pH-sensitive Release Behavior Research Articles

Simple way to obtain pH-sensitive drug release from functional mesoporous silica materials.

A novel pH-sensitive drug release system has been synthesised by functional mesoporous silica materials. SBA-15, calcium modified SBA-15 (Ca-SBA-15) and phosphate modified SBA-15 (PO4-SBA-15) were synthesised using solvent evaporation method. It is a simple and feasible way to prepare the doping mesoporous silica materials. They show the large surface are, high pore volume and uniform pore size. Metformin hydrochloride was used as the model drug, and the control release behaviour was investigated. The functional mesoporous silica materials show the pH sensitive drug release behaviour because of the adjustable interaction between the drug molecule and the host.

Development of poly(lactic-co-glycolic acid) microparticles with pH-sensitive drug release behaviors

We developed a novel pH-sensitive microparticle using poly(lactide-co-glycolide) (PLGA) and 3-diethylaminopropylated poly(l-lysine) [poly(Lys-DEAP)] (pKb of DEAP ~6.5). Here, the design of the microparticle takes advantage of the unique pH-sensitive feature of poly(Lys-DEAP) as either a non-ionic characteristic of DEAP moieties at pH 7.4 or an ionic characteristic of DEAP moieties at acidic pH. In particular, the ionized DEAP in PLGA microparticles modulated acidic pH-activated microparticle-destruction and allowed accelerated release of the encapsulated drug content when the pH of the solution was decreased to from 7.4 to 6.8 or 6.0. We believe that this microparticle system is expected to improve the treatment efficacy for lung diseases with chronic respiratory acidosis.

PH and Thermo Dual-Stimuli-Responsive Drug Carrier Based on Mesoporous Silica Nanoparticles Encapsulated in a Copolymer–Lipid Bilayer

A pH and thermo dual-controllable composite structure was developed as a triggerable drug delivery carrier. In such a drug carrier, a mesoporous silica nanoparticle (MSN) acts as the drug loading core, while a layer of copolymer-lipid serves as the dual-responsive gating shell. Specifically, the copolymer-lipid bilayer consists of natural phospholipids (soy phosphatidylcholine, SPC) and the poly(N-isopropylacrylamide-methacrylic acid-octadecyl acrylate) (p(NIPAM-MAA-ODA)) copolymer. With this structure, a high drug loading capacity and a sustained release effect could be provided by the MSN core, while a pH and thermo dual-responsive releasing ability could be offered by the copolymer-lipid bilayer. In addition, the introduction of SPC instead of the traditionally used phospholipids (such as dioleoyl phosphatidylethanolamine (DOPE) or dipalmitoyl phosphatidylcholine (DPPC)) results in a much lower cost and a better serum stability. Using doxorubicin (DOX) as the drug model, our results confirmed that either pH or temperature can trigger the drug release. However, much more drugs could be released by simultaneously controlling the pH and temperature. Furthermore, after being cocultured with cancer cells (MCF-7), the drug carriers transported DOX into the cells and exhibited a pH-sensitive release behavior. Since most tumor sites usually exhibit a more acidic environment or a higher temperature, the pH- and thermo-responsive releasing ability of this drug carrier is particularly useful and important for the targeted release at the tumor region. Thus, due to the powerful controlled releasing ability, the straightforward preparation method, and low cost, the demonstrated nanocarrier will have potential applications in controllable drug delivery and cancer therapy.

