-L) had high bioavailability, for example, the oral (or intravenous) relative bioavailability of AMCNS-S (or AMCNS-L) to free AM increased to 273.19% (or 163.50%). After intravenous administration, AMCNS-S (or AMCNS-L) had obvious lung targeting efficiency, for example, the lung AM concentration of AMCNS-S (or AMCNS-L) increased 16 (or 28) times that of free AM at 12 h; the AM concentration of AMCNS-S (or AMCNS-L) in lung was higher than that in heart and kidney all the time. CONCLUSIONS: The development of niosome-based AM nanocarriers provides valuable tactics in antibacterial therapy and in non-lecithoid niosomal application.

Novel taste-masked orally disintegrating tablets for a highly soluble drug with an extremely bitter taste: design rationale and evaluation.

The purpose of this study was to evaluate the taste masking potential of novel solid dispersions (SDs) using Eudragit® EPO as the excipient when incorporated into the orally disintegrating tablets (ODTs) for delivering a highly soluble drug with an extremely bitter taste. The pyridostigmine bromides (PB) SDs (PBSDs) were prepared by solvent evaporation-deposition method. The physicochemical properties of PBSDs were investigated by means of differential scanning calorimetry and Fourier transformed infrared spectroscopy. The dissolution test showed that only about 8% of PB was released from PBSDs in the simulated salivary fluid in 30 s. Therefore, PBSDs were considered taste-masked and selected for formulation of PBODTs. A central composite design was employed for process optimization. Multiple linear regression analysis for process optimization revealed that the optimal PBODTs were obtained, when the microcrystalline cellulose and crospovidone were 17.16 and 5.55 (%, w/w), respectively, and the average in vivo disintegration time was 25 s. The bitterness threshold of PB was examined by a sensory test, and the threshold value was set as 3 mg in each tablet. Taste evaluation of PBODTs in 18 volunteers revealed considerable taste masking with bitterness below the threshold value. PBODTs also revealed rapid drug release (around 99%, 2 min) in the simulated gastric fluid. The mean PB plasma concentration-time profiles of PBODTs and that of the commercial tablets were comparable, with closely similar pattern. Bioequivalence assessment results demonstrated that PBODTs and the commercial tablets were bioequivalent. In conclusion, PBODTs are prepared successfully, with taste masking and rapid disintegration in the oral cavity.

Effect of preparation conditions on the size and encapsulation properties of mPEG-PLGA nanoparticles simultaneously loaded with vincristine sulfate and curcumin.

This study prepared monomethoxy poly(ethylene glycol)-poly(lactide-co-glycolide) (mPEG-PLGA) nanoparticles simultaneously loaded with vincristine sulfate (Vin) and curcumin (Cur) via O/W emulsion solvent evaporation. Five independent processing parameters were systematically evaluated to enhance the entrapment of dual agents with different properties (i.e. Vin and Cur, which are the hydrophilic and hydrophobic, respectively) into mPEG-PLGA nanoparticles and to control the particle size. The approaches used to investigate the enhancement of drug entrapment efficiencies and control over the particle size included mPEG-PLGA concentration, polyvinyl alcohol (PVA) concentration, initial Vin/Cur content, dichloromethane-to-acetone volume ratio, and aqueous-to-organic phase volume ratio. The nanoparticles produced using the optimum formulation conditions had a particle size of 131.5 nm with a low polydispersity index of 0.047. The entrapment efficiencies were 63.52 ± 2.36% for Vin and 54.60 ± 2.46% for Cur (n = 3). The drug loadings were 1.06 ± 0.04% for Vin and 3.64 ± 0.16% for Cur (n = 3).

A structure-function relationship for the optical modulation of phenyl boronic acid-grafted, polyethylene glycol-wrapped single-walled carbon nanotubes.

