Effects of polymer degradation on drug release from PLGA‐mPEG microparticles: A dynamic study of microparticle morphological and physicochemical properties

In vitro degradation and drug release of poly (DL ‐lactide‐co‐glycolic acid)‐methoxypoly(ethyleneglycol) (PLGA‐mPEG) microparticles were performed through a dynamic monitoring process, to investigate the effect of degradation on drug release from microparticles and to elucidate the dominant factor that governed the drug release kinetics. Methotrexate (MTX), an antirheumatic drug, was employed as the model drug. Drug release showed a triphasic pattern: an initial burst release followed by a lag period and subsequently a second burst release. The initial burst release was mainly caused by dissolution and diffusion of drugs at/near the surface of microparticles. During the following lag period, microparticles suffered little morphological changes, whereas the physicochemical changes of the polymer contributed to the increasing mobility of drug molecules, and then provided transport pathways for drug release. Later on, the erosion of the polymer matrix became significant. Morphology study showed that the trend of porosity change was in accordance with last phase release profile, indicating that porosity played an extremely important role in controlling drug release. The liberation pattern of mPEG was elucidated. The more pores formed, the more mPEG chains were exposed to the aqueous medium and disengaged from the polymer. Scanning electron micrography observation further confirmed these conclusions. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

PLA/chain‐extended PEG blends with improved ductility

Melt blending of polylactic acid (PLA) and a chain‐extended polyethylene glycol (CE‐PEG) have been performed in an effort to toughen the PLA without significant loss of modulus and ultimate tensile strength. The chain‐extended PEG was prepared with melt condensation of a low molecular weight PEG and 4,4′‐methylenebis(phenylisocyanate) (MDI) for enhancement of the molecular weight of PEG. The thermal and mechanical properties, miscibility and phase morphologies of blends were investigated. By using thermal and fracture surface analysis, the blends were found to be a partially miscible system with shifted glass transition temperatures. The addition of CE‐PEG leads to slight decrease in tensile strength and modulus, while the elongation at break is characterized by an important increase (540%), compared with neat PLA and PLA/PEG (low molecular weight PEG, M_n = 35,000). The relative ductility of PLA/CE‐PEG is 40 times higher than that of neat PLA. The brittle fracture of neat PLA was transformed into a ductile fracture by the addition of CE‐PEG. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Preparation,properties, and mathematical modeling of microparticle drug delivery systems based on biodegradable amphiphilic triblock copolymers

A series of biodegradable amphiphilic A‐B‐A type triblock copolymers P(BLA‐PEG‐BLA), composed of hydrophilic poly(ethylene glycol) (PEG) as a middle block component (B) and hydrophobic poly(β‐benzyl‐L ‐aspartate) as outer polypeptide block components (A), were synthesized by copolymerization of β‐benzyl‐L ‐aspartate N‐carboxy anhydride (BLA‐NCA) and the diaminated PEG with the primary amino groups capped at both ends. These P(BLA‐PEG‐BLA) copolymers were characterized by ¹H‐NMR, DSC, and GPC. The triblock copolymers were used to prepare three kinds of drug delivery systems including Norfloxacin (INN)‐incorporated P(BLA‐PEG‐BLA) microparticles and tablets. The morphologies of the microparticles were characterized by SEM. The in vitro release properties of the microparticles and tablets in PBS were also evaluated. A mathematical model, which incorporates a linear first‐order dissolution term and the transient Fickian diffusion equation, was developed to account for the kinetics of drug release from the INN‐incorporated P(BLA‐PEG‐BLA) microparticles. The results indicated that the overall release process was well controlled by both drug dissolution and diffusion. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 3869–3873, 2004     

