Preparation and properties of monodispersed rifampicin-loaded poly(lactide-co-glycolide) microspheres

Monodispersed rifampicin (RFP)-loaded poly(lactide-co-glycolide) (PLGA) microspheres were prepared by a solvent evaporation method. In order to control the sizes of the microspheres, a membrane emulsification technique using Shirasu porous glass (SPG) membranes was applied. RFP/PLGA microspheres with the average diameters of 1.3, 2.2, 5.2, and 9.0 microm were obtained. They were relatively monodisperse and the values of the coefficient of variation (CV) for the size distributions of the microspheres were in the range between 7.0 and 16.0%. The loading efficiency of RFP was in the range between 50.3 and 67.4% independent of the microsphere size. The release ratio of RFP from RFP/PLGA microspheres was measured in pH 7.4 PBS at 37 degrees C. From RFP/PLGA microspheres with average diameters of 1.3 and 2.2 microm, almost 60% of RFP loaded in the microspheres was released in the initial day and the release was terminated almost within 10 days. On the other hand, from those with average diameters of 5.2, and 9.0 microm, the release of RFP was observed even 20 days after the release started.     

Preparation of uniform-sized pH-sensitive quaternized chitosan microsphere by combining membrane emulsification technique and thermal-gelation method

In this study, uniform-sized pH-sensitive quaternized chitosan microsphere was prepared by combining Shirasu porous glass (SPG) membrane emulsification technique and a novel thermal-gelation method. In this preparation process, the mixture of quaternized chitosan solution and alpha-beta-glycerophosphate (alpha-beta-GP) was used as water phase and dispersed in oil phase to form uniform W/O emulsion by SPG membrane emulsification technique. The droplets solidified into microspheres at 37 degrees C by thermal-gelation method. The whole process was simple and mild. The influence of process conditions on the property of prepared microspheres was investigated and the optimized preparation condition was obtained. As a result, the coefficient of variation (C.V.) of obtained microspheres diameters was below 15%. The obtained microsphere had porous structure and showed apparent pH-sensitivity. It dissolved rapidly in acid solution (pH 5) and kept stable in neutral solution (pH 7.4). The pH-sensitivity of microspheres also affected its drug release behavior. Bovine serum albumin (BSA) as a model drug was encapsulated in microspheres, and it was released rapidly in acid solution and slowly in neutral medium. The novel quaternized chitosan microspheres with pH-sensitivity can be used as drug delivery system in the biomedical field, such as tumor-targeted drug carrier.     

Thermally reversible pluronic/heparin nanocapsules exhibiting 1000-fold volume transition

Novel Pluronic/heparin composite nanocapsules that exhibit a thermally responsible swelling and deswelling behavior were synthesized. Pluronic F-127 preactivated with p-nitrophenyl chloroformate at its two terminal hydroxyl groups was dissolved in a methylene chloride phase. The organic phase was dispersed in an aqueous phase containing heparin. At an organic/aqueous interface, Pluronic-cross-linked heparin nanocapsules were produced. They exhibited a 1000-fold volume transition (ca. 336 nm at 25 degrees C; ca. 32 nm at 37 degrees C), and a reversible swelling and deswelling behavior when the temperature was cycled between 20 and 37 degrees C. The reversible volume transition of Pluronic nanocapsules was caused by micellization and demicellization of cross-linked Pluronic polymer chains within the nanocapsule structure in response to temperature. The morphological characters were investigated with transmission electron microscopy and small angle neutron scattering. Pluronic/heparin nanocapsules had an aqueous fluid-filled hollow interior with a surrounding shell layer below the critical temperature, but they became a collapsed core/shell structure similar to that of Pluronic micelles above it.     

