Micelles formed by self‐assembling of low molecular weight phosphorylcholine‐containing poly(L‐lactide)

Phosphorylcholine‐containing poly(L‐lactide) (PLLA‐PC) was synthesized by ring‐opening polymerization of L‐lactide in the presence of glycerophosphorylcholine originated from egg lecithin. Self‐assembling micelles were then obtained by film hydration, ultrasonication and stirring. Transmission electron microscopy and confocal laser scanning microscopy confirmed the micellar structure with hydrophobic core and hydrophilic shell. The critical micellar concentration (CMC) value of PLLA‐PC was only 1/50 that of naturally occurring PC, in agreement with a better surfactant property of the former. Dynamic light scattering showed that the size and size distribution of micelles varied with dilution, but the CMC was independent of the concentration of NaCl solution within 0.9 wt%, indicating that the micelles could be stable upon intravenous injection. In addition, the micelle solution could be stored at 4 °C over 30 days without any noticeable changes, whereas at 37 °C, the size, size distribution and the number of micelles decreased over time due to degradation. The solubility of clofazimine, a highly hydrophobic drug, was found to be 11.9 µg/ml in the PLLA‐PC micellar solution, which was 40 times that in pure water. This preliminary study suggests that PLLA‐PC micelles present a great potential as delivery system for hydrophobic drugs. Copyright © 2011 John Wiley & Sons, Ltd.     

Comparative study of paclitaxel physically encapsulated in and chemically conjugated with PEG‐PLA

Paclitaxel‐loaded poly(ethylene glycol)‐b‐poly(l ‐lactide (LA)) (PEG‐PLA) micelles were prepared by two methods. One is physical encapsulation of paclitaxel in micelles composed of a PEG‐PLA block copolymer and the other is based on a PEG‐PLA–paclitaxel conjugate, abbreviated as “conjugate micelles”. Their physicochemical characteristics, e.g. critical micelle concentration (CMC), morphology, and micelle size distribution were then evaluated by means of fluorescence spectroscopy, scanning electron microscopy (SEM), and dynamic light scattering (DLS). The results show that the CMC of PEG‐PLA–paclitaxel and PEG‐PLA are 6.31 × 10^?4 and 1.78 × 10^?3 g L^?1, respectively. Both micelles assume a spherical shape with comparable diameters and have unimodal size distribution. Moreover, invitro drug delivery behavior was studied by high performance liquid chromatography (HPLC). The antitumor activity of the paclitaxel‐loaded micelles against human liver cancer H7402 cells was evaluated by 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) method. The conjugate micelles show a lower burst release during the initial stage and higher accumulative release amount of paclitaxel after a period of time while the encapsulated ones behave in the opposite way. Both the paclitaxel‐loaded micelles showed comparable anticancer efficacy with the free drug. Copyright © 2008 John Wiley & Sons, Ltd.     

Micelles‐Encapsulated Microcapsules for Sequential Loading of Hydrophobic and Water‐Soluble Drugs

Layer‐by‐layer (LbL) assembly was conducted on CaCO₃ microparticles pre‐doped with polystyrene‐block‐poly(acrylic acid) (PS‐b‐PAA) micelles, and resulted in micelles encapsulation in the microcapsules after core removal. Distribution of the micelles in the templates and capsules was characterized by transmission electron microscopy and confocal laser scanning microscopy. The micelles inside the capsules connected with each other to form a chain and network‐like structure with a higher density near the capsule walls. The hydrophobic PS cores were then able to load small uncharged hydrophobic drugs while the negatively charged PAA corona could induce spontaneous deposition of water‐soluble positively charged drugs such as doxorubicin.