PH 감응성 P(MAA-co-PEGMA) 수화젤이 알부민의 방출과 안정성에 미치는 영향

본 연구에서는 pH 감응성 수화젤 입자를 이용하여 외부환경에 불안정한 활성물질을 화장품 제형 내에서는 안정하게 보존하고, 피부에 도포 시 빠른 방출로 피부에 흡수될 수 있는 지능형 전달시스템의 구현 가능성을 확인하기 위하여, 분산광중합을 이용하여 pH 감응성을 가지는 P(MAA-co-PEGMA) 수화젤 입자를 평균 크기 약 <TEX>$2{\mu}m$</TEX>의 구형 입자로 합성하였다. 합성된 P(MAA-co-PEGMA) 수화젤 입자는 수화젤의 MAA에 존재하는 카르복시기의 이온화에 의하여 pH 5를 전후로 한 급격한 팽윤비의 변화를 보여주었다. pH에 따른 수화젤 내부에 탑재된 알부민의 방출 및 피부투과 실험결과, P(MAA-co-PEGMA) 수화젤 입자는 pH 4.0에서는 소량의 알부민이 방출되어 피부 투과가 거의 일어나지 않은 반면, pH 6.0에서는 초기부터 다량의 알부민이 방출되어 상대적으로 높은 피부투과율을 나타내었다. 펩신을 이용한 알부민의 안정성 실험결과, P(MAA-co-PEGMA) 수화젤은 내부에 탑재된 알부민을 외부 환경으로부터 보호하여 알부민의 안정성을 유지시켜 주었다. pH-sensitive P(MAA-co-PEGMA) hydrogel particles were prepared and their feasibility as smart delivery carriers for cosmetic ingredients was evaluated. P(MAA-co-PEGMA) hydrogel particles having an average size of approx. <TEX>$2{\mu}m$</TEX> were synthesized via dispersion photopolymerization. There was a drastic change in the swelling ratio of P(MAA-co-PEGMA) particles at a pH of around 5 due to the ionization of MAA in the hydrogel and as the amount of MAA in the hydrogel increased, the swelling ratio increased at a pH above 5. The P(MAA-co-PEGMA) hydrogel particles showed a pH-sensitive release behavior. Thus, at pH 4 almost none of the albumin permeated through the skin while at pH 6 relatively high skin permeability was obtained. The albumin loaded in the P(MAA-co-PEGMA) hydrogel particles was hardly degraded in the presence of pepsin and its stability was maintained.

Selectively functionalized mesoporous silica particles with the PEGylated outer surface and the doxorubicin-grafted inner surface: Improvement of loading content and solubility

We prepared selectively functionalized, spherical mesoporous silica particles (SMSPs) with a polyethylene glycol (PEG)-grafted outer surface and a doxorubicin-grafted inner surface for drug delivery. The SMSPs were fabricated by co-condensation of an amphiphilic organotriethoxysilane with a thermally cleavable urethane bond and tetraethoxysilane (TEOS) in the presence of cetyltrimethylammonium bromide (CTAB) under basic conditions. The outer surface of the as-precipitated silica particles was functionalized by grafting with 3-(triethoxysilyl)propyloxy–PEG. The PEG-grafted SMSPs were refluxed in methanol in the presence of HCl, resulting in the removal of surfactant molecules and the formation of a methoxy urethane group tethered to the pore wall. After the reaction of the methoxy urethane group with hydrazine, doxorubicin was chemically introduced into the pores through a pH-sensitive hydrazone linkage. A high loading content was achieved through chemical loading followed by physical loading. The doxorubicin-loaded SMSPs showed a pH-sensitive and sustained release behavior.

Self-assembled inorganic/organic hybrid nanoparticles with multi-functionalized surfaces for active targeting drug delivery.

With the aim to develop a facile strategy to prepare multi-functional drug carriers and construct a new smart drug delivery platform, we prepared KALA/heparin-biotin/heparin/chitosan/CaCO3 (KALA/HPB/HP/CTS/CaCO3) hybrid nanoparticles with pH sensitivity, active targeting properties and cell penetrating abilities. All the functional components were introduced to the nanoparticles by self-assembly. The usage of the hybrid nanoparticles as an anti-cancer drug delivery platform was investigated. For comparison, HP/CTS, HP/CTS/CaCO3 and HPB/HP/CTS/CaCO3 hybrid nanoparticles were also prepared. The sizes and size distributions of the nanoparticles were determined by dynamic light scattering (DLS). The structure and morphology of the nanoparticles were characterized by X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analyzer (TGA). Doxorubicin hydrochloride (DOX) was loaded in the hybrid nanoparticles and the in vitro release study showed that the CaCO3 containing nanoparticles exhibited pH sensitive release behavior and could efficiently sustain the drug release. In vitro cellular cytotoxicity indicated the blank hybrid nanoparticles had good biocompatibility. DOX loaded KALA/HPB/HP/CTS/CaCO3 hybrid nanoparticles exhibited the strongest tumor cell inhibition effects compared with free DOX and other DOX loaded nanoparticles because of the enhanced cell uptake caused by the cell penetrating peptide and the biotin moiety in the nanoparticles. All those results indicated that the KALA/HPB/HP/CTS/CaCO3 hybrid nanoparticles could be promising carriers for drug delivery.

