Nanoparticles Based on Linear and Star-Shaped Poly(Ethylene Glycol)-Poly(ε-Caprolactone) Copolymers for the Delivery of Antitubulin Drug

Purpose

Biodegradable polymeric nanoparticles of different architectures based on polyethylene glycol-co-poly(ε-caprolactone) block copolymers have been loaded with noscapine (NOS) to study their effect on its anticancer activity. It was intended to use solubility of NOS in an acidic environment and ability of the nanoparticles to passively target drugs into cancer tissue to modify the NOS pharmacokinetic properties and reduce the requirement for frequent injections.

Methods

Linear and star-shaped copolymers were synthetized and used to formulate NOS loaded nanoparticles. Cytotoxicity was performed using a sulforhodamine B method on MCF-7 cells, while biocompatibility was determined on rats followed by hematological and histopathological investigations.

Results

Formulae with the smallest particle sizes and adequate entrapment efficiency revealed that NOS loaded nanoparticles showed higher extent of release at pH 4.5. Colloidal stability suggested that nanoparticles would be stable in blood when injected into the systemic circulation. Loaded nanoparticles had IC₅₀ values lower than free drug. Hematological and histopathological studies showed no difference between treated and control groups. Pharmacokinetic analysis revealed that formulation P1 had a prolonged half-life and better bioavailability compared to drug solution.

Conclusions

Formulation of NOS into biodegradable polymeric nanoparticles has increased its efficacy and residence on cancer cells while passively avoiding normal body tissues.

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Graphical Abstract ?

     

Preparation and Drug Loading of Poly(Ethylene Glycol)-block-Poly(ε-Caprolactone) Micelles Through the Evaporation of a Cosolvent Azeotrope

PURPOSE: The aim of this work was to study the assembly, drug loading, and stability of poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PEG-b-PCL) micelles. METHODS: Three PEG-b-PCL compositions with PCL number average molecular weights of 1000, 2500, and 4000 g/mol were used. The assembly of PEG-b-PCL micelles, induced by the addition of water to acetonitrile (ACN), was characterized with 1H nuclear magnetic resonance spectroscopy (1H-NMR) and dynamic light scattering (DLS) with and without the presence of fenofibrate, a poorly water-soluble drug. PEG-b-PCL micelles with encapsulated fenofibrate were prepared through the removal of a negative ACN-water azeotrope under reduced pressure. Fenofibrate content was measured using reverse-phase high-performance liquid chromatography (HPLC), whereas the kinetic stability of PEG-b-PCL micelles with and without encapsulated fenofibrate was evaluated using size exclusion chromatography (SEC). RESULTS: The critical water content (CWC), the water content at which amphiphilic block copolymer (ABC) micelle assembly begins, was determined using DLS and ranged from 10% to 30% water, depending on both PCL molecular weight and PEG-b-PCL concentration. As the water content was increased, the PEG-b-PCL unimers assembled into swollen structures with hydrodynamic diameters ranging from 200 to 800 nm. The 1H-NMR peaks associated with the PCL block exhibited line-broadening, following the addition of D2O, indicating that the PCL blocks reside in the core of the PEG-b-PCL micelle. With further addition of water, the PCL cores collapsed to form fairly monodisperse PEG-b-PCL micelles (20-60 nm). In the presence of fenofibrate, the CWC value was lowered, perhaps due to hydrophobic interactions of fenofibrate and the PCL block. Further addition of water and subsequent evaporation of the negative ACN-water azeotrope resulted in fenofibrate-loaded PEG-b-PCL micelles of under 50 nm. The extent of fenofibrate encapsulation was dependent on PCL block size. At a polymer concentration of 1.0 mg/ml, PEG-b-PCL (5000:4000) and (5000:2500) micelles could encapsulate more than 90% of the initial loading level of fenofibrate, whereas PEG-b-PCL (5000:1000) micelles encapsulate only 28%. SEC experiments revealed that PEG-b-PCL (5000:4000) and (5000:2500) micelles eluted intact, indicating kinetic stability, whereas PEG-b-PCL (5000:1000) micelles eluted primarily as unimers. CONCLUSIONS: PEG-b-PCL in ACN assembles with fenofibrate into drug-loaded polymeric micelles with the addition of water and the subsequent removal of a negative ACN-water azeotrope.     

Synthesis and Pharmacological Properties of the Azo-Conjugate of Erythropoietin β with Poly(Ethylene Glycol)

Pharmaceutical Chemistry Journal - A conjugate of erythropoietin β with 30 kDa linear methoxy poly(ethylene glycol) characterized by the presence of an azo spacer between the protein fragment...     