Chromatographic studies of mitomycin C degradation in albumin microspheres

Serum albumins and polylactic acid (PLA) have been used as bioerodable polymers in the preparation of drug-containing microspheres for parenteral drug delivery. The albumin microsphere may be prepared via either chemical cross-linking or heat denaturation of the protein. Heat-denatured albumin microspheres containing mitomycin C (MMC) have been used in pre-clinical and clinical investigations. Due to the high reactivity of MMC as a bifunctional alkylating agent, a study on the stability of MMC in the albumin and PLA microspheres has been carried out using a high-performance liquid chromatographic (HPLC) method. Human serum albumin (HSA) microspheres were prepared using an emulsion method via either heat denaturation at 120 or 170 degrees C or the use of 0.5 M biacetyl as a cross-linking agent. The PLA microspheres were prepared by an emulsion method at 55 degrees C. HPLC analysis of the HSA microspheres showed that about 37% of MMC was converted to 2,7-diaminomitosene derivatives in microspheres prepared by heat denaturation at 120 degrees C. The degradation increased to 82% when the microspheres were prepared with a denaturation temperature of 170 degrees C. The use of biacetyl as a cross-linking agent in the preparation of HSA microspheres resulted in a complete degradation of the incorporated MMC. Biacetyl was found to interact with MMC leading to the formation of 7-aminomitosene derivatives. In contrast to the albumin system, MMC may be incorporated into PLA microspheres without degradation.     

Aqueous two-phase systems containing self-associating block copolymers. Partitioning of hydrophilic and hydrophobic biomolecules.

A series of proteins and one membrane-bound peptide have been partitioned in aqueous two-phase systems consisting of micelle-forming block copolymers from the family of Pluronic block copolymers as one polymer component and dextran T500 as the other component. The Pluronic molecule is a triblock copolymer of the type PEO-PPO-PEO, where PEO and PPO are poly(ethylene oxide) and poly(propylene oxide), respectively. Two different Pluronic copolymers were used, P105 and F68, and the phase diagrams were determined at 30 degrees C for these polymer systems. Since the temperature is an important parameter in Pluronic systems (the block copolymers form micellar-like aggregates at higher temperatures) the partitioning experiments were performed at 5 and 30 degrees C, to explore the effect of temperature-triggered micellization on the partitioning behaviour. The temperatures correspond to the unimeric (single Pluronic chain) and the micellar states of the P105 polymer at the concentrations used. The degree of micellization in the F68 system was lower than that in the P105 system, as revealed by the phase behaviour. A membrane-bound peptide, gramicidin D, and five different proteins were partitioned in the above systems. The proteins were lysozyme, bovine serum albumin, cytochrome c, bacteriorhodopsin and the engineered B domain of staphylococcal protein A, named Z. The Z domain was modified with tryptophan-rich peptide chains in the C-terminal end. It was found that effects of salt dominated over the temperature effect for the water-soluble proteins lysozyme, bovine serum albumin and cytochrome c. A strong temperature effect was observed in the partitioning of the integral membrane protein bacteriorhodopsin, where partitioning towards the more hydrophobic Pluronic phase was higher at 30 degrees C than at 5 degrees C. The membrane-bound peptide gramicidin D partitioned exclusively to the Pluronic phase at both temperatures. The following trends were observed in the partitioning of the Z protein. (i) At the higher temperature, insertion of tryptophan-rich peptides increased the partitioning to the Pluronic phase. (ii) At the lower temperature, lower values of K were observed for ZT2 than for ZT1.     

Controlling degradation of acid-hydrolyzable pluronic hydrogels by physical entrapment of poly(lactic acid-co-glycolic acid) microspheres

Chemically crosslinked biodegradable hydrogels based on di-acrylated Pluronic F-127 tri-block copolymer were prepared by a photopolymerization method. Poly(lactic acid-co-glycolic acid) (PLGA) microspheres were physically entrapped within the Pluronic hydrogel in order to modulate the local pH environment by acidic degradation by-products of PLGA microspheres. The PLGA microspheres were slowly degraded to create an acidic microenvironment, which facilitated the cleavage of an acid-labile ester-linkage in the biodegradable Pluronic hydrogel network. The presence of PLGA microspheres accelerated the degradation of the Pluronic hydrogel and enhanced the protein release rate when protein was loaded in the hydrogel.SEM image of photo-crosslinked Pluronic hydrogel entrapping PLGA microspheres.     