Preparation and biological characterization of hollow magnetic Fe3O4@C nanoparticles as drug carriers with high drug loading capability, pH-control drug release and MRI properties.

Fe3O4@C nanocapsules were synthesized via a sacrificial-template method by coating SiO2 nanospheres with an Fe3O4@C double-shell structure, followed by dissolving SiO2 nanospheres through ammonia water under hydrothermal conditions. The nanocapsules show a loading capacity as high as 1300 mg g-1 for doxorubicin (DOX), and the DOX loaded on the surface of the carbon shells displays pH-sensitive release behavior. Drug release experiments were carried out at pH 7.4, 6.2 and 5.0. It was found that the drug release rate at pH 6.2 was about two times as fast as that at pH 7.4, and even faster at pH 5.0. A MTT assay was used to test the cytotoxicity of the DOX, nanocapsules and DOX-nanocapsules, which indicated the low cytotoxicity of the nanocapsules towards cells. The DOX-nanocapsules can be taken up by cancer cells through endocytosis, releasing DOX into the cytoplasm, which was observed by both transmission electron microscopy and confocal microscopy. In vitro magnetic resonance imaging (MRI) experiments validated the potential use of these nanocapsules as MRI contrast agents.

Cosynthesis of Cargo-Loaded Hydroxyapatite/Alginate Core–Shell Nanoparticles (HAP@Alg) as pH-Responsive Nanovehicles by a Pre-gel Method

A new core-shell nanostructure consisting of inorganic hydroxyapatite (HAP) nanoparticles as the core and organic alginate as the shell (denoted as HAP@Alg) was successfully synthesized by a pre-gel method and applied to pH-responsive drug delivery systems (DDS). HAP@Alg nanoparticles have the advantages of hydroxyapatite and alginate, where hydroxyapatite provides pH-responsive degradability, and alginate provides excellent biocompatibility and COOH functionality. Through the subsequent addition of CaCl(2) and phosphate solutions to the alginate solution, HAP@Alg nanoparticles with controllable particle sizes (ranging from 160 to 650 nm) were obtained, and their core-shell structure was confirmed through transmission electron microscopy (TEM) observation. Rhodamine 6G (R6G), a positively charged dye, was selected as a model drug for pH-sensitive DDS. R6G was encapsulated in the HAP/Alg nanoparticles upon synthesis, and its loading efficiency could reach up to approximately 63.0%. The in vitro release behavior of the loaded R6G at different pH values was systematically studied, and the results indicated that more R6G molecules were released at lower pH conditions. For example, after releasing for 8 h, the release amount of R6G at pH 2.0 was 2.53-fold the amount at pH 7.4. We attributed this pH-sensitive release behavior to the dissolution of the HAP core in acidic conditions. The results of the MTT assay and confocal laser scanning microscopy indicated that the HAP@Alg were successfully uptaken by liver cancer cells (HepG2) without apparent cytotoxicity. The synthesized HAP@Alg nanoparticles show great potential as drug nanovehicles with high biocompatibility, enhanced drug loading, and pH-responsive features for future intracellular DDS.