     

Drug release and biocompatibility of self‐assembled micelles prepared from poly (ɛ‐caprolactone/glycolide)‐poly (ethylene glycol) block copolymers

A series of poly(?‐caprolactone/glycolide)‐poly(ethylene glycol) (P(CL/GA)‐PEG) diblock copolymers were prepared by ring opening polymerization of a mixture of ?‐caprolactone and glycolide using mPEG as macro‐initiator and stannous octoate as catalyst. Self‐assembled micelles were prepared from the copolymers using nanoprecipitation method. The micelles were spherical in shape. The micelle size was larger for copolymers with longer PEG blocks. In contrast, the critical micelle concentration of copolymers increased with decreasing the overall hydrophobic block length. Drug loading and drug release studies were performed under in vitro conditions, using paclitaxel as a hydrophobic model drug. Higher drug loading was obtained for micelles with longer poly(ε‐caprolactone) blocks. Faster drug release was obtained for micelles of mPEG2000 initiated copolymers than those of mPEG5000 initiated ones. Higher GA content in the copolymers led to faster drug release. Moreover, drug release rate was enhanced in the presence of lipase from Pseudomonas sp., indicating that drug release is facilitated by copolymer degradation. The biocompatibility of copolymers was evaluated from hemolysis, dynamic clotting time, and plasma recalcification time tests, as well as MTT assay and agar diffusion test. Data showed that copolymer micelles present outstanding hemocompatibility and cytocompatibility, thus suggesting that P(CL/GA)‐PEG micelles are promising for prolonged release of hydrophobic drugs.     

Synthesis and characterization of temperature‐sensitive block‐graft PNiPAAm‐b‐(PαN3CL‐g‐alkyne) copolymers by ring‐opening polymerization and click reaction

This study synthesized thermo‐sensitive amphiphilic block‐graft PNiPAAm‐b‐(PαN₃CL‐g‐alkyne) copolymers through ring‐opening polymerization of α‐chloro‐ε‐caprolactone (αClCL) with hydroxyl‐terminated macroinitiator poly(N‐isopropylacrylamide) (PNiPAAm), substituting pendent chlorides with sodium azide. This was then used to graft various kinds of terminal alkynes moieties by means of the copper‐catalyzed Huisgen's 1,3‐dipolar cycloaddition (“click” reaction). ¹H NMR, FTIR, and gel permeation chromatography (GPC) was used to characterize these copolymers. The solubility of the block‐graft copolymers in aqueous media was investigated using turbidity measurement, revealing a lower critical solution temperature (LCST) in the polymers. These solutions showed reversible changes in optical properties: transparent below the LCST, and opaque above the LCST. The LCST values were dependant on the composition of the polymer. With critical micelle concentrations (CMCs) in the range of 2.04–9.77 mg L^?1, the block copolymers formed micelles in the aqueous phase, owing to their amphiphilic characteristics. An increase in the length of hydrophobic segments or a decrease in the length of hydrophilic segments amphiphilic block‐graft copolymers produced lower CMC values. The research verified the core‐shell structure of micelles by ¹H NMR analyses in D₂O. Transmission electron microscopy was used to analyze the morphology of the micelles, revealing a spherical structure. The average size of the micelles was in the range of 75–145 nm (blank), and 105–190 nm (with drug). High drug entrapment efficiency and drug loading content were observed in the drug micelles. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Photo‐responsive amphiphilic poly(α‐hydroxy acids) with pendent o‐nitrobenzyl ester constructed via copper‐catalyzed azide‐alkyne cycloaddition reaction

Photo‐responsive block copolymer mPEG‐b‐poly(Tyr)‐g‐NB was prepared by introduction of o‐nitrobenzyl ester group into the side chain of amphiphilic poly(ethylene glycol)‐b‐poly(α‐hydroxy acids) (mPEG‐b‐poly(Tyr)) containing pendent alkynyl group via copper‐catalyzed azide‐alkyne cycloaddition reaction. The amphiphilic mPEG‐b‐poly(Tyr) was synthesized via the ring‐opening polymerization of O‐carboxyanhydrides, with monomethoxy poly(ethylene glycol) (mPEG) as macroinitiator. The molecular structure, self‐assembly, and photo‐controlled release of the obtained mPEG‐b‐poly(Tyr)‐g‐NB were thoroughly investigated. mPEG‐b‐poly(Tyr)‐g‐NB could self‐assemble into spherical micelles in water and showed disassembly under UV light irradiation, which was demonstrated by means of UV‐vis spectroscopy, scan electron microscopes, and dynamic light scattering measurement. Fluorescence emission measurements demonstrated that Nile red, encapsulated by micelles, can be released upon UV irradiation. This study provides a convenient way to construct smart poly(α‐hydroxy acids)‐based nanocarriers for controlled release of hydrophobic drugs. Copyright © 2015 John Wiley & Sons, Ltd.     