Nano-gel containing thermo-responsive microspheres with fast response rate owing to hierarchical phase-transition mechanism

A new strategy is developed in this study to achieve thermo-responsive microspheres with fast response rates by designing a hierarchical phase-transition mechanism. The proposed thermo-responsive microspheres are composed of poly(N-isopropylacrylamide-co-acrylic acid) (PNA) microsphere matrixes and embedded poly(N-isopropylacrylamide) (PNIPAM) nano-gels, which have different volume phase-transition temperatures (VPTTs). The VPTT of PNIPAM nano-gels (VPTT(1)) is lower than that of PNA microsphere matrixes (VPTT(2)). Upon heating-up, the temperature increases across the VPTT(1) first and then the VPTT(2), as a result the PNIPAM nano-gels shrink earlier than the PNA microsphere matrixes. Upon cooling-down, the temperature decreases across the VPTT(2) first and then the VPTT(1), as a result the PNA microsphere matrixes swell earlier than the PNIPAM nano-gels. Consequently, large amounts of voids and channels form around the nano-gels inside the microsphere matrixes when the temperature changes across the range between VPTT(1) and VPTT(2), which are beneficial to the enhancement of water transport rate inside the microsphere matrixes. The experimental results show that, compared with normal homogeneous PNA (N-PNA) microspheres, the nano-gel containing PNA (C-PNA) microspheres exhibit remarkably fast response rate due to the hierarchical phase-transition mechanism attributed to different VPTT values of the embedded nano-gels and the microsphere matrixes.     

Thermal characteristics of poly (DL-lactic acid) microspheres containing neurotensin analogue.

The thermal characteristics of poly (DL-lactic acid) (DL-PLA) microspheres containing a hexapeptide (NA: H(CH3)-Arg-Lys-Pro-Trp-tert-Leu-Leu-OEt) with neurotensin activity were investigated. PLA microspheres with a drug content of 1.5-11.0% were prepared by a novel o/w (oil-in-water) solvent evaporation method. Both DL-PLA and NA were amorphous in form, and an increase in heat capacity at glass transition temperature (Tg) of the polymer was observed in DL-PLA microspheres containing NA. The Tg of DL-PLA (PLA2000 bulk) was 307.8 K, while Tg of microspheres containing NA (content 6.0%) shifted to 321.2 K. The Tg of PLA2000 microspheres was found to increase with an increase in the content of NA, and its increasing tendency reached a plateau at an NA content of greater than 6%. The apparent activation energy of glass transition of PLA2000 bulk and the microspheres was calculated to be 86.3 and 99.3 kcal/mol, respectively. As a result of the release test after storage at 4 degrees C and 40 degrees C for 1 month, nearly the same release profiles of NA from PLA2000 microspheres were found. The release rate of NA after the initial release became slow after storage at 45 degrees C for 1 month. This may be attributed mainly to a decrease in surface area caused by the formation of agglomerates of PLA2000 microspheres under conditions near Tg.     

Effect of preparation temperature in solvent evaporation process on Eudragit RS microsphere properties

Eudragit RS 100 microspheres containing ketoprofen as a model drug were prepared by the solvent evaporation method using an acetone/liquid paraffin solvent system. The influence of various preparation temperatures: 10, 25, 35, and 40 degrees C, on particle size and morphology, drug content and release kinetics, and drug crystal state was evaluated. With increasing temperature, microsphere average size was found to increase and particle size distribution to widen significantly. At 10 degrees C particles of irregular shape are formed, whereas higher temperatures gradually improve the sphericity of microspheres. As can be seen from SEM photographs, particle surface roughness decreases as preparation temperature increases. It was found that temperature had no effect either on ketoprofen microencapsulation efficiency or on its crystal state, but it does influence emulsion-stabilizer incorporation. Ketoprofen forms solid solution in Eudragit matrix and maintains amorphous state for significant period of time. Drug release rates from microspheres correlated with microspheres' surface roughness and to a lesser extent with particle size.     