Host–Guest Assembly of pH-Responsive Degradable Microcapsules with Controlled Drug Release Behavior

Biodegradable microcapsules with pH-responsibility were fabricated with host–guest interaction between β-cyclodextrin (β-CD) and adamantane (AD). Two biocompatible polymers, dextran-graft-β-CD (Dex-g-β-CD) and poly(aspartic-graft-adamantane) (PASP-g-AD), were assembled on CaCO3 particles. Rhodamine B (Rh B) was captured in the core as a model drug. With CaCO3 particles removed by EDTA, hollow microcapsules loaded with Rh B were obtained. As β-CD was grafted to polyaldehyde dextran (PAD) through pH-sensitive C═N bonds, the capsules could degrade and release Rh B in an acidic environment, showing a pH-sensitive release behavior. Confocal laser scanning microscopy (CLSM), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) were used to characterize the capsules. In vitro drug release and degradation of the microcapsules were studied. The capsules were coincubated with HeLa cells at different pH values, further proving the controlled release behavior. In conclusion, the pH-sensitive microcapsules have great application potential in drug delivery.

Smart delivery system for cosmetic ingredients using pH-sensitive polymer hydrogel particles

pH-Sensitive P(MAA-co-EGMA) hydrogel microparticles were prepared and their feasibility as smart delivery carriers for cosmetically active ingredients such as arbutin, adenosine, and niacinamide was evaluated. P(MAAco-EGMA) hydrogel microparticles were synthesized via dispersion photopolymerization. There was a drastic change in the swelling ratio of P(MAA-co-EGMA) microparticles at a pH of around 5. The loading efficiency of the cosmetic ingredients was affected by the electrostatic interaction between the hydrogel and the cosmetic ingredients. The P(MAAco-EGMA) hydrogel microparticles showed a pH-sensitive release behavior. Thus, at pH 4 almost none of the cosmetic ingredients except adenosine permeated through the skin, while at pH 6 relatively high skin permeability was obtained. These results indicate that the P(MAA-co-EGMA) hydrogel microparticles synthesized in this study have the potential to be used as a smart carrier for cosmetic ingredients triggered by an external pH change for cosmetic applications.

Preparation and characterization of polymeric pH-sensitive STEALTH® nanoparticles for tumor delivery of a lipophilic prodrug of paclitaxel

Paclitaxel is an effective and widely used anti-cancer agent. However, the drug is difficult to formulate for parenteral administration because of its low water solubility and Cremophor EL, the expient used for its formulation, has been shown to cause serious side effects. The present study reports an alternative administration vehicle involving a lipophilic paclitaxel prodrug, paclitaxel oleate, incorporated in the core of a nanoparticle-based dosage form. A hydrophobic poly (β-amino ester) (PbAE) was used to formulate the nanoparticles, which were stabilized with a mixture of phosphatidylcholine, Synperonic® F 108, and poly(ethylene glycol)-dipalmitoyl phosphatidyl ethanolamine. PbAE undergoes rapid dissolution when the pH of the medium is less than 6.5 and is expected to rapidly release its content within the acidic tumor microenvironment and endo/lysosome compartments of cancer cells. PbAE nanoparticles were prepared by an ultrasonication method and characterized for particle size and physical stability. The nanoparticles obtained had a diameter of about 70nm and a good physical stability when stored at 4°C. In vitro cellular uptake and release of paclitaxel oleate PbAE nanoparticles were studied in Jurkat acute lymphoblastic leukemia cells. The results were compared with pclitaxel oleate in poly(ɛ-caprolactone) (PCL) particles, that do not display pH-sensitive release behavior, and paclitaxel in PbAE particles. Both uptake and release of the prodrug were faster when administered in PbAE than in PCL, but much slower than those of the free drug in PbAE. Cytotoxicity assay was performed on the formulations at different doses. Paclitaxel and paclitaxel oleate showed almost identical activity, IC50 123 and 128nM, respectively, while that of the prodrug in PCL was much lower with IC50 at 2.5μM. Thus, PbAE nanoparticles with the incorporated paclitaxel prodrug paclitaxel oleate may prove useful for replacement of the toxic Cremophor EL and also by improving the distribution of the drug to the tumor.