Development of polylactide microspheres for protein encapsulation and delivery

The development of injectable microparticles for protein delivery is a major challenge. We demonstrated the possibility of entrapping human serum albumin (HSA) and thrombin (Thr) in poly(ethylene glycol) (PEG)‐coated, monodisperse, biodegradable microspheres with a mean diameter of about 10 μm. In our earlier studies, diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) analysis was used to characterize the surface of PEG‐coated, taxol‐loaded poly(lactic acid) (PLA) microspheres. An analysis by DRIFTS revealed that PEG was incorporated well on the PLA microsphere surface. An emulsion of protein (in water) and PLA dissolved in an acetone–dichloromethane (or acetone–chloroform) mixture were poured into an aqueous solution of PEG [or poly(vinyl alcohol) (PVA)] with stirring with a high‐speed homogenizer for the formation of microparticles. HSA recovery in microspheres ranged from 13 to 40%, depending on the solvent and emulsification systems used for the preparation. PLA dissolved in a dichloromethane/acetone system and albumin loaded via a PEG emulsification solution (PLA–PEG–HSA) showed maximum drug recovery (39.5%) and drug content (9.9%). Scanning electron microscopy revealed that PEG‐coated microspheres had less surface micropores than PVA‐based preparations. The drug‐release behavior of microspheres suspended in phosphate‐buffered saline exhibited a biphasic pattern. An initial burst release (30%) followed by a constant slow release for 20 days was observed for HSA and Thr from PLA–PEG microspheres. PEG‐coated PLA microspheres show great potential for protein‐based drug delivery. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 1285–1295, 2002     

Poly(D,L‐lactide‐co‐glycolide)/poly(ethylenimine) blend matrix system for pH sensitive drug delivery

Poly(D ,L ‐lactide‐co‐glycolide) (PLGA) and poly(ethylenimine) (PEI) were blended and found to form a homogeneous pH sensitive matrix for drug release. Differential scanning calorimetry (DSC) studies of the PLGA/PEI blends showed a single glass transition temperature at all compositions. Fourier transform infrared spectroscopy (FTIR) demonstrated that the PLGA carbonyl peak at 1760 cm^?1 shifted to 1666 cm^?1 as a result of amide bond formation between the two polymers. This was confirmed by ¹³C nuclear magnetic resonance studies. A PLGA/PEI matrix of 90/10 weight ratio was chosen for evaluation for controlled drug release. Both hydrophobic β‐lapachone and hydrophilic rhodamine B showed pH dependent release profiles with faster release kinetics at lower pH values. The observed pH sensitive drug release was mainly attributed to two factors, pH dependent swelling and protonation of the PEI‐PLGA matrix. These results demonstrate utility of a PLGA/PEI matrix and its potential application in pH responsive drug delivery. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 89–96, 2006     

Preparation and in vitro characterization of poly(sebacic acid‐co‐ricinoleic acid)‐based tamoxifen citrate‐loaded microparticles for breast cancer

This study was aimed to develop an injectable polymeric drug delivery system for tamoxifen citrate (TC) using poly(sebacic acid‐co‐ricinoleic acid) [poly(SA‐RA) 70 : 30 w/w] as a drug carrier for the treatment of estrogen receptor positive breast cancer. Injectable biodegradable microparticles of TC were produced by solvent displacement technique of microencapsulation and were characterized by surface morphology (scanning electron microscopy), particle size, size distribution, physical and chemical interaction (Fourier transform infrared), nature and physical state of drug [DSC and X‐ray diffraction (XRD)], and in vitro release studies. TC loading over different concentrations was analyzed by high performance liquid chromatography (HPLC) technique. Polyanhydride microparticles obtained after lyophilization were nearly spherical in shape with smooth surface and size less than 2.5 μm. TC was dispersed in the form of amorphous state, and TC remains intact and stable during the process of microencapsulation. In vitro drug release studies demonstrated prolonged controlled release of TC with zero‐order kinetics. Stability studies revealed that the production process of microparticles itself did not affect the chemical stability of the drug and polymer forming the particle matrix. Significant difference in drug release capacity was observed in microparticles with different drug loadings, and the drug release was more sustained in microparticles prepared with high TC. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Thermosensitive nanoparticles prepared from poly(N‐isopropylacrylamide‐acrylamide‐vinilpyrrolidone) and its blend with poly(lactide‐co‐glycolide) for efficient drug delivery system