Poly(δ-valerolactone-co-allyl-δ-valerolactone) cross-linked microparticles: Formulation,characterization and biocompatibility

A novel polymeric material, poly(δ-valerolactone-co-allyl-δ-valerolactone) (PVL-co-PAVL), was used to manufacture microparticles (MPs) for sustained drug delivery. PVL-co-PAVL MPs were formulated using a modified oil-in-water approach, followed by a UV-initiated cross-linking process. Prepared MPs had a smooth spherical morphology and cross-linking of the copolymer was found to improve the integrity and thermal stability of the MPs. Paclitaxel (PTX) was successfully loaded into the MPs at a high drug loading capacity, using a post-loading swelling-equilibrium method. In vitro evaluation showed that the PVL-co-PAVL MPs provide sustained release of PTX, which exhibited first-order release kinetics. A subsequent pilot pharmacokinetic study was carried out on the PTX-loaded PVL-co-PAVL MPs. During this study, serum levels of PTX were monitored following subcutaneous administration of the MPs to Sprague-Dawley rats. Overall, the in vivo release of PTX from the MPs was lower than expected based on the in vitro release studies. Detectable serum levels of PTX suggest that sustained release of drug was achieved in vivo. Minimal changes in subcutaneous tissue were observed at the site of injection. Future studies will further examine the localized and systemic distribution of drug following administration in this new polymer-based MP system.     

Polymeric Modification and Its Implication in Drug Delivery: Poly-ε-caprolactone (PCL) as a Model Polymer

Biodegradable polymers provided the opportunity to explore beyond conventional drug delivery and turned out to be the focus of current drug delivery. In spite of availability of diverse class of polymers, several of these polymers lack important physicochemical and biological properties, limiting their widespread application in pharmaceutical drug delivery. However, most polymers in the form of blends, copolymers and functionally modified polymers have exhibited their applicability to overcome specific limitations and to produce novel and/or functionalized formulations for drug delivery as well as tissue engineering. This review aims to provide the need of polymeric modification, approaches adopted to modify and their scope. Special emphasis has been given to synthetic polyester PCL, as it is widely demonstrated in its modified form to overcome its problem of hydrophobicity and much slower degradation over the past decade. Past studies show a significantly higher utility of modified form of PCL in comparison to its native form. From the statistical analysis of these modifications and the formulations prepared, we present a basic understanding of the impact of selective modifications on the formulation design. In conclusion, we remark that a thorough understanding of the polymer and its modification has a huge potential to be the future trend for drug delivery and tissue engineering applications.     

Liquid Crystalline Systems Based on Glyceryl Monooleate and Penetration Enhancers for Skin Delivery of Celecoxib: Characterization,In Vitro Drug Release,and In Vivo Studies

Celecoxib (CXB) is a widely used anti-inflammatory drug that also acts as a chemopreventive agent against several types of cancer, including skin cancer. As the long-term oral administration of CXB has been associated with severe side effects, the skin delivery of this drug represents a promising alternative for the treatment of skin inflammatory conditions and chemoprevention of skin cancer. We prepared and characterized liquid crystalline systems based on glyceryl monooleate and water containing penetration enhancers which were primarily designed to promote skin delivery of CXB. Analysis of their phase behavior revealed the formation of cubic and hexagonal phases depending on the systems' composition. The systems' structure and composition markedly affected the in vitro CXB release profile. Oleic acid reduced CXB release rate, but association oleic acid/propylene glycol increased the drug release rate. The developed systems significantly reduced inflammation in an aerosil-induced rat paw edema model. The systems' composition and liquid crystalline structure influenced their anti-inflammatory potency. Cubic phase systems containing oleic acid/propylene glycol association reduced edema in a sustained manner, indicating that they modulate CXB release and permeation. Our findings demonstrate that the developed liquid crystalline systems are potential carriers for the skin delivery of CXB.     