Formation of polymeric micelles with amino surfaces from amphiphilic AB‐type diblock copolymers composed of poly(glycolic acid lysine) segments and polylactide segments

Amphiphilic AB‐type diblock copolymers composed of hydrophobic poly(L ‐lactide) (PLA) segments and hydrophilic poly(glycolic acid lysine) [poly(Glc‐Lys)] segments with amino side‐chain groups self‐associated to form PLA‐based polymeric micelles with amino surfaces in an aqueous solution. The average diameter of the loose core–shell polymeric micelles for poly(Glc‐Lys) [number‐average molecular weight (M_n) = 1240]‐b‐PLA (M_n = 7000) obtained by a dimethyl sulfoxide/water dialysis method was estimated to be about 50 nm in water by dynamic light scattering measurements. The size and shape of the obtained polymeric micelles were further observed with transmission electron microscopy and atomic force microscopy. To investigate the possibility of applying the obtained PLA‐based polymeric micelles as bioabsorbable vehicles for hydrophobic drugs, we tested the entrapment of drugs in poly(Glc‐Lys) (M_n = 1240)‐b‐PLA (M_n = 7000) micelles and their release with doxorubicin as a hydrophobic drug. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 1426–1432, 2002     

Thermosensitive and photocleavable polyaspartamide derivatives for drug delivery

The development of novel thermo‐ and photo‐dual‐responsive biodegradable polymeric micelles based on amphiphilic polyaspartamide derivatives (NB‐g‐PHPA‐g‐mPEG) for anticancer drug delivery is reported. The obtained polymers containing hydrophobic photocleavable o‐nitrobenzyl groups exhibit thermo‐ and photosensitivity. The micelles and paclitaxel‐loaded micelles based on the thermo‐ and photo‐dual‐sensitive polymers were prepared by a quick heating method without using toxic organic solvent. The paclitaxel release from the drug‐loaded micelles can be triggered under photoirradiation. Enhancement of the anticancer activity against HeLa cells was observed for paclitaxel‐loaded NB‐g‐PHPA‐g‐mPEG micelles after light irradiation, while the empty NB‐g‐PHPA‐g‐mPEG micelles with or without irradiation did not show any toxicity. Therefore, the thermo‐ and photo‐dual‐responsive NB‐g‐PHPA‐g‐mPEG micelles have a promising future applied as a light controlled drug delivery system for anticancer drugs. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 2855–2863     

Supramolecular inclusion complexes of star‐shaped poly(ε‐caprolactone) with α‐cyclodextrin

Both star‐shaped poly(ε‐caprolactone) (PCL) having 4 arms (4sPCL) and 6 arms (6sPCL) and linear PCL having 1 arm (LPCL) and 2 arms (2LPCL) were synthesized and then investigated for inclusion complexation with α‐cyclodextrin (α‐CD). The supramolecular inclusion complexes (ICs) were in detail characterized by ¹H NMR, differential scanning calorimetry, thermogravimetric analysis, wide angle X‐ray diffraction, solid‐state carbon nuclear magnetic resonance spectroscopy using cross‐polarization and magic‐angle spinning, and Fourier transform infrared, respectively. The stoichiometry (CL:CD, mol:mol) of all ICs increased with the increasing branch arm of PCL polymers, and it was in the order of α‐CD‐6sPCL1 ICs > α‐CD‐4sPCL ICs > α‐CD‐2LPCL ICs > α‐CD‐LPCL ICs. All analyses indicated that the branch arms of star‐shaped PCL polymers were included into the hydrophobic α‐CD cavities and their original crystalline properties were completely suppressed. Moreover, the ICs of star‐shaped PCL with α‐CD had a channel‐type crystalline structure similar to that formed between the linear PCL and α‐CD. Furthermore, the thermal stability of the free PCL polymers probably controlled that of the guest polymers included in the ICs. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 4721–4730, 2005     