Phenyl boronic acids (PBA) are important binding ligands to pendant diols useful for saccharide recognition. The aromatic ring can also function to anchor an otherwise hydrophilic polymer backbone to the surface of hydrophobic graphene or carbon nanotube. In this work, we demonstrate both functions using a homologous series of seven phenyl boronic acids conjugated to a polyethylene glycol, eight-membered, branched polymer (PPEG8) that allows aqueous dispersion of single-walled carbon nanotubes (SWNT) and quenching of the near-infrared fluorescence in response to saccharide binding. We compare the 2-carboxyphenylboronic acid (2CPBA); 3-carboxy- (3CPBA) and 4-carboxy- (4CPBA) phenylboronic acids; N-(4-phenylboronic)succinamic acid (4SCPBA); 5-bromo-3-carboxy- (5B3CPBA), 3-carboxy-5-fluoro- (5F3CPBA), and 3-carboxy-5-nitro- (5N3CPBA) phenylboronic acids, demonstrating a clear link between SWNT photoluminescence quantum yield and boronic acid structure. Surprisingly, quantum yield decreases systematically with both the location of the BA functionality and the inclusion of electron-withdrawing or -donating substituents on the phenyl ring. For three structural isomers (2CPBA, 3CPBA, and 4CPBA), the highest quantum yields were measured for para-substituted PBA (4CPBA), much higher than ortho- (2CPBA) and meta- (3CPBA) substituted PBA, indicating the first such dependence on molecular structure. Electron-withdrawing substituents such as nitro groups on the phenyl ring cause higher quantum yield, while electron-donating groups such as amides and alkyl groups cause a decrease. The solvatochromic shift of up to 10.3 meV was used for each case to estimate polymer surface coverage on an areal basis using a linear dielectric model. Saccharide recognition using the nIR photoluminescence of SWNT is demonstrated, including selectivity toward pentoses such as arabinose, ribose, and xylose to the exclusion of the expected fructose, which has a high selectivity on PBA due to the formation of a tridentate complex between fructose and PBA. This study is the first to conclusively link molecular structure of an adsorbed phase to SWNT optical properties and modulation in a systematic manner.

[Preparation and quality control of pyridostigmine bromide orally disintegrating tablet].

OBJECTIVE: To prepare orally disintegrating tablets containing pyridostigmine bromide and optimize formulations. METHODS: Solid dispersion was prepared using solvent evaporation-deposition method. The formulation was optimized by central composite design-response surface methodology (RSM plus CCD) with disintegration time as a reference parameter. RESULTS: The orally disintegrating tablets showed integrity and were smooth with desirable taste and feel in mouth. The disintegration time was less than 30 s. The cumulative drug dissolution was around 8.5% (around 2.5 mg which was less than bitterness threshold of pyridostigmine bromide of 3 mg) within 5 min in water while the cumulative drug dissolution was higher than 95% within 2 min in 0.1 N HCl. CONCLUSION: The orally disintegrating tablets are reasonable in formulation, feasible in technology and patient-friendly.

Cytomembrane-mimicking nanocarriers with a scaffold consisting of a CD44-targeted endogenous component for effective asparaginase supramolecule delivery.

Highly effective and safe delivery of therapeutic enzymes is pivotal to the success of antitumor therapy. Herein, we report on a targeted enzyme delivery system based on cytomembrane-mimicking nanocarriers (CmN) and a supramolecular technique (SmT). Specifically, each CmN had a scaffold that mainly consisted of a CD44-targeted endogenous component conjugated with polyethylene glycol 2000 (HA-g-PEG) that self-assembled with α-cyclodextrin (ACD). The CmN acted as a microbioreactor with an inner hollow space with the capacity to confine the large molecule asparaginase (Asp) in an Asp/ACD-supramolecular complex conjugated to the inner region. The supramolecular Asp loaded into the CmN (A-S-CmN) exhibited superior stability, kinetic properties, catalytic activity and antitumor effects compared to free Asp due to the dual protection of the supramolecular complex and the nanovesicle, the CD44 targeting-homing ability, the prolonged effects of HA-g-PEG, and the favorable inner microenvironment of the constructed supramolecular CmN. The A-S-CmN also showed a decrease in in vivo toxicity and immunogenicity. CmN combined with SmT therapeutics are easy to implement and extend for use in the delivery of various enzymes and for many types of cancer treatment.

Biomimetic Membrane-Structured Nanovesicles Carrying a Supramolecular Enzyme to Cure Lung Cancer.

Platforms for enzyme delivery must simultaneously have plasma stability, high catalytic activity, and low/no immunogenicity of the enzyme. Here, we designed a novel biomimetic membrane-structured nanovesicle (BNV) to efficiently carry supramolecular enzymes to meet the above requirements. We complexed l-asparaginase (Aase) with hydroxypropyl-ß-cyclodextrin (HPCD) to form a supramolecular amphiphile (AS) by self-assembly via noncovalent reversible interactions. We then used the first synthesized polyethylene glycol (PEG 2 kDa)-decorated hyaluronan (12 kDa) and HPCD to self-assemble a semipermeable biomimetic membrane-structured nanovesicle (BNV) together with AS loading. As compared to native Aase, AS@BNV exhibited superior catalytic activity preservation, improved catalytic activity, better pharmacokinetics in rats, enhanced cytotoxic effects, increased antitumor efficacy, and decreased side effects. The underlying mechanisms, such as the autophagy inhibition action against tumor cells, protein-protein docking of the interaction between Aase-serum albumin, and decreased hepatic enzymatic activity, were investigated. This approach paves the way for new types of powerful biomimetic-, supramolecular-, and nanocarrier-based enzymatic therapies.