PH-responsive hydrogel microparticles as intelligent delivery carriers for α-MSH antagonists

For a first step in the development of an intelligent delivery system for a nonapeptide as an α-MSH antagonist, pH-responsive P(MAA-co-EGMA) hydrogel microparticles were prepared and their feasibility as intelligent delivery carriers was evaluated. There was a drastic change in the swelling ratio of P(MAA-co-EGMA) microparticles at a pH of around 5 and as the MAA amount in the hydrogel increased, the swelling ratio increased at a pH above 5. The loading efficiency of the nonapeptide at pH 7 increased with the amount of Methacrylic acid (MAA) in the hydrogel and at pH 2, where the electrostatic attraction was greatest, a high loading efficiency was not obtained because of the low swelling ratio of the hydrogel. The P(MAA-co-EGMA) microparticles demonstrated a pH-sensitive release behavior for the nonapeptide. In addition, the P(MAA-co-EGMA) microparticles showed a protective ability for the nonapeptide and preserved the stability of the nonapeptide. © 2010 American Institute of Chemical Engineers AIChE J, 2010

Development of smart delivery system for ascorbic acid using pH-responsive P(MAA-co-EGMA) hydrogel microparticles

pH-Responsive P(MAA-co-EGMA) hydrogel microparticles were prepared and their feasibility as intelligent delivery carriers was evaluated. P(MAA-co-EGMA) hydrogel microparticles were synthesized via dispersion photopolymerization. There was a drastic change in the swelling ratio of P(MAA-co-EGMA) microparticles at a pH of ~ 5 and, as the amount of MAA in the hydrogel increased, the swelling ratio increased at a pH above 5. The loading efficiency of the ascorbic acid into the hydrogel was affected more by the degree of swelling of the hydrogel than the electrostatic interaction between the hydrogel and the loaded ascorbic acid. The P(MAA-co-EGMA) hydrogel microparticles showed a pH-sensitive release behavior. Thus, at pH 4 almost none of the ascorbic acid permeated through the skin while at pH 6 relatively high skin permeability was obtained. The ascorbic acid loaded in the hydrogel particles was hardly degraded and its stability was maintained at high temperature.

Preparation and pH-Sensitive Release Behavior of Alginate/Activated Carbon Composite Magnetic Hydrogels

The alginate-based hydrogel was prepared as a pH-sensitive drug delivery system. To enhance the drug loading capacity, activated carbon was introduced as a drug absorbent. The iron oxide was incorporated into the alginate matrix for the magnetic transferring to the target organ. The activated carbon and iron-oxide were dispersed uniformly in the alginate hydrogel. The drug release from the alginate/activated carbon composite hydrogel was carried out in various pH conditions with vitamin B12 and Lactobacillus lamnosers as model drugs. The fast and sustainable release of drug was observed in the basic condition due to the pH-sensitive solubility of alginate. The novel drug delivery system having pH-sensitive release property and magnetic movement to target place was developed by using the alginate/activated carbon composite magnetic hydrogels.

Preparation and Characterization of pH-Sensitive Anionic Hydrogel Microparticles for Oral Protein-Delivery Applications

pH-sensitive P(MAA-g-EG) anionic hydrogel microparticles having an average diameter of approx. 4 μm were prepared by suspension photopolymerization. The pH-sensitive swelling and release behaviors of the P(MAA-g-EG) hydrogel microparticles were investigated as a biological on–off switch for the design of an oral protein delivery system triggered by external pH changes in the human GI tract. There was a drastic change of the equilibrium weight swelling ratio of P(MAA-g-EG) particles at a pH of around 5, which is the pK a of PMAA. At pH < 5, the particles were in a relatively collapsed state, while at a pH > 5 the particles swelled to a high degree. When the concentration of the cross-linker of the hydrogel increased, the swelling ratio of the P(MAA-g-EG) hydrogel microparticles decreased at a pH higher than 5 and the pK a of all the microparticles was in the pH range 4.0–6.0. In release experiments using Rhodamine B (Rh-B) as a model solute, the P(MAA-g-EG) hydrogel microparticles showed a pH-responsive release behavior. At low pH (pH 4.0) only a small amount of Rh-B was released while at high pH (pH 6.0) a relatively large amount of Rh-B was released from the hydrogel particles.