in vitro biological evaluation of folate-functionalized block copolymer micelles for selective anti-cancer drug delivery

The main objective of this study was to evaluate the ability of folic acid-functionalized diblock copolymer micelles to improve the delivery and uptake of two poorly water-soluble anti-tumor drugs, tamoxifen and paclitaxel, to cancer cells through folate receptor targeting. The diblock copolymer used in this study comprised a hydrophilic poly[2-(methacryloyloxy)ethyl phosphorylcholine] (MPC) block, carrying at the chain end the folate targeting moiety, and a pH-sensitive hydrophobic poly[2-(diisopropylamino)ethyl methacrylate] (DPA) block (FA-MPC-DPA). The drug-loading capacities of tamoxifen- and paclitaxel-loaded micelles were determined by high performance liquid chromatography and the micelle dimensions were determined by dynamic light scattering and transmission electron microscopy. Cell viability studies were carried out on human chronic myelogenous leukaemia (K-562) and colon carcinoma cell lines (Caco-2) in order to demonstrate that drug-loaded FA-MPC-DPA micelles exhibited higher cytotoxicities toward cancer cells than unfunctionalized MPC-DPA micelles. Uptake studies confirmed that folate-conjugated micelles led to increased drug uptake within cancer cells, demonstrating the expected selectivity toward these tumor cells.     

Core Crosslinking of Biodegradable Block Copolymer Micelles Based on Poly(ester carbonate)

A biodegradable amphiphilic block copolymer, PEG‐b‐P(LA‐co‐MAC), was used to prepare spherical micelles consisting of a hydrophobic P(LA‐co‐MAC) core and a hydrophilic PEG shell. To improve their stability, the micelles were crosslinked by radical polymerization of the double bonds in the hydrophobic blocks. The crosslinked micelles had similar sizes and a narrow size distribution compared to their uncrosslinked precursor. The improved stability of the crosslinked micelles was confirmed by measurements of the CMC and a thermodynamic investigation. These micelles can internalize into Hela cells in vitro as demonstrated by inverted fluorescence microscopy and CLSM. These stabilized nanoscale micelles have potential use in biomedical applications such as drug delivery and disease diagnosis.

     

Nucleobase‐Functionalized Supramolecular Micelles with Tunable Physical Properties for Efficient Controlled Drug Release

Complementary nucleobase‐functionalized polymeric micelles, a combination of adenine‐thymine (A‐U) base pairs and a blend of hydrophilic–hydrophobic polymer pairs, can be used to construct 3D supramolecular polymer networks; these micelles exhibit excellent self‐assembly ability in aqueous solution, rapid pH‐responsiveness, high drug loading capacity, and triggerable drug release. In this study, a multi‐uracil functionalized poly(ε‐caprolactone) (U‐PCL) and adenine end‐capped difunctional oligomeric poly(ethylene glycol) (BA‐PEG) are successfully developed and show high affinity and specific recognition in solution owing to dynamically reversible A‐U‐induced formation of physical cross‐links. The U‐PCL/BA‐PEG blend system produces supramolecular micelles that can be readily adjusted to provide the desired critical micellization concentration, particle size, and stability. Importantly, in vitro release studies show that doxorubicin (DOX)‐loaded micelles exhibit excellent DOX‐encapsulated stability under physiological conditions. When the pH value of the solution is reduced from 7.4 to 5.0, DOX‐loaded micelles can be rapidly triggered to release encapsulated DOX, suggesting these polymeric micelles represent promising candidate pH‐responsive nanocarriers for controlled‐release drug delivery and pharmaceutical applications.