[Preparation and in vitro release characteristics of curcumin loaded biodegradable microspheres].

OBJECTIVE: To prepare curcumin-loaded poly-(D,L-lactide-co-glycolide) microspheres and study its release characteristics in vitro. METHOD: Curcumin-loaded poly-(D,L-lactide-co-glycolide) microspheres were prepared by W/O/W emulsification solvent-evaporation process. The microspheres were characterized in terms of morphology, size, encapsulation efficiency, the rate of drug loading and in vitro drug release. RESULT: The formed microspheres were spherical with smooth surfaces. The distribution of particle size was uniform and average size was 1 151 nm. The rate of drug loading was (1.98 +/- 0.14)% and the encapsulation efficiency was (59.44 +/- 4.05)%. In vitro release study revealed that the 71-hour accumulative release percentage reached 77%. CONCLUSION: Curcumin loaded poly-(D,L-lactide-co-glycolide) microspheres are prepared successfully and show good sustained-release characteristics.

Uricase alkaline enzymosomes with enhanced stabilities and anti-hyperuricemia effects induced by favorable microenvironmental changes.

Enzyme therapy is an effective strategy to treat diseases. Three strategies were pursued to provide the favorable microenvironments for uricase (UCU) to eventually improve its features: using the right type of buffer to constitute the liquid media where catalyze reactions take place; entrapping UCU inside the selectively permeable lipid vesicle membranes; and entrapping catalase together with UCU inside the membranes. The nanosized alkaline enzymosomes containing UCU/(UCU and catalase) (ESU/ESUC) in bicine buffer had better thermal, hypothermal, acid-base and proteolytic stabilities, in vitro and in vivo kinetic characteristics, and uric acid lowering effects. The favorable microenvironments were conducive to the establishment of the enzymosomes with superior properties. It was the first time that two therapeutic enzymes were simultaneously entrapped into one enzymosome having the right type of buffer to achieve added treatment efficacy. The development of ESU/ESUC in bicine buffer provides valuable tactics in hypouricemic therapy and enzymosomal application.

[Preparation and characterization of uricase in uricase-catalase liposomes prepared using borate buffer].

OBJECTIVE: To characterize the property of uricase loaded in uricase-catalase liposomes (BUCLPs) prepared using borate buffer. METHODS: BUCLPs were prepared using reverse-phase evaporation, and the physicochemical properties of uricase in the prepared BUCLPs were examined. RESULTS: The optimal temperature of BUCLP and URI was 40 degrees celsius, their optimal pH values were 8.0 and 8.5, and their Michaelis-Menten constants were 14.207 µmol/L and 13.623 µmol/L, respectively. Fluorescence intensity of nanoliposome-loaded uricase-catalase that bound to FITC was higher than that of uricase-catalase binding directly with FITC; the fluorescence intensity of BUCLP was higher than that of free uricase-catalase at 280 nm. CONCLUSION: Uricase activity is enhanced after loading in uricase and catalase liposomes.

Optimization and evaluation of a thermoresponsive ophthalmic in situ gel containing curcumin-loaded albumin nanoparticles.

This study aimed to optimize and evaluate a thermoresponsive ophthalmic in situ gel containing curcumin-loaded albumin nanoparticles (Cur-BSA-NPs-Gel). Albumin nanoparticles were prepared via a desolvation method, and the gels were prepared via a cold method. The central composite design and response surface method was used to evaluate the effects of varying Pluronic F127 and Pluronic F68 concentrations on the sol-gel transition temperature, which is an indicator of optimum formulations. The optimized formulation was a free-flowing liquid below 30.9°C that transformed into a semi-solid gel above 34.2°C after dilution with simulated tear fluid. Results of the in vitro release and erosion behavior study indicated that Cur-BSA-NPs-Gel achieved superior sustained-release effects and that incorporation of albumin nanoparticles exerted minimal effects on the gel structure. In addition, in vivo ophthalmic experiments employing Cur-BSA-NPs-Gel were subsequently performed in rabbits. In vivo eye irritation results showed that Cur-BSA-NPs-Gel might be considered safe for ophthalmic drug delivery. The in vivo study also revealed that the formulation could significantly increase curcumin bioavailability in the aqueous humor. In conclusion, the optimized in situ gel formulation developed in this work has significant potential for ocular application.