Biodegradable Pseudolatexes: The Chemical Stability of Poly(D,L-Lactide) and Poly (ε-Caprolactone) Nanoparticles in Aqueous Media

Pseudolatexes of the biodegradable polyesters poly(D,L-lactide) (PLA) and poly(-caprolactone) (PCL) have been developed as potential aqueous coatings for sustained release. Since PLA and PCL are known to hydrolyze, the influence of the surfactant system, temperature, pH, and particle size on the chemical stability of the polymers as aqueous colloidal dispersions was investigated. Pseudolatexes of PLA and PCL formulated with a nonionic surfactant system were the most stable. When these dispersions were stored in unbuffered media for 350 days at 5°C, only small changes in the weight-average molecular weights (M _w) of the polymers were observed. At 37°C there was rapid degradation of both polymers in the dispersions. Arrhenius plots for the degradation of PLA and PCL resulted in a linear relationship for PCL. The nonlinear relationship for PLA was attributed to the polymer being in two different physical states within the 5 to 37°C range which was used for the Arrhenius plots. PCL was in the rubbery state at all temperatures studied. Storage of the pseudolatexes in pH 1.65 buffer at 37°C catalyzed the rates of degradation of both PLA and PCL. However, refrigeration of the pseudolatexes stabilized the polymers even at pH 1.65 for up to 4 months. Particle size had an insignificant effect on PLA and PCL stability in pseudolatexes prepared with either a nonionic or an anionic surfactant system.     

Tamoxifen Citrate Loaded Solid Lipid Nanoparticles (SLN™): Preparation,Characterization, In Vitro Drug Release,and Pharmacokinetic Evaluation

Solid lipid nanoparticles (SLN) were prepared by emulsification and high pressure homogenization technique and characterized by size analysis and differential scanning calorimetry. The influence of experimental factors such as homogenization pressure, time, and surfactant concentration on the nanoparticle size and distribution were investigated to optimize the formulation. Homogenization at 15,000 psi for 3 cycles was found to be optimum and resulted in smaller sized nanoparticles. In case of tristearin SLN (TSSLN), tripalmitin SLN (TPSLN), and glycerol behenate SLN (GBSLN), the relatively smaller sized nanoparticles were obtained with 3% sodium tauroglycocholate. The SLN were loaded with an anticancer agent, tamoxifen citrate (TC). The TC-loaded TSSLN shown lower entrapment efficiency (78.78%) compared to the TPSLN (86.75%) and GBSLN (98.64%). Short term stability studies indicated a significant increase in size of nanoparticles when stored at 50°C, compared to those stored at 30°C and 4°C. The particle destabilization upon storage in case of all the types of nanoparticles studied was in the order of day light > artificial light > dark. An ultraviolet (UV) spectrophotometric method of estimation of tamoxifen in rat plasma was developed and validated. The TC‐loaded TSSLN was administered to the rats intravenously and the pharmacokinetic parameters in the plasma were determined. The t_1/2 and mean residence time of TC-loaded TSSLN in plasma was about 3.5-fold (p < 0.001) and 3-fold (p < 0.001) higher, respectively, than the free tamoxifen, indicating the potential of TC-loaded TSSLN as a long circulating system in blood. Thus the above mentioned solid lipid nanoparticles can be a beneficial system to deliver tamoxifen to cancer tissues through enhanced permeability and retention (EPR) effect.     

Complement Activation by Core–Shell Poly(isobutylcyanoacrylate)–Polysaccharide Nanoparticles: Influences of Surface Morphology, Length, and Type of Polysaccharide

Purpose Biodistribution of intravenously administered nanoparticles depends on opsonization. The aim of this study was the evaluation of complement activation induced by nanoparticles coated with different polysaccharides. Influences of size and configuration of dextran, dextran sulfate, or chitosan bound onto nanoparticles were investigated. Method Core–shell nanoparticles were prepared by redox radical or anionic polymerization of isobutylcyanoacrylate in the presence of polysaccharides. Conversion of C3 into C3b in serum incubated with nanoparticles was evaluated. Results Cleavage of C3 increased with size of dextran bound in “loops” configuration, whereas it decreased when dextran was bound in “brush.” It was explained by an increasing steric repulsive effect of the brush, inducing poor accessibility to OH groups. The same trend was observed for chitosan-coated nanoparticles. Nanoparticles coated with a brush of chitosan activated the complement system lesser than nanoparticles coated with a brush of dextran. This was explained by an improved repelling effect. Dextran-sulfate-coated nanoparticles induced a low cleavage of C3 whereas it strongly enhanced protein adsorption. Conclusion Complement activation was highly sensitive to surface features of the nanoparticles. Type of polysaccharide, configuration on the surface, and accessibility to reactive functions along chains are critical parameters for complement activation.     