Synthesis and thermoresponsive behaviors of biodegradable Pluronic analogs

Pluronic analogs based on block copolymers of poly(propylene oxide) and poly(ethyl ethylene phosphate) (PEEP‐PPO‐PEEP) were synthesized, and the thermoresponsive behavior, including aggregation at low concentration and gelation at high concentration were studied. At lower concentrations up to 10 wt %, thermo‐induced aggregation of PEEP‐PPO‐PEEP was demonstrated by UV‐vis absorbance measurements using 1,6‐diphenyl‐1,3,5‐hexatriene as a probe. Microthermal analyzes showed symmetrically endothermic and exothermic thermograms during the thermo‐induced aggregation and de‐association processes, which was also associated with the dehydration and rehydration of PPO blocks, as revealed by the variable temperature NMR measurements. Thermo‐induced aggregation with the increased temperatures was also observed by dynamic light scattering. At higher concentration from 20 to 40 wt %, the aqueous solution of PEEP‐PPO‐PEEP underwent thermo‐induced phase transitions from a clear solution to a turbid solution, then to opaque gel and syneresis phases, depending on the molecular weights of PEEP blocks. Such a thermoresponsive hydrogel was used for doxorubicin incorporation. Sustained release of drug was achieved from the gel, demonstrating the polyphosphoester‐based Pluronic analogs' potential for biomedical applications. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 6168–6179, 2009     

Facile fabrication of thermally responsive Pluronic F127-based nanocapsules for controlled release of doxorubicin hydrochloride

Novel core–shell-structured Pluronic-based nanocapsules with thermally responsive properties were successfully prepared using a modified emulsification/solvent evaporation method. The nanocapsules were constructed through the cross-linking reaction between p-nitrophenyl-activated Pluronic F127 and hyaluronic acid (HA) (named Pluronic F127/HA) or poly(ε-lysine) (PL) (named Pluronic F127/PL) at the organic/aqueous interface. The formation, size, and thermal responsiveness of the nanocapsules were characterized by ¹H NMR, transmission electron microscopy (TEM) and dynamic light scattering (DLS). The resultant shell-cross-linked nanocapsules exhibit a larger volume transformation (26 times change in volume for Pluronic F127/HA and 31 times for Pluronic F127/PL) over a temperature range of 4–37 °C because of the temperature-dependent dehydration of cross-linked Pluronic F127 polymer chains. The nanocapsules are about 72?±?4 nm (polydispersity index [PDI]?=?0.08) for Pluronic F127/PL (69?±?5 nm, PDI?=?0.10 for Pluronic F127/HA) at 37 °C with narrow size distribution and expand to about 226?±?23 nm (PDI?=?0.34) for Pluronic F127/PL (206?±?20 nm, PDI?=?0.3) for Pluronic F127/HA at 4 °C with broad size distribution in aqueous solutions. The nanocapsules were used to encapsulate and control the release of doxorubicin hydrochloride (DOX·HCl) in aqueous solution. DOX·HCl was physically encapsulated in the nanocapsules using a soaking–freeze-drying–heating procedure. The release curve and release kinetics disclosed that the thermally responsive hollow nanocapsules are good carries for drug delivery.     

Effects of lung surfactants on rifampicin release rate from monodisperse rifampicin-loaded PLGA microspheres