Complexation hydrogels for intestinal delivery of interferon β and calcitonin

Recent studies have suggested that complexation hydrogels poly(methacrylic acid-g-ethylene glycol) (henceforth designated as P(MAA-g-EG)) exhibit high insulin incorporation efficiency, rapid insulin release in the intestine based on their pH-dependent complexation properties, enzyme-inhibiting effects and mucoadhesive characteristics. Therefore, they are promising carriers for insulin delivery via an oral route. As we designed these hydrogels as carriers suitable for oral administration of various peptide/protein drugs, in this study we aimed at investigating the applicability of P(MAA-g-EG) hydrogels to improving the intestinal absorption of various peptide/protein drugs. High loading efficiency into hydrogels was observed for insulin, calcitonin, and interferon β. In addition, polymer microparticles loaded with calcitonin and interferon β exhibited complexation/decomplexation and pH-sensitive release behavior. The molecular weight and chemical structure appeared to affect the efficiency of loading and release depending on the peptides and proteins. Furthermore, a drastic reduction of plasma calcium concentration accompanied by calcium absorption and a dose-dependent enhancement of plasma interferon β concentration were observed after the administration of particles loaded with calcitonin or interferon β into closed rat ileal segments. These findings indicate that P(MAA-g-EG) hydrogels are promising carriers for administration of various peptides and proteins via an oral route.

Chitosan/pectin polyelectrolyte complexes: Selection of suitable preparative conditions for colon-specific delivery of vancomycin

The influence of polyelectrolyte complexes composed of chitosan and pectin on the release behaviour of vancomycin has been investigated. Polyelectrolyte complexes between chitosan and pectin were prepared in various pH regions and at different molar ratios by mixing solutions of pectin and chitosan with the same ionic strength. The precipitates were collected by spray-drying and tablets were obtained with the different complexes and vancomycin. FT-IR spectra and TGA thermograms were analysed to study the degree of interactive strength between polyions. In vitro swelling, mucoadhesion and release tests were performed in order to investigate the chitosan/pectin complex ability in the delivery of vancomycin in the gastro-intestinal tract. The results confirmed the formation of polyelectrolyte complexes between pectin and chitosan at pH values in the vicinity of the p K a interval of the two polymers. Chitosan/pectin complexes showed a pH-sensitive swelling ability and drug release behaviour suggesting their possible use for colon-specific localization of vancomycin. Among the different complexes, chitosan/pectin complex prepared in molar ratio of 1:9 showed the highest mucoadhesive properties and a pH-dependent swelling sensitivity suitable for colon-delivery. Moreover, the particular composition of these complexes improved vancomycin availability at alkaline pH on the bases of an enzyme-dependent degradation as confirmed from release studies performed in presence of beta-glucosidase.

Formulation Variables Influencing Drug Release from Layered Matrix System Comprising Chitosan and Xanthan Gum

The purpose of this study was to investigate the formulation variables influencing the drug release from the layered tablets containing chitosan and xanthan gum as matrix component. Increasing the amount of lactose could diminish pH sensitive release behavior of these matrix tablets. Effect of formulation variables on drug release from the prepared three-layered matrix tablets was investigated. The amount of drug loading did not affect the drug release which was influenced by the hydrodynamic force and the matrix composition. An increase in stirring rate correspondingly increased the release rate. Moreover, incorporation of soluble diluents in core or barrier could enhance the drug release. Least square fitting the experimental dissolution data to the mathematical expressions (power law, first order, Higuchi's and zero order) was carried out to study the drug release mechanism. Most dissolution profiles of the prepared three-layered tablets provided a better fit to zero order kinetic than to first order kinetic and Higuchi's equation.