Delivery of a peptide via poly(d,l-lactic-co-glycolic) acid nanoparticles enhances its dendritic cell–stimulatory capacity

Nanoparticles (NPs) are attractive carriers for vaccines. We have previously shown that a short peptide (Hp91) activates dendritic cells (DCs), which are critical for initiation of immune responses. In an effort to develop Hp91 as a vaccine adjuvant with NP carriers, we evaluated its activity when encapsulated in or conjugated to the surface of poly(d,l-lactic-co-glycolic) acid (PLGA) NPs. We found that Hp91, when encapsulated in or conjugated to the surface of PLGA-NPs, not only activates both human and mouse DCs, but is in fact more potent than free Hp91. Hp91 packaged within NPs was about fivefold more potent than the free peptide, and Hp91 conjugated to the surface of NPs was ～20-fold more potent than free Hp91. Because of their capacity to activate DCs, such NP-Hp91 systems are promising as delivery vehicles for subunit vaccines against infectious disease or cancer.From the Clinical EditorIn this paper, nanoparticle-based dendritic cell activating vaccines are described and discussed. The authors report that the presented PLGA NP based vaccine constructs increase the potency of the studied vaccine by up to 20-fold, making them promising as delivery vehicles for subunit vaccines against infectious diseases or cancer.     

Translational Pharmacokinetic/Pharmacodynamic Characterization and Target-Mediated Drug Disposition Modeling of an Anti–Tissue Factor Pathway Inhibitor Antibody,PF-06741086

Tissue factor pathway inhibitor (TFPI) exhibits multiple isoforms, which are known to present in multiple locations such as plasma, endothelium, and platelets. TFPI is an endogenous negative modulator of the coagulation pathway, and therefore, neutralization of TFPI function can potentially increase coagulation activity. A human monoclonal antibody, PF-06741086, which interacts with all isoforms of TFPI is currently being tested in clinic for treating hemophilia patients with and without inhibitors. To support clinical development of PF-06741086, pharmacokinetics (PK) and pharmacodynamics of PF-06741086 were characterized in monkeys. In addition, a mechanistic model approach was used to estimate PK parameters in monkeys and simulate PK profiles in human. The results show that PF-06741086 exhibited target-mediated drug disposition and had specific effects on various hemostatic markers including diluted prothrombin time, thrombin generation, and thrombin-antithrombin complex in monkeys after administration. The model-predicted and observed human exposures were compared retrospectively, and the result indicates that the exposure prediction was reasonable within less than 2-fold deviation. This study demonstrated in vivo efficacy of PF-06741086 in monkeys and the utility of a rational mechanistic approach to describe PK for a monoclonal antibody with complex target binding.     

The 3′-Keto–Diol Equilibrium of Trospectomycin Sulfate Bulk Drug and Freeze-Dried Formulation: Solid-State Carbon-13 Cross-Polarization Magic Angle Spinning (CP/MAS) and High-Resolution Carbon-13 Nuclear Magnetic Resonance (NMR) Spectroscopy Studies

Understanding how moisture interacts with a drug or formulation is a critical component of product development. This study demonstrates how water affects the 3-gem-diol 3-keto equilibrium in trospectomycin sulfate bulk drug and freeze-dried formulation, as probed by solid-state carbon-13 cross-polarization magic angle spinning (CP/MAS) and high-resolution nuclear magnetic resonance (NMR) spectroscopy. Drying the bulk drug or formulation to low water levels dehydrates trospectomycin sulfate from the diol to the keto form. Carbon-13 CP/MAS NMR spectroscopy measures the keto drug concentration in solid samples directly. The bulk drug, which contains approximately 16% water, is more than 90% in the 3-diol form. Oven drying to <3% water converts approximately 75% of the drug to the 3-keto form. The drug is formulated as a freeze-dried, sterile powder that can contain up to 12% water depending on the freeze-drying conditions. These studies show that the 3-keto concentration rises uniformly (up to 75%) with decreasing residual water in the freeze-dried cake. The keto–diol equilibrium was also studied in solution by high-resolution carbon-13 NMR experiments, and it was found that raising the temperature or using dimethyl sulfoxide (DMSO) as a solvent also dehydrates the drug. For example, in aqueous solution at 25°C, nearly all (>95%) of the drug is in the 3-diol form. After equilibration at 60°C, however, the 3-keto content increases to 7%, and in d ₆-DMSO solvent at 25°C the drug is mostly (60%) in the 3-keto form.     