We have prepared inhalable and monodisperse poly(lactide-co-glycolide) (PLGA) microspheres targeting tubercle bacilli residing in alveolar macrophages. The effects of pulmonary surfactant on the rifampicin (RFP) release rate from RFP-loaded poly (lactide-co-glycolide) microspheres were studied. Also, those of their surface properties of RFP-loaded PLGA microspheres were studied. The RFP release from RFP/PLGA microspheres was accelerated by adsorption of pulmonary surfactant on the particle surface. The fastest RFP release rate was observed from pulmonary surfactant-adsorbed PLGA particles in pH 7.4 buffer solution compared with those in pH 4.0 buffer solution and saline solution. The slowest release rate was observed in the case when saline solution was used as dispersion phase of RFP/PLGA microspheres, although RFP release rate increased by the addition of pulmonary surfactant. From these results it is suggested that when RFP/PLGA microspheres are administrated by inhalation, the RFP release rates from the particles which are not taken up by alveolar macrophages and remain in the alveoli will be small. On the other hand, the RFP release rates and release amounts will be high after RFP/PLGA microspheres are taken up by alveolar macrophages existing in phagosomes, but they become relatively small after RFP/PLGA microspheres move into phagosome-lysosomes by the fusion of phagosomes with lysosomes. The absolute values of the electrophoretic mobility of PLGA microspheres increased by the adsorption of pulmonary surfactants on the surfaces of PLGA microspheres. By analyzing the experimental data using the soft-particle theory, it was indicated that the microspheres became 'softer' and the surface charge density of microspheres increases by the degradation. On the other hand, the surface of PLGA microspheres became harder and the electric charge density increased by the adsorption of pulmonary surfactant on the surfaces of PLGA microspheres. The changes in the surface charge density with degradation became larger by the adsorption of the lung surfactant on PLGA microsphere surfaces. It is considered that the changes in surface properties of PLGA microspheres affect their uptake efficiency by alveolar macrophage.     

Effect of freeze-drying and rehydrating treatment on the thermo-responsive characteristics of poly(<Emphasis Type="Italic">N</Emphasis>-isopropylacrylamide) microspheres

Investigations on the effect of freeze-drying and rehydrating treatment on equilibrium volume changes and on the thermo-response rate of poly(N-isopropylacrylamide) (PNIPAM) microspheres were carried out. The experimental results showed that freeze-drying and rehydrating treatment had nearly no effect on the low critical solution temperature and equilibrium volume changes of PNIPAM microspheres. Furthermore, when the PNIPAM microspheres were frozen in only liquid nitrogen through rapid cooling, the response rate of PNIPAM microspheres to environmental temperature change was nearly not affected by the treatment, which was surprisingly different from the macroscopic hydrogel. The dimension effect was responsible for this phenomenon. The micron-sized PNIPAM microsphere itself has a much quicker response rate compared with the bulky hydrogel because the characteristic time of gel deswelling is proportional to the square of a linear dimension of the hydrogel.     

Properties of poly(styrene/alpha-tert-butoxy-omega-vinylbenzyl-polyglycidol) microspheres suspended in water. Effect of sodium chloride and temperature on particle diameters and electrophoretic mobility

Hydrodynamic and electrophoretic properties of core-shell poly(styrene/alpha- tert-butoxy-omega-vinylbenzyl-polyglycidol) (P(S/PGL)) microspheres suspended in water are described. The microspheres were obtained by surfactant-free emulsion copolymerization of styrene and alpha- tert-butoxy-omega-vinylbenzyl-polyglycidol macromonomer ( M n = 2800, M w/ M n = 1.05). The process yielded microspheres with number average diameter D n = 270 nm and with low diameter dispersity index D w/ D n = 1.01. Shells of P(S/PGL) microspheres were enriched in polyglycidol. Molar fraction of polyglycidol monomeric units in the shells (determined by X-ray photoelectron spectroscopy) was equal to 0.34, which is much higher than the average molar fraction of polyglycidol monomeric units in whole particles of 0.048. Influences of NaCl concentration and temperature on P(S/PGL) microsphere diameters and on their electrophoretic mobility were investigated. It was found that hydrodynamic diameter of P(S/PGL) microspheres, determined by photon correlation spectroscopy, decreased significantly when temperature did exceed a certain value (transition temperature, T t). It has been found that the decrease is more pronounced for higher concentrations of NaCl in the medium. For microspheres suspended in 10 (-1) M NaCl, the hydrodynamic diameter decreased by 8% whereas for the same particles in pure water the diameter decreased by 5.2%. The process of shrinkage was fully reversible. Values of T t for P(S/PGL) microspheres were lower for higher concentrations of NaCl. Adjustment of salt concentration allowed controlling T t in a range from 44.4 to 49.9 degrees C. 13C NMR relaxation time measurements (T 1) for carbon atoms in polyglycidol macromonomer revealed that T 1 did increase with increasing temperature (in temperature range from 25 to 75 degrees C) indicating higher motion of chains at higher temperature. Addition of NaCl did not induce a substantial change of T 1 in the mentioned temperature range. The swelling-deswelling properties of P(S/PGL) microspheres' interfacial layer affected adsorption of P(S/PGL) particles on modified with (3-aminopropyl)triethoxysilane mica. It was shown that the deposition of P(S/PGL) microspheres at 25 degrees C on mica led to formation of two-dimensional crystal-shape assemblies, whereas at 60 degrees C (far above T t = 49.8 degrees C in H2O) the microspheres were randomly adsorbed without formation of colloidal crystal assemblies.     