Temperature‐responsive polymers have become increasingly attractive as carrier for the injectable drug delivery systems. In the present work, we have studied the preparation of poly(N‐isopropylacrylamide‐acrylamide‐vinilpyrrolidone) (NIPAAm‐AAm‐VP terpolymer) nanoparticulated terpolymer and its blend with poly(lactide‐co‐glycolide, PLGA; molar ratio of lactide/glycolid 1/3). Thermosensitive terpolymer, poly(NIPAAm‐AAm‐VP) was prepared by free‐radical polymerization in aqueous solution. The nanoparticles of poly(NIPAAm‐AAm‐VP) and its blend with PLGA containing naltrexone were prepared using the evaporation and w/o emulsion‐solvent evaporation methods, respectively. Nanoparticles prepared from terpolymer‐PLGA blend at low polymer concentration (5%) shows larger particle size (>300 nm) and higher drug content%. Various types of nanoparticles showed a burst release of less than 10% after 24 h . The results suggest that by regulating different variables, desired release profiles of naltrexone can be achieved using a blend of PLGA‐poly(NIPAAm‐AAm‐VP) nanoparticulate system. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Drug Release Kinetics and Mechanism from PLGA Formulations

The release kinetics of indomethacin (IND) and hydrochlorothiazide (HCT) from drug/PLGA formulations with different copolymer composition and molecular weight of PLGA were measured in vitro by using a rotating disk system (USP II). The release mechanism of IND and HCT from their PLGA formulations was analyzed using a chemical‐potential‐gradient model combined with the Perturbed‐Chain Statistical Associating Fluid Theory (PC‐SAFT). Furthermore, the release kinetics of IND and HCT from the PLGA formulations with different copolymer composition and molecular weight of PLGA were correlated and predicted in good accordance with the experimental data. It was found that the chemical‐potential‐gradient model combined with the PC‐SAFT helped to understand the drug release mechanism from the drug/PLGA formulations. It also well correlated and predicted the drug release kinetics as function of copolymer composition and molecular weight of PLGA as well as of drug type. It helps to save time and costs for determination of the long‐term drug release kinetics, especially for sustained drug release as obtained from the drug/PLGA formulations in this work. © 2016 American Institute of Chemical Engineers AIChE J, 62: 4055–4065, 2016     

Thermosensitive polymeric micelles based on the triblock copolymer poly(d,l‐lactide)‐b‐poly(N‐isopropyl acrylamide)‐b‐poly(d,l‐lactide) for controllable drug delivery

A thermosensitive amphiphilic triblock copolymer, poly(d,l ‐lactide) (PLA)‐b‐poly(N‐isopropyl acrylamide) (PNIPAAM)‐b‐PLA, was synthesized by the ring‐opening polymerization of d,l ‐lactide; the reaction was initiated from a dihydroxy‐terminated poly(N‐isopropyl acrylamide) homopolymer (HO‐PNIPAAM‐OH) created by radical polymerization. The molecular structure, thermosensitive characteristics, and micellization behavior of the obtained triblock copolymer were characterized with Fourier transform infrared spectroscopy, ¹H‐NMR, gel permeation chromatography, dynamic light scattering, and transmission electron microscopy. The obtained results indicate that the composition of PLA‐b‐PNIPAAM‐b‐PLA was in good agreement with what was preconceived. This copolymer could self‐assemble into spherical core–shell micelles (ca. 75–80 nm) in aqueous solution and exhibited a phase‐transition temperature around 26 °C. Furthermore, the drug‐delivery properties of the PLA‐b‐PNIPAAM‐b‐PLA micelles were investigated. The drug‐release test indicated that the synthesized PLA‐b‐PNIPAAM‐b‐PLA micelles could be used as nanocarriers of the anticancer drug adriamycin (ADR) to effectively control the release of the drug. The drug‐delivery properties of PLA‐b‐PNIPAAM‐b‐PLA showed obvious thermosensitive characteristics, and the release time of ADR could be extended to 50 h. This represents a significant improvement from previous PNIPAAM‐based drug‐delivery systems. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45304.     