     

Synthesis,crystallization, and morphology of star‐shaped poly(ε‐caprolactone)

Six‐arm star‐shaped poly(ε‐caprolactone) (sPCL) was successfully synthesized via the ring‐opening polymerization of ε‐caprolactone with a commercial dipentaerythritol as the initiator and stannous octoate (SnOct₂) as the catalyst in bulk at 120 °C. The effects of the molar ratios of both the monomer to the initiator and the monomer to the catalyst on the molecular weight of the polymer were investigated in detail. The molecular weight of the polymer linearly increased with the molar ratio of the monomer to the initiator, and the molecular weight distribution was very low (weight‐average molecular weight/number‐average molecular weight = 1.05–1.24). However, the molar ratio of the monomer to the catalyst had no apparent influence on the molecular weight of the polymer. Differential scanning calorimetry analysis indicated that the maximal melting point, cold crystallization temperature, and degree of crystallinity of the sPCL polymers increased with increasing molecular weight, and crystallinities of different sizes and imperfect crystallization possibly did not exist in the sPCL polymers. Furthermore, polarized optical microscopy analysis indicated that the crystallization rate of the polymers was in the order of linear poly(ε‐caprolactone) (LPCL) > sPCL5 > sPCL1 (sPCL5 had a higher molecular weight than both sPCL1 and LPCL, which had similar molecular weights). Both LPCL and sPCL5 exhibited a good spherulitic morphology with apparent Maltese cross patterns, whereas sPCL1 showed a poor spherulitic morphology. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5449–5457, 2005     

Nonionic Dendritic and Carbohydrate Based Amphiphiles: Self‐Assembly and Transport Behavior

Herein, a new series of non‐ionic dendritic and carbohydrate based amphiphiles is synthesized employing biocompatible starting materials and studied for supramolecular aggregate formation in aqueous solution. The dendritic amphiphiles 12 and 13 possessing poly(glycerol) [G2.0] as hydrophilic unit and C‐10 and C‐18 hydrophobic alkyl chains, respectively, exhibit low critical aggregation concentration (CAC) in the order of 10⁻⁵m and hydrodynamic diameters in the 8–10 nm range and supplemented by cryogenic transmission electron microscopy. Ultraviolet‐visible (UV‐Vis) and fluorescence spectroscopy suggests the effective solubilization of hydrophobic guests by the self‐assembled architectures, with the nanotransporters 12 and 13 possessing the highest encapsulation efficiency of 80.74 and 98.03% for curcumin. Efficient uptake of encapsulated curcumin in adenocarcinomic human alveolar basal epithelial (A549) cells is observed by confocal laser scanning microscopy. Amphiphiles 12 and 13 are non‐cytotoxic at the concentrations studied, however, curcumin encapsulated samples efficiently reduce the viability of A549 cells in vitro. Experimental studies indicate the ability of amphiphile 13 to encapsulate 1‐anilinonaphthalene‐8‐sulfonic acid (ANS) and curcumin with binding constant of 1.16 × 105⁵m ⁻¹ and 1.43 × 10⁶m ⁻¹, respectively. Overall, our findings demonstrate the potential of these dendritic amphiphiles for the development of prospective nanocarriers for the solubilization of hydrophobic drugs.     