Poly(ethylene oxide)-Modified Poly(β-amino ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs. 1. In Vitro Evaluations

A representative poly(beta-amino ester) (PbAE) with biodegradable and pH-sensitive properties was used to formulate a nanoparticle-based dosage form for tumor-targeted paclitaxel delivery. The polymer undergoes rapid dissolution when the pH of the medium is less than 6.5 and hence is expected to release its contents at once within the acidic tumor microenvironment and endo/lysosome compartments of cells. PbAE nanoparticles were prepared by solvent displacement method and characterized for particle size, charge, and surface morphology. Pluronic F-108, a triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), was blended with PbAE to induce surface modification of the nanoparticles. In vitro cellular uptake of tritiated [(3)H]-paclitaxel in solution form and as a nanoparticulate formulation was studied in MDA-MB-231 human breast adenocarcinoma cells grown in 12-well plates. We also examined the intracellular degradation pattern of the formulations within the cells by estimating the drug release profile. Cytotoxicity assay was performed on the formulations at different doses and time intervals. Nanoparticles prepared from poly(epsilon-caprolactone) (PCL) that do not display pH-sensitive release behavior were used as control. Spherical nanoparticles having positive zeta potential ( approximately 40 mV) were obtained in the size range of 150-200 nm with PbAE. The PEO chains of the Pluronic were well-anchored within the nanomatrix as determined by electron spectroscopy for chemical analysis (ESCA). The intracellular accumulation of paclitaxel within tumor cells was significantly higher when administered in the nanoparticle formulations as compared to aqueous solution. Qualitative fluorescent microscopy confirmed the rapid release of the payload into the cytosol in the case of PbAE nanoparticles, while the integrity of the PCL nanoparticles remained intact. The cytotoxicity assay results showed significantly higher tumoricidal activity of paclitaxel when administered in the nanoparticle formulations. The cell-kill effect was maximal for paclitaxel-loaded PbAE nanoparticles when normalized with respect to intracellular drug concentrations. Thus, PEO-modified PbAE nanoparticles show tremendous potential as novel carriers of cytotoxic agents for achieving improved drug disposition and enhanced efficacy.

Elucidation of the mechanism of incorporation of insulin in controlled release systems based on complexation polymers

The objective of this study was to investigate the insulin incorporation and release properties of poly(methacrylic acid- g-ethylene glycol) P(MAA- g-EG) microparticles as a function of copolymer composition. These microparticles exhibited unique pH-responsive characteristics in which interpolymer complexes were formed in acidic media and dissociated in neutral/basic environments. The microparticles containing equimolar amounts of MAA and PEG were capable of efficient insulin loading using equilibrium partitioning (>90%). Additionally, insulin release from the gel was significantly retarded in acidic media while rapid release occurred under neutral/basic conditions. In contrast, as the amount of MAA of the polymer was increased, the entrapment efficiency of insulin within the gel greatly reduced and the insulin was readily released from the polymer network in the acidic and neutral/basic media. In addition, in order to evaluate the potential application of the microparticles to other drugs, theophylline, vancomycin, fluorescein-isothiocyanate-labeled dextrans (FITC-Ds) with average molecular weights of 4400 (FITC-D-4), 12,000 (FITC-D-10) and 19,500 (FITC-D-20) were utilized as model hydrophilic drugs. The incorporation profiles showed that the uptake of theophylline and vancomycin to the microparticles was lower than that of insulin. Additionally, polymer microparticles loaded with theophylline and vancomycin exhibited pH-sensitive release behavior, however, the oscillatory behavior is less pronounced than those of insulin. The values of drug incorporation ratio showed that the microparticles were capable of incorporating almost 90% of insulin and 15% of vancomycin from solution. On the other hand, the other hydrophilic drugs showed very low incorporation efficiency to the microparticles. These data suggest that gels containing equimolar amounts of MAA:EG have the potential to be used as an oral carrier of peptide drugs, especially for insulin.