Poly(Ethylene Oxide)-Modified Poly(β-Amino Ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs: Part 2. <Emphasis Type="BoldItalic">In Vivo</Emphasis> Distribution and Tumor Localization Studies

Purpose This study was carried out to determine the biodistribution profiles and tumor localization potential of poly(ethylene oxide) (PEO)-modified poly(β-amino ester) (PbAE) as a novel, pH-sensitive biodegradable polymeric nanoparticulate system for tumor-targeted drug delivery. Methods The biodistribution studies of PEO-modified PbAE and PEO-modified poly(ɛ-caprolactone) (PCL), a non-pH-sensitive polymer, nanoparticle systems were carried out in normal mice using ¹¹¹indium-oxine [¹¹¹In] as a lipophilic radiolabel encapsulated within the polymeric matrix, and the distribution of the nanoparticles was studied in plasma and all the vital organs following intravenous administration. Solid tumors were developed on nude mice using human ovarian carcinoma xenograft (SKOV-3) and the change in concentrations of tritium [³H]-labeled paclitaxel encapsulated in polymeric nanoparticles was examined in blood, tumor mass, and liver. Results Study in normal mice with a gamma-emitting isotope [¹¹¹In] provided a thorough biodistribution analysis of the PEO-modified nanoparticulate carrier systems, whereas ³H-paclitaxel was useful to understand the change in concentration and tumor localization of anticancer compound directly in major sites of distribution. Both PEO-PbAE and PEO-PCL nanoparticles showed long systemic circulating properties by virtue of surface modification with PEO-containing triblock block copolymer (Pluronic?) stabilizer. Although the PCL nanoparticles showed higher uptake by the reticuloendothelial system, the PbAE nanoparticles effectively delivered the encapsulated payload into the tumor mass. Conclusions PEO-modified PbAE nanoparticles showed considerable passive tumor targeting potential in early stages of biodistribution via the enhanced permeation and retention (EPR) mechanism. This prompts a detailed biodistribution profiling of the nanocarrier for prolonged periods to provide conclusive evidence for superiority of the delivery system.     

Prediction of Clinical Drug–Drug Interactions of Veliparib (ABT-888) with Human Renal Transporters (OAT1, OAT3, OCT2, MATE1, and MATE2K)

Veliparib (ABT-888) is largely eliminated as parent drug in human urine (70% of the dose). Renal unbound clearance exceeds glomerular filtration rate, suggesting the involvement of transporter-mediated active secretion. Clinically relevant pharmacokinetic interactions in the kidney have been associated with OAT1, OAT3, OCT2, MATE1, and MATE2K. In the present study, interactions of veliparib with these transporters were investigated. Veliparib inhibited OAT1, OAT3, OCT2, MATE1, and MATE2K with IC₅₀ values of 1371, 505, 3913, 69.9, and 69.5 μM, respectively. The clinical unbound maximum plasma concentration of veliparib after single oral dose of 50 mg (0.45 μM) is manyfold lower than IC₅₀ values for OAT1, OAT3, OCT2, MATE1, or MATE2K. These results indicate a low potential for drug–drug interaction (DDI) with OAT1/3, OCT2, or MATE1/2 K. Additional studies demonstrated that veliparib is a substrate of OCT2. In Oct1/Oct2 double-knockout mice, the plasma exposure of veliparib was increased by 1.5-fold, and the renal clearance was decreased by 1.8-fold as compared with wild-type mice, demonstrating that organic cation transporters contribute to the renal elimination in vivo. In summary, the in vitro transporter data for veliparib predicts minimal potential for an OAT1/3-, OCT2-, and MATE1/2 K-mediated DDI given the clinical exposure after single oral dose of 50 mg.     

Fabrication of Hierarchical Polymeric Thin Films by Spin Coating Toward Production of Amorphous Solid Dispersion for Buccal Drug Delivery System: Preparation,Characterization, and In Vitro Release Investigations

The landscape of thin films is continuously evolving as an attractive self-administration mean to drive patient compliance. This work reports incorporation of drugs into various polymeric compositions using spin coating technology to screen amorphous solid dispersion film formation for buccal applications. Polarized light microscopy and differential scanning calorimetry were used for characterization. Physical stability was assessed after films storage at 0% RH/25°C for 6 months. Chlorpheniramine maleate, theophylline, and famotidine were used as model drugs and mixed with Opadry amb II^® or Kollicoat IR^®. Acryl-EZE II^® or Zein was also used as surface (design I) or surface and base polymers (design II). Of all the drug-Opadry combinations, only chlorpheniramine was amorphously dispersed up to 25% (w/w). In contrast, Kollicoat IR^® resulted in amorphous dispersions of all the tested drugs, suggesting that it has a better solubilization capacity. Drugs prepared in design II achieved higher in vitro release compared to respective design I, indicating that lower content of Acryl-EZE II^® or Zein can decrease drug release over 3 h. It has been also revealed that Zein could improve physical stability of the aged theophylline solid-dispersed films. Release kinetics of model drugs were satisfactory when described by first-order kinetics, facilitated through anomalous transport of both diffusion and polymer swelling.     