Molecular design of outermost surface functionalized thermoresponsive polymeric micelles with biodegradable cores

We prepared well‐defined diblock copolymers of thermoresponsive poly(N‐isopropylacrylamide‐co‐N,N‐dimethylacrylamide) blocks and biodegradable poly(D ,L ‐lactide) blocks by combination of reversible addition‐fragmentation chain transfer radical (RAFT) polymerization and ring‐opening polymerization. α‐Hydroxyl, ω‐dithiobenzoate thermoresponsive polymers were synthesized by RAFT polymerization using hydroxyl RAFT agents. Biodegradable blocks were prepared by ring‐opening polymerization of D ,L ‐lactide initiated by α‐hydroxyl groups of thermoresponsive polymers, which inhibit the thermal decomposition of ω‐dithioester groups. Terminal dithiobenzoate (DTBz) groups of thermoresponsive blocks were easily reduced to thiol groups and reacted with maleimide (Mal). In aqueous media, diblock copolymer products formed surface‐functionalized thermoresponsive micelles. These polymeric micelles had a low critical micelle concentration of 22 μg/L. In thermoresponsive studies of the micelles, hydrophobic DTBz‐surface micelles demonstrated a significant shift in lower critical solution temperature (LCST) to a lower temperature of 30.7 °C than that for Mal‐surface micelles (40.0 °C). In addition, micellar LCST was controlled by changing bulk mixture ratios of respective heterogeneous end‐functional diblock copolymers. Micellar disruption at acidic condition (pH 5.0) was completed within 5 days due to hydrolytic degradation of PLA cores, regardless of showing a slow disruption rate at physiological condition. Furthermore, we successfully improved water‐solubility of hydrophobic drug, paclitaxel by incorporating into the micellar cores. © Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7127–7137, 2008     

Increasing the hydrophilicity of star‐shaped amphiphilic co‐networks by using of PEG and dendritic s‐PCL cross‐linkers

New hyperbranched hydrophobic cross‐linkers with peripheral azide groups were synthesized as follows: First, star‐shaped polycaprolactones (sPCL) were synthesized by ring‐opening polymerization of caprolactone in the presence of pentaerythritol and tin (II) octoate. In the next step, sequential acrylation, Micheal addition, tosylation, and azidation by acryloyl chloride, diethanol amine, tosyl chloride, and sodium azide were respectively exploited to synthesize azide‐functionalized hyperbranched star‐shaped polycaprolactones which were named sPCL‐acrylate‐diethanolamine‐azide (sPCL‐AC‐DEA‐N₃) and sPCL‐acrylate‐diethanolamine‐acrylate‐diethanolamine‐azide (sPCL‐AC‐DEA‐AC‐N₃). All steps were thoroughly characterized by FT‐IR and ¹H NMR spectroscopy. The GPC analysis showed that the molecular weight of sPCL increased after two azide functionalizations. Amphiphilic hydrogels based on sPCL‐AC‐DEA‐N₃ (M_n = 8130 g/mol) and sPCL‐AC‐DEA‐AC‐N₃ (M_n = 10112 g/mol) with linear alkyne‐terminated polyethylene glycols (PEG) (M_n = 2000, 4000, and 6000 g/mol) were synthesized through click coupling between azide and alkyne groups. In both hydrogels, the swelling ratio increased by increasing the molecular weight of PEG. The obtained results showed that the branching of the cross‐linker, significantly affected the swelling ratio of hydrogels. For instance, the swelling ratio of sPCL‐AC‐DEA‐AC‐N₃ and PEG‐6000 (Q = 900) was higher than sPCL‐AC‐DEA‐N₃ and PEG‐6000 (Q = 600). Despite the high cross‐linking density of sPCL‐AC‐DEA‐AC‐DEA‐N₃–based hydrogels, the amount of released theophylline was higher than sPCL‐AC‐DEA‐N₃–based hydrogels, due to the high content of PEG in these hydrogels.     

PEO‐b‐PCL Block Copolymers: Synthesis,Detailed Characterization,and Selected Micellar Drug Encapsulation Behavior

Summary: A series of poly(ethylene glycol)‐block‐poly(ε‐caprolactone) diblock copolymers was synthesized and fully characterized. In particular, MALDI‐TOF MS results revealed interesting new insights into their molecular architecture. Small and defined micelles could be prepared from these block copolymers. Utilizing a high‐throughput screening approach, it was observed that these micelles are able to encapsulate/solubilize different guest molecules (e.g. drugs) depending on the solubility of the guest in water. Furthermore, it could be proven that a guest is located within a micelle and that these micelles can be utilized as transport vehicles for the encapsulated guest molecules.

