Terminal modification of polymeric micelles with π-conjugated moieties for efficient anticancer drug delivery

High drug loading content is the critical factor to polymeric micelles for efficient chemotherapy. Small molecules of cinnamic acid, 7-carboxymethoxy coumarin and chrysin with different π-conjugated moieties were immobilized on the terminal hydroxyl groups of PCL segments in mPEG-PCL micelles to improve drug loading content via the evocation of π-π stacking interaction between doxorubicin (DOX) and polymeric micelles. The modification of π-conjugated moieties enhanced the capability of crystallization of mPEG-PCL block copolymers. The drug loading content increased dramatically from 12.9% to 25.5% after modification. All the three modified mPEG-PCL micelles were nontoxic to cells. Chrysin modified polymeric micelles exhibited the most efficient anticancer activity. The in vivo anticancer activity of 10 mg/kg DOX dose of chrysin modified micelle formulation for twice injections was comparable to that of 5 mg/kg dose of free DOX·HCl for four injections under the circumstance of same total DOX amount. The systemic toxicity of DOX loaded chrysin modified micelles was significantly reduced. This research provided a facile strategy to achieve polymeric micelles with high drug loading content and efficient anticancer activity both in vitro and in vivo.     

Synthesis and antitumor activity of doxorubicin conjugated stearic acid-g-chitosan oligosaccharide polymeric micelles

Doxorubicin conjugated stearic acid-g-chitosan oligosaccharide polymeric micelles (DOX–CSO–SA) was synthesized via cis-aconityl bond between the anticancer drug doxorubicin (DOX) and stearic acid grafted chitosan oligosaccharide (CSO–SA) in this paper. The CSO–SA micelles had been demonstrated faster internalization ability into tumor cells. Here, the CSO–SA with 6.47% amino substituted degree (SD%) was used to synthesize DOX–CSO–SA. The critical micelle concentration (CMC) was about 0.14 mg mL⁻¹. The micelles with 1 mg mL⁻¹ CSO–SA concentration had 32.7 nm number average diameter with a narrow size distribution and 51.5 mV surface potential. After conjugating with doxorubicin, CMC of DOX–CSO–SA descended; the micellar size increased; and the zeta potential decreased. The DOX–CSO–SA micelles indicated pH-dependent DOX release behavior. The release rate of DOX from DOX–CSO–SA micelles increased significantly with the reductions of the pH for release medium from 7.2 to 5.0. In vitro antitumor activity tests of DOX–CSO–SA micelles against human breast carcinoma (MCF-7) cells and their multi-drug resistant (MCF-7/Adr) cells presented the reversal activity against DOX resistance MCF-7 cells (MCF-7/Adr). The in vivo antitumor activity results showed that DOX–CSO–SA micelles treatments effectively suppressed the tumor growth and reduced the toxicity against animal body than commercial doxorubicin hydrochloride injection.     

Synthesis,characterization, and in vitro evaluation of TRAIL-modified,cabazitaxel -loaded polymeric micelles for achieving synergistic anticancer therapy

Abstract

Combination therapy of two or more drugs has gradually become of outmost importance in cancer treatment. Cabazitaxel (CTX) is a taxoid drug and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of TNF superfamily. In this study, we prepared TRAIL-modified and CTX-loaded polymer micelle (TRAIL-M-CTX). This nanoparticle was self-assembled from biodegradable amphiphilic copolymers, monomethoxyl poly(ethylene glycol)–b-poly(DL-lactide) (mPEG-PLA) and COOH-PEG-PLA, via a nanoprecipitation method and were modified with the TRAIL protein, resulting in a particle size of 39.75 ± 0.17 nm in diameter and a drug encapsulation efficiency of 95.52 ± 1.69%. The successful coupling was confirmed by ¹H NMR, FTIR spectroscopy, and DLS article size measurement. Pharmacodynamic analysis in two human cancer cell lines with different TRAIL sensitivities showed that TRAIL-M-CTX has a significantly better anticancer efficacy than the individual CTX and TRAIL protein. Importantly, TRAIL-M-CTX showed synergistic effects against TRAIL-insensitive cells (MCF-7). A study of cellular uptake implied that the modified micelles were internalized into MCF-7 cells more effectively than unmodified micelles, owing to the coupled TRAIL protein. A cell cycle assay of MCF-7 cells revealed that TRAIL-M-CTX significantly increased the sub-G1 population compared with CTX or TRIAL, thus, facilitating cancer cell apoptosis. These results suggest that TRAIL-M-CTX micelles have potential as a cancer chemotherapy formulation.     