Preparation and evaluation of novel blend microspheres of poly(lactic‐co‐glycolic)acid and pluronic F68/127 for controlled release of repaglinide

The objective of the present work was to study the release behavior of plain and blend microspheres (MS) of PLGA and Pluronic F68/127. In this study, a novel blend MS of poly(D ,L ‐lactic‐co‐glycolic acid) (PLGA) and Pluronic F68/127 (PLF68/127) were prepared by the emulsion–solvent evaporation method. Repaglinide, an antidiabetic drug with a very short half‐life, was successfully encapsulated into the blend MS. Various formulations were prepared by varying the ratio of PLGA and PLF68/127. Drug encapsulation up to 91% was achieved as measured by UV spectroscopy. Scanning electron microscopy showed that MS have smooth surfaces even after incorporation of PLF68/127. Particle size, as measured by using laser light scattering technique, gave an average size ranging from 12 to 47 μm. Differential scanning calorimetry (DSC) was performed to understand the crystalline nature of the drug after encapsulation into MS. DSC revealed the crystalline dispersion in the polymer matrix. In vitro release experiments performed in simulated intestinal fluid, indicated the dependence of release rate on the amount of PLF68/127 present in the MS; slow release was extended up to 153 h. Release data have been fitted to an empirical equation to compute the diffusional exponent (n), which indicated that the release mechanism to be non‐Fickian type. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

The effect of process variables on the morphology and release characteristics of protein‐loaded PLGA particles

Poly(lactide‐co‐glycolide) (PLGA 75 : 25), IV 0.94 dL/g was chosen as the matrix of the microparticles. Bovine serum albumin (BSA) (Fraction V) as the model drug was incorporated in the microparticles by a W/O/W emulsification and solvent evaporation technique. The effect of the various preparation parameters on particle morphology, drug loading efficiency, and drug release profiles of the resultant microparticles were examined. Particle size varied from 5 to 60 μm. The final morphology of the microparticles varied dramatically with preparation variables such as equipment used to produce the primary emulsion (W1/O) and the water‐to‐oil ratio (W1/O) in the primary emulsion. In general, the viscosity of the primary emulsion had a significant effect on the porosity of particles produced. The release of BSA showed a strong relationship with the preparation parameters of microparticles, partly due to the morphological effects. For example, microparticles made from the vortex mixer that was used to disperse inner aqueous phase (W1) to oil phase (O) showed a lower burst effect than that made from the homogenizer because of its better surface morphology. W1/O ratio, speed of dispersing the primary emulsion into W2, PLGA concentration, and different matrix materials also affected the drug release profiles. In all the samples studied here, only diffusion‐controlled release was observed. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 3053–3061, 2006     

Synthesis and characterization of biodegradable low molecular weight aliphatic polyesters and their use in protein‐delivery systems

Poly(lactic acid) (PLA) and poly(lactic‐co‐GA) (PLGA) with low molecular weights were synthesized by a one‐step polycondensation of lactic acid (LA) with glycolic acid (GA) molecules using stannous octoate as a catalyst at 160°C. A high yield (>80%) of all the polymers was obtained in the study. The PLA and PLGA copolymers were characterized by ¹H‐NMR, GPC, and DSC measurements, etc. We elaborated HSA‐loaded microspheres based on PLA and PLGA copolymers with different monomer ratios (LA/GA = 85:15, 75:25, 65:35, and 50:50) by the solvent‐extraction method based on the formation of double w/o/w emulsion. Microspheres were characterized in terms of the morphology, size, and encapsulation efficiency (E.E.). The highest E.E. (69.3%) of HSA was obtained for HSA‐loaded PLGA (65/35) microspheres among all the formulations. In vitro matrix degradation and protein release of these microspheres were performed in phosphate‐buffer saline (PBS; 154 mM, pH 7.4). The degradation profiles were characterized by measuring the loss of the microsphere mass and the decrease of the polymer intrinsic viscosity. The release profiles were investigated from the measurement of the protein presented in the release medium at various intervals. It was shown that the matrix degradation and protein‐release profiles were highly LA/GA ratio‐dependent. It is suggested that these matrix polymers may be optimized as carriers in protein‐ and peptide‐delivery systems for different purposes. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 91: 1848–1856, 2004     