Synthesis of bio‐based poly (cyclotriphosphazene‐resveratrol) microspheres acting as both flame retardant and reinforcing agent to epoxy resin

A highly cross‐linked poly (cyclotriphosphazene‐resveratrol) microsphere (PRV) was synthesized by using hexachlorocyclotriphosphazene (HCCP) and bio‐based resveratrol (REV) as raw materials, and the obtained PRV microspheres were applied to improve the flame retardancy and mechanical property of epoxy resin (EP). The TGA results showed that the PRV microsphere is an excellent charring agent and the char yield is as high as 62% at 800°C. The incorporation of PRV makes the initial degradation earlier yet significantly increases the char residue of EP composites. Moreover, the introduction of PRV microspheres into EP greatly promoted the flame retardancy performance. Under 3% of addition of PRV microspheres, the peak heat release rate (PHRR) and total heat release (THR) were decreased by 58.3% and 29.6%, respectively, the limited oxygen index (LOI) value was increased to 29.7% from 25.3% of pure EP. In addition, because of the uniform distribution in EP matrix and the enhancing effect of PRV microspheres, the mechanical properties including tensile modulus of EP composites were strengthened. PRV microspheres in this paper provide a possibility to synthesize a dual functional filler, which acts as both flame retardant and strengthening agent.     

Preparation of poly(N-isopropylacrylamide) emulsion gels and their drug release behaviors

Stimuli-sensitive drug delivery systems (DDSs) have attracted considerable attention in medical and pharmaceutical fields; thermosensitive DDS dealing with poly(N-isopropylacrylamide) (poly(NIPA)) have been widely studied. Novel NIPA emulsion gels, i.e., NIPA hydrogels containing distributed oil (oleyl alcohol) microdroplets, were synthesized by means of an emulsion-gelation method in which the polymerization of hydrogels in an aqueous phase in an oil-in-water (O/W) emulsion and the loading of a lipophilic drug (indomethacin) dissolved in an oil phase were accomplished simultaneously. The pulsatile (on-off) drug release from the NIPA emulsion gel loading indomethacin to a phosphate buffered saline (PBS) solution was successfully controlled by a temperature swing between 25 degrees C (release off) and 40 degrees C (release on). The mechanism of the pulsatile drug release was discussed in relation to the diffusion rate, distribution ratio, solvent exchange of NIPA hydrogels, and drug release from an NIPA organogel. The mechanism was as follows: the solvent exchange occurred within the NIPA emulsion gel (the NIPA gel-network absorbed oleyl alcohol with indomethacin) at temperatures above the LCST, and the diffusion rate of indomethacin through the solvent-exchanged gel was higher at 40 degrees C than at 25 degrees C.     