A novel plug-controlled colon-specific pulsatile capsule with tablet of curcumin-loaded SMEDDS.

This study developed and evaluated a colon-specific pulsatile capsule with tablet of self-microemulsifying drug delivery system (SMEDDS). This system is based on an impermeable capsule containing a rapid-disintegrating curcumin-loaded SMEDDS tablet inside it, and a highly methoxylated pectin (H-pectin)/lactose tablet plugged in the capsule mouth. The SMEDDS tablet enhanced the solubility of curcumin, a water-insoluble drug. An in vitro release study of the pulsatile capsule showed a typical pulsatile release profile with a specific lag time. The lag time, which determines the efficiency of colon-specific delivery, could be regulated by varying the H-pectin/lactose ratio. Pectinase and rat cecal contents added to the release medium significantly shortened the erosion time, which proved that the H-pectin plug is sensitive to enzyme degradation. These results show that the pulsatile capsule with SMEDDS tablet has potential for the colon-specific delivery of water-insoluble drugs.

Nanosized sustained-release pyridostigmine bromide microcapsules: process optimization and evaluation of characteristics.

BACKGROUND: Pyridostigmine bromide (3-[[(dimethylamino)-carbonyl]oxy]-1-methylpyridinium bromide), a reversible inhibitor of cholinesterase, is given orally in tablet form, and a treatment schedule of multiple daily doses is recommended for adult patients. Nanotechnology was used in this study to develop an alternative sustained-release delivery system for pyridostigmine, a synthetic drug with high solubility and poor oral bioavailability, hence a Class III drug according to the Biopharmaceutics Classification System. Novel nanosized pyridostigmine-poly(lactic acid) microcapsules (PPNMCs) were expected to have a longer duration of action than free pyridostigmine and previously reported sustained-release formulations of pyridostigmine. METHODS: The PPNMCs were prepared using a double emulsion-solvent evaporation method to achieve sustained-release characteristics for pyridostigmine. The preparation process for the PPNMCs was optimized by single-factor experiments. The size distribution, zeta potential, and sustained-release behavior were evaluated in different types of release medium. RESULTS: The optimal volume ratio of inner phase to external phase, poly(lactic acid) concentration, polyvinyl alcohol concentration, and amount of pyridostigmine were 1:10, 6%, 3% and 40 mg, respectively. The negatively charged PPNMCs had an average particle size of 937.9 nm. Compared with free pyridostigmine, PPNMCs showed an initial burst release and a subsequent very slow release in vitro. The release profiles for the PPNMCs in four different types of dissolution medium were fitted to the Ritger-Peppas and Weibull models. The similarity between pairs of dissolution profiles for the PPNMCs in different types of medium was statistically significant, and the difference between the release curves for PPNMCs and free pyridostigmine was also statistically significant. CONCLUSION: PPNMCs prepared by the optimized protocol described here were in the nanometer range and had good uniformity, with significantly slower pyridostigmine release than from free pyridostigmine. This novel sustained-release delivery nanosystem for pyridostigmine might alleviate the need to identify new acetylcholinesterase inhibitors.

Molecular recognition using corona phase complexes made of synthetic polymers adsorbed on carbon nanotubes.

Understanding molecular recognition is of fundamental importance in applications such as therapeutics, chemical catalysis and sensor design. The most common recognition motifs involve biological macromolecules such as antibodies and aptamers. The key to biorecognition consists of a unique three-dimensional structure formed by a folded and constrained bioheteropolymer that creates a binding pocket, or an interface, able to recognize a specific molecule. Here, we show that synthetic heteropolymers, once constrained onto a single-walled carbon nanotube by chemical adsorption, also form a new corona phase that exhibits highly selective recognition for specific molecules. To prove the generality of this phenomenon, we report three examples of heteropolymer-nanotube recognition complexes for riboflavin, L-thyroxine and oestradiol. In each case, the recognition was predicted using a two-dimensional thermodynamic model of surface interactions in which the dissociation constants can be tuned by perturbing the chemical structure of the heteropolymer. Moreover, these complexes can be used as new types of spatiotemporal sensors based on modulation of the carbon nanotube photoemission in the near-infrared, as we show by tracking riboflavin diffusion in murine macrophages.