Microparticles based on hydrophobically modified chitosan as drug carriers

In this work, a hydrophobically modified (HM) chitosan derivative was prepared by covalent linkage of C₁₂ groups to the chitosan backbone. HM‐chitosan microparticles were prepared according to an emulsification‐solvent evaporation method and naltrexone (NTX) was used as a model drug. For comparison, unmodified chitosan and poly lactic‐co‐glycolic acid (PLGA) microparticles were also tested as carriers for NTX. HM‐chitosan formed viscous semi‐dilute solutions, suggesting a high level of chain entanglements and hydrophobic associations. HM‐chitosan microparticles generally showed higher production yield and encapsulation efficiency, as compared with chitosan and PLGA. The burst release shown by chitosan microparticles was significantly reduced when using the HM‐chitosan derivative. An enhanced control of drug release was observed over at least 50 days. PLGA particles demonstrated inferior controlled release properties as compared to HM‐chitosan subsequent to the initial release stage. These results revealed the potential of hydrophobic modification of chitosan as a means to improve the stability and sustained delivery properties of the polymer. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40055.     

Intrinsic factor and vitamin B12 complex‐loaded poly[lactic‐co‐(glycolic acid)] microspheres: preparation,characterization and drug release

BACKGROUND: Vitamin B12 is an essential vitamin required by all mammals. Absorption of vitamin B12 is facilitated by binding of intrinsic factor–vitamin B₁₂ complex to specific receptors in the ileum. In humans a deficiency of this vitamin or a lack of intrinsic factor leads to pernicious anaemia. The major objective of the present study was to prepare intrinsic factor–vitamin B12 complex‐loaded poly[lactic‐co‐(glycolic acid)] (PLGA)‐based microparticles and to investigate their release kinetics. RESULTS: PLGA copolymer was synthesized by the ring‐opening polymerization method and characterized using gel permeation chromatography, Fourier transform infrared spectroscopy and ¹H NMR. The glass transition temperature measurement showed a single T_g at 40 °C. The intrinsic factor–vitamin B12 complex‐loaded PLGA microspheres were prepared by a water‐in‐oil‐in‐water double emulsion solvent extraction/evaporation technique. An environmental scanning electron microscopy investigation demonstrated that the PLGA particles had a mean particle diameter of 38 µm. Interestingly, different drug release patterns (bi‐ and triphasic ones) were observed for vitamin B12‐loaded and intrinsic factor–vitamin B12 complex‐loaded microspheres. In contrast to the rapid release of vitamin B12 by itself, in vitro release tests showed that intrinsic factor and vitamin B12 in the complex were released from PLGA microspheres in a sustained manner over 15 days. CONCLUSION: PLGA microspheres can be an effective carrier for the intrinsic factor–vitamin B12 complex. Copyright © 2007 Society of Chemical Industry     

Encapsulation of diclofenac sodium with acidic copolymer hydrogels based on PEG/poly(N‐isopropylacrylamide‐co‐2‐acrylamido‐2‐methyl‐1‐propanesulfonic acid) semi‐interpenetrating network using in situ loading technique