A Fourier transform infrared study of the phase transition in aqueous solutions of Ethylene oxide–propylene oxide triblock copolymer

The phase transition between unimer and micellar phases of poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (PEO–PPO–PEO) triblock copolymer Pluronic P105 in aqueous solution has been investigated as a function of temperature using Fourier transform infrared spectroscopy. The transition of 8 wt% Pluronic P105 in aqueous solution was found to occur at 25 °C. As temperature increases, PO blocks appear to be stretched conformers with strong interchain interaction, and the formation of a hydrophobic core in the micellar phase. The EO chains are found to change to a more disordered structure with low-chain packing density from the unimer phase to the micellar phase. Both the EO and PO blocks exhibit dehydration during the phase transition. Received: 17 September 1998 Accepted in revised form: 10 December 1998     

Biodegradable heparin-loaded microspheres: carrier molecular composition and microsphere structure

Microspheres of amphiphilic triblock polymers PLLA-PEG-PLLA were investigated as carriers for heparin delivery. Two series of PLLA-PEG-PLLA triblock were synthesized and prepared into microspheres with heparin loaded. The microspheres were hollow and the surface morphology varied from smooth to porous. The pore size increased with increasing PEG content. The microsphere size distribution showed that higher PEG content increased the average microsphere size. The release rate of heparin was closely related to the surface morphology of the microspheres. DSC spectra showed that both cold crystalline temperature (Tc) and crystalline melting temperature (Tm) of heparin-loaded microspheres were related to the copolymer composition and the Tc was lower than those of corresponding pure microspheres. [IMAGES: SEE TEXT]     

Dependence of Temperature-Sensitivity of Poly(N-isopropylacrylamide-co-acrylic acid) Hydrogel Microspheres upon Their Sizes

Monodisperse poly(N-isopropylacrylamide-co-acrylic acid) hydrogel microspheres were prepared by a membrane emulsification method using membranes of pore diameters of 0.33, 0.73, 1.15, and 1.70 μm. The hydrogels were synthesized by polymerization of 3.6 M N-isopropylacrylamide (N-IPAAm or NIPAM) and 0.4 M acrylic acid (AAc). Their surface properties were studied by measuring the electrophoretic mobility of the microspheres in electrolyte solutions at pH 7.4 at 25, 30, 33, 35, 40, and 45 degrees C. Poly(N-IPAAm-co-AAc) microspheres have shown negative mobility. More negative values of electrophoretic mobility were obtained with the smaller microspheres than the larger ones at each temperature. The surface charge density of the microspheres increased and their surfaces became harder above 35 degrees C, since the microspheres contained thermosensitive poly(N-IPAAm) moiety and LCST increased by the addition of AAc, while that of poly(N-IPAAm) was 33 degrees C. It has recently been found that the smaller microspheres exhibit the stronger dependence of both surface charge density and softness on the temperature. Copyright 2000 Academic Press.     

Investigation of a new thermosensitive block copolymer micelle: hydrolysis, disruption, and release

Thermosensitive polymer micelles are generally obtained with block copolymers in which one block exhibits a lower critical solution temperature in aqueous solution. We investigate a different design that is based on the use of one block bearing a thermally labile side group, whose hydrolysis upon heating shifts the hydrophilic-hydrophobic balance toward the destabilization of block copolymer micelles. Atom transfer radical polymerization was utilized to synthesize a series of diblock copolymers composed of hydrophilic poly(ethylene oxide) (PEO) and hydrophobic poly(2-tetrahydropyranyl methacrylate) (PTHPMA). We show that micelles of PEO-b-PTHPMA in aqueous solution can be destabilized as a result of the thermosensitive hydrolytic cleavage of tetrahydropyranyl (THP) groups that transforms PTHPMA into hydrophilic poly(methacrylic acid). The three related processes occurring in aqueous solution, namely, hydrolytic cleavage of THP, destabilization of micelles, and release of loaded Nile Red (NR), were investigated simultaneously using 1H NMR, dynamic light scattering, and fluorescence spectroscopy, respectively. At 80 degrees C, the results suggest that the three events proceed with a similar kinetics. Although slower than at elevated temperatures, the disruption of PEO-b-PTHPMA micelles can take place at the body temperature (approximately 37 degrees C), and the release kinetics of NR can be adjusted by changing the relative lengths of the two blocks or the pH of the solution.