Physiologically based pharmacokinetics in Drug Development and Regulatory Science: A workshop report (Georgetown University, Washington, DC, May 29–30, 2002)

A 2-day workshop on "Physiologically Based Pharmacokinetics (PBPK) in Drug Development and Regulatory Science" came to a successful conclusion on May 30, 2002, in Washington, DC. More than 120 international participants from the environmental and predominantly pharmaceutical industries, Food and Drug Administration (FDA), and universities attended this workshop, organized by the Center for Drug Development Science, Georgetown University, Washington, DC. The first of its kind specifically devoted to the subject, this intensive workshop, comprising 7 plenary presentations and 10 breakout sessions addressed 2 major objectives: (1) to "define demonstrated and potential contributions of PBPK in drug development and regulatory science," and (2) to "assess current PBPK methodologies with the identification of their limitations and outstanding issues." This report summarizes the presentations and recommendations that emerged from the workshop, while providing key references, software, and PBPK data sources in the appendices. The first day was initially devoted to presentations setting the stage and providing demonstrated applications to date. This was followed by breakout sessions that considered further opportunities and limitations, and which extended into Day 2 to deal with developments in methodologies and tools. Although the primary emphasis was on pharmacokinetics, consideration was also given to its integration specifically with mechanism-based pharmacodynamics.     

Paclitaxel Prodrugs with Sustained Release and High Solubility in Poly(ethylene glycol)-b-poly(ε-caprolactone) Micelle Nanocarriers: Pharmacokinetic Disposition, Tolerability, and Cytotoxicity

Purpose

Develop a Cremophor® and solvent free formulation of paclitaxel using amphiphilic block co-polymer micelles of poly(ethylene glycol)-b-poly(?-caprolactone) (PEG-b-PCL) and characterize their release, solubility, cytotoxicity, tolerability, and disposition.

Methods

Hydrophobic prodrugs of paclitaxel were synthesized via DCC/DMAP or anhydride chemistry to overcome the poor loading (<1% w/w) of paclitaxel in micelles of PEG-b-PCL. Micelles were prepared by a co-solvent extraction technique. A micellar formulation of paclitaxel prodrug (PAX7′C₆) was dosed intravenously to rats (10 mg/kg) and compared to Taxol® (paclitaxel in CrEL:EtOH) and PAX7′C₆ in CrEL:EtOH as controls at the same dose. Pharmacokinetic parameters and tissue distribution were assessed.

Results

Paclitaxel prodrugs had solubilities >5 mg/ml in PEG-b-PCL micelles. Resulting PEG-b-PCL micelles contained 17-22% w/w prodrug and were less than 50 nm in diameter. PEG-b-PCL micelles released paclitaxel prodrugs over several days, t_1/2>3 d. Only the 7′derivative of paclitaxel with the shortest acylchain 7′hexonoate (PAX7′C₆) maintained cytotoxic activity similar to unmodified paclitaxel. PAX7′C₆ micelles demonstrated an increase in area under the curve, half-life, and mean residence time while total clearance and volume of distribution decreased.

Conclusions

Paclitaxel prodrugs in PEG-b-PCL micelle nanocarriers augment the disposition and increase tolerability making further studies on tumor efficacy warranted.     

Stability of Interleukin 1β (IL-1β) in Aqueous Solution: Analytical Methods,Kinetics, Products,and Solution Formulation Implications

The thermal stability of IL-1 in aqueous solution as a function of temperature (5–60°C), pH (2–9), buffer (acetate, citrate, tris, and phosphate), and cyroprotectants (sugars, HSA) was investigated in this study. The analytical methodologies included RP-HPLC, SEC, ELISA, IEF-PAGE, SDS-PAGE, and bioassay. The degradation and inactivation of IL-1 at or above 39°C were attributed to autoxidation of the two cysteine residues in the denatured protein, followed by hydrophobic/covalent aggregation and precipitation. At or below 30°C, IEF- and SDS-PAGE results suggest a possible deamidation reaction. The difference in mechanism of degradation precludes the prediction of formulation shelf life from accelerated temperature data. Nonetheless, the good stability observed at 5°C suggests that a solution formulation may be feasible for IL-1.