A pH‐ and temperature‐responsive semi‐interpenetrating copolymer PEG6000/poly(NIPA‐co‐AMPS) (PEG/AMPS‐co‐NIPA SIPN), for short PEG SIPN, was made by ammonium persulfate‐initiated suspension copolymerization of N‐isopropylacrylamide, 2‐acrylamido‐2‐methylpropanesulphonic acid, and N,N′‐methylene‐bis‐acrylamide (MBAA; crosslinker) in the presence of PEG6000. The PEG SIPN copolymer matrices containing nanostructures made in the high‐temperature copolymerization resulted in channels for PEG and facile migration of drugs. In drug encapsulation or drug‐loading process, one can easily ignore or pay less attention to the interaction between a drug and its encapsulation materials; however, the ignored interactions may induce problems in drug properties or the release behavior in use. Sodium diclofenac (DFNa) precipitates as the carboxylic acid form in an acidic environment, and it is challenging to encapsulate sodium diclofenac in such an acidic matrix without precipitation of the sparingly soluble acid form of DFNa on the surface of the polymer substrate. To avoid bulky precipitation in drug loading, an in situ loading technique was developed for producing gel spheres with DFNa uniformly distributed in the polymer matrix. The technique is based on fast polymerization of spherical droplets of a pregel solution in which the drug is dissolved. Diffusion‐loading prodrugs were made in comparison with in situ loading prodrugs in thermal, release kinetics, and release behavior. Drug release profiles (in pH 7.4 phosphate buffer) show that the new drug loading technique gives controlled release during a period of about 7 days at 37°C. By contrast, gel spheres loaded with sodium diclofenac using the conventional diffusion technique produced almost total release of the drug within about 24 h. The thermal stability of sodium diclofenac, the PEG/AMPS‐co‐NIPA SIPN, and the prodrugs made with the SIPN and sodium diclofenac was studied. A near zero‐order release kinetics was found in the in vitro release of sodium diclofenac with in situ loading PEG SIPN prodrug. We have, for the first time, studied sodium diclofenac release behavior from the PEG SIPN hydrogel systems. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

In vitro degradation and drug‐release behavior of electrospun,fibrous webs of poly(lactic‐co‐glycolic acid)

Ultrafine fibrous webs of poly(lactide‐co‐glycolic acid) (PLGA) containing the bactericidal antibiotic drug rifampin were prepared by electrospinning, and their properties were investigated for wound‐dressing applications. Because PLGA is a biodegradable and biocompatible polymer, it is one of the best materials for the preparation of wound‐dressing substrates. Through this investigation of PLGA/rifampin electrospun webs, we found that the in vitro degradation reached approximately 60% in 10 days, and the drug release from the webs showed a fast and constant profile suitable for wound‐dressing applications. Also, we observed that both the web‐degradation rate and the drug‐release rate increased as the drug concentration in the PLGA/rifampin electrospun webs and the content level of glycolide units in the PLGA polymer matrix increased. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Investigation of poly(lactide) stereocomplexation between linear poly(L‐lactide) and PDLA‐PEG‐PDLA tri‐block copolymer

In this study, stereocomplexed poly(lactide) (PLA) was investigated by blending linear poly(l ‐lactide) (PLLA) and tri‐block copolymer poly(d ‐lactide) ? (polyethylene glycol) ? poly(d ‐lactide) (PDLA‐PEG‐PDLA). Synthesized PDLA‐PEG‐PDLA tri‐block copolymers with different PEG and PDLA segment lengths were studied and their influences on the degree of sterecomplexation and non‐isothermal crystallization behaviour of the PLLA/PDLA‐PEG‐PDLA blend were examined in detail by DSC, XRD and polarized optical microscopy. A full stereocomplexation between PLLA and PDLA‐PEG_4k‐PDLA200 could be formed when the L/D ratio ranged from 7/3 to 5/5 without the presence of PLA homocrystals. The segmental mobility and length of both PEG and PDLA are the dominating factors in the critical D/L ratio to achieve full stereocomplexation and also for nucleation and spherulite growth during the non‐isothermal crystallization process. For fixed PEG segmental length, the stereocomplexed PLA formed showed first an increasing and then a decreasing melting temperature with increasing PDLA segments due to their intrinsic stiff mobility. Furthermore, the effect of PEG segmental mobility on PLA stereocomplexation was investigated. The results clearly showed that the crystallization temperature and melting temperature of stereocomplexed‐PLA kept increasing with increasing PEG segmental length, which was due to PEG soft mobility in the tri‐block copolymers. However, PEG was not favourable for nucleation but could facilitate the spherulite growth rate. Both the PDLA and PEG segmental lengths in the tri‐block copolymers affect the crystallinity of stereocomplexed‐PLA and the stereocomplexation formation process; they have a different influence on blends prepared by solution casting or the melting method. © 2015 Society of Chemical Industry     