PEO‐b‐PCL diblock copolymers can encapsulate small guest molecules in the core of the polymeric micelles.     

Dual Responsive Block Copolymer Micelles Functionalized by NIPAM and Azobenzene

A novel amphiphilic diblock copolymer composed of a hydrophilic poly(ethylene oxide) block and a hydrophobic block copolymerized by azobenzene‐containing methacrylate and N‐isopropylacrylamide was synthesized using ATRP. The polymer micelles showed dual responsiveness to heat and light. The size of the micelles was dependent on temperature and the encapsulated substance in the hydrophobic cores was released during heating and cooling processes. The hydrophobicity of the micellar cores appeared as a reversible change in response to light with neither disruption of the micelles nor leakage of the encapsulated substance while H‐aggregation of the azobenzene moieties was detected.

     

Thiol‐responsive micelles based on nonionic gemini surfactants with a cystine disulfide spacer

Thiol‐responsive micelles consisting of novel nonionic gemini surfactants with a cystine disulfide spacer are reported. The gemini surfactants, (C₁₈‐Cys‐mPEG)₂ and ((C₁₈)₂‐Lys‐Cys‐mPEG)₂, were synthesized from polyethylene glycol, cysteine, and stearic acid, and their structures were confirmed by ¹H NMR and gel permeation chromatography. (C₁₈‐Cys‐mPEG)₂ and ((C₁₈)₂‐Lys‐Cys‐mPEG)₂ formed micelles with average diameters of 13 and 22 nm above the critical micelle concentration of 6.5 and 4.7 µg mL^?1, respectively. The micelles of ((C₁₈)₂‐Lys‐Cys‐mPEG)₂ containing more stearoyl groups showed encapsulated more hydrophobic indomethacin (IMC) with higher entrapment efficiencies than those of (C₁₈‐Cys‐mPEG)₂. The gemini surfactant micelles exhibited an accelerated release of encapsulated IMC with the concentration of the reducing agent, glutathione (GSH), whereas they were unaffected by the presence of reduced GSH (GSSG). The 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)?2‐(4‐sulfophenyl)?2H‐tetrazolium studies revealed the noncytotoxic nature of the gemini surfactant micelles. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 582–589     

Predicting the Loading Capability of mPEG‐PDLLA to Hydrophobic Drugs Using Solubility Parameters†

Physical encapsulation of drugs into polymer micelles is a common method of loading hydrophobic drugs. Methoxy polyethylene glycol‐poly(D,L‐lactide) (mPEG‐PDLLA) is one of the most commonly used drug carrier. At present, whether a carrier is suitable for the loading of a certain drug is determined by drug loading experiments. This process costs a lot of time. Therefore, an efficient predicting method to avoid time‐consuming tests is critical. In this study, we prepared mPEG_5k‐PDLLA_5k and used it to load a series of drugs. Three parameters were used to test the miscibility of mPEG_5k‐PDLLA_5k with drugs, including absolute difference in Hildebrand solubility parameters (|Δδ|), Flory–Huggins interaction parameter (χ) and the distance (D value) calculated from the two‐dimensional solubility parameters. We found the two‐dimensional solubility parameters obtained from JB2013 group contribution (GC) method was useful. By comparing the drug loading content (DLC) with the D value, we found that when the D value was less than 5.0 (MJ/m³)^1/2, the miscibility of drug and mPEG_5k‐PDLLA_5k was good and drug loading capability was high; when the D value was more than 8.0 (MJ/m³)^1/2, the drug was barely loaded. Thus, this work provided a rationale to qualitatively predict the loading capability of mPEG_5k‐PDLLA_5k for hydrophobic drugs.