Liver‐targeting doxorubicin‐conjugated polymeric prodrug with pH‐triggered drug release profile

The aim of the research presented was to develop a potential liver‐targeting prolonged‐circulation polymeric prodrug of doxorubicin (Dox) with a pH‐triggered drug release profile. In particular, linear dendritic block copolymers composed of polyamidoamine dendrimer (PAMAM) and poly(ethylene glycol) (PEG; number‐average molecular weight of 2000 g mol^?1) with or without galactose (Gal) were synthesized. Dox was coupled to the copolymers via an acid‐labile hydrazone linker. These prodrugs, designated Gal‐PEG‐b‐PAMAM‐Dox_n and mPEG‐b‐PAMAM‐Dox_m, showed accelerated Dox release as the pH decreased from 8.0 to 5.6. Cytotoxicity of the prodrugs was lower than that of free Dox due to the gradual drug release nature. Compared to mPEG‐b‐PAMAM‐Dox_m, Gal‐PEG‐b‐PAMAM‐Dox_n showed rather high cytotoxicity against Bel‐7402, suggestive of its galactose receptor‐mediated enhanced tumor uptake. This galactose receptor‐mediated liver‐targeted profile was further confirmed by the prolonged retention time in hepatoma tissue monitored using magnetic resonance imaging. Gal‐PEG‐b‐PAMAM‐Dox_n showed better in vivo antitumor efficacy than free Dox, suggesting its great potential as a polymeric antitumor prodrug. Copyright © 2010 Society of Chemical Industry     

Fluorescent microspheres of poly(ethylene glycol)–poly(lactic acid)–fluorescein copolymers synthesized by Ugi four‐component condensation

Microparticles formed by poly(lactic acid) (PLA) and poly(ethylene glycol) (PEG) diblock copolymers containing fluorescein grafted to the polymer chain were synthesized by a Ugi four‐component condensation (UFCC) reaction. To synthesize these copolymers, lactide was first polymerized by a ring‐opening polymerization with alcohol initiators containing functional groups to give carboxyl‐ and aldehyde‐end‐functionalized PLA. Two different fluorescent block copolymers (FCPs) of PEG–PLA conjugated to fluorescein (FCP 1 and FCP 2) were then synthesized by UFCC; they gave yields in the range 65–75%. These copolymers were characterized well according their chemical structures and thermal properties, and we prepared fluorescent microspheres (FMSs) from them with the single emulsion–solvent evaporation method (FMS 1 and FMS 2). A new application of UFCC in the preparation of biomasked drug‐delivery systems is proposed. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 42994.     

The polymer free volume as a controlling factor for drug release from poly(lactide‐co‐glycolide) microspheres

Drug release from poly(lactide‐co‐glycolide) (PLGA) microspheres is strongly determined by the pore structure of the particles. This study examines how swelling‐induced pore constriction delays the drug release and by which factors this process is controlled. Combination of different porosimetric and pycnometric methods enabled insight into the submicroscopic range of the pore structure and revealed that remarkably the polymer free volume plays a crucial role in drug release from PLGA microspheres. Surprisingly, the latter was shown to be inversely correlated to the degree of diffusional drug release. This can be explained by a swelling‐induced constriction of the macroporous channel system in the microspheres which is related to the availability of free volume. The hole free volume was shown to be well controllable by the manufacturing conditions. Thus, the study deepens comprehension of the mechanism of drug release from biodegradable microparticles and offers an effective approach for controlling the release behavior. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39740.