Tetraphenylsilane‐Cored Star‐Shaped Amphiphilic Block Copolymers for pH‐Responsive Anticancer Drug Delivery

Four‐arm star‐shaped poly[2‐(diethylamino)ethyl methacrylate]‐b‐poly[2‐hydroxyethyl methacrylate]s block copolymers using tetraphenylsilane (TPS) as a core with adjustable arm lengths are synthesized through two‐step atom transfer radical polymerizations. For comparison, a linear block copolymer with similar molecular weight is also prepared. The assembled star‐shaped copolymer micelles exhibit sizes of 102–139 nm and critical micelle concentrations of 1.49–3.93 mg L^?1. Moreover, the bulky and rigid TPS core is advantageous for propping up the four star‐shaped arms to generate large intersegmental space. As a result, the drug‐loading capacity in the micelles is up to 33.97 wt%, much surpassing the linear counterpart (8.92 wt%) and the previously reported star‐shaped copolymers prepared using pentaerythritol as the core. Furthermore, the micelles show sensitive pH‐responsive drug release when the pH changes from 7.4 to 5.0. The in vitro cytotoxicity to Hela cells indicates that the doxorubicin (DOX)‐loaded micelles have similar anticancer activity to the pristine DOX. The combination of excellent micelle stability, high drug‐loading, sensitive pH response, and good anticancer activity endows the copolymers with promising application in drug control delivery for anticancer therapy.     

Thermosensitive AB4 four-armed star PNIPAM-b-HTPB multiblock copolymer micelles for camptothecin drug release

Thermo-sensitive poly(N-isoproplacrylamide)_m-block-hydroxyl-terminated polybutadiene-block-poly(N-isoproplacrylamide)_m (PNIPAM_m-b-HTPB-b-PNIPAM_m, m = 1 or 2) block copolymers, AB₄ four-armed star multiblock and linear triblock copolymers, were synthesized by ATRP with HTPB as central blocks, and characterization was performed by ¹H NMR, Fourier transform infrared, and size exclusion chromatography. The multiblock copolymers could spontaneously assemble into more regular spherical core–shell nanoscale micelles than the linear triblock copolymer. The physicochemical properties were detected by a surface tension, nanoparticle analyzer, transmission electron microscope (TEM), dynamic light scattering, and UV–vis measurements. The multiblock copolymer micelles had lower critical micelle concentration than the linear counterpart, TEM size from 100 to 120 nm, and the hydrodynamic diameters below 150 nm. The micelles exhibited thermo-dependent size change, with low critical solution temperature of about 33–35 °C. The characteristic parameters were affected by the composition ratios, length of PNIPAM blocks, and molecular architectures. The camptothecin release demonstrated that the drug release was thermo-responsive, accompanied by the temperature-induced structural changes of the micelles. MTT assays were performed to evaluate the biocompatibility or cytotoxicity of the prepared copolymer micelles.     

Thermo-triggered and biotinylated biotin-P(NIPAAm-co-HMAAm)-b-PMMA micelles for controlled drug release

Thermosensitive and biotinylated biotin-poly (N-isopropylacrylamide-co-N-hydroxymethylacrylamide)-block-poly(methyl methacrylate) (biotin-P(NIPAAm-co-HMAAm)-b-PMMA) block copolymers were designed and synthesized. The conjugation of biotin molecule with the copolymer as well as the capability of easily functionalizing with ligands for pretargeting approach of the biotinylated multifunctional drug carrier was confirmed by a novel method called capillary electrophoresis immunoassay (CEIA) based on enhanced chemiluminescence (CL) detection. The biotin-P(NIPAAm-co-HMAAm)-b-PMMA copolymer was capable of self-assembling into nanometer-sized micelle. The anticancer drug methotrexate (MTX), used as a model drug, was loaded in the self-assembled micelles and the thermo-triggered release behavior of MTX was investigated.     

Biotinylated thermoresponsive micelle self-assembled from double-hydrophilic block copolymer for drug delivery and tumor target

A multifunctional micellar drug carrier formed by the thermosensitive and biotinylated double-hydrophilic block copolymer (DHBC), biotin-poly(ethylene glycol)-block-poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide) (biotin-PEG-b-P(NIPAAm-co-HMAAm)), was designed and prepared. The P(NIPAAm-co-HMAAm) block with an molar feed ratio of NIPAAm and HMAAm (10:1) was identified to exhibit the reversible phase transition at the lower critical solution temperature (LCST) of 36.7 degrees C. Cytotoxicity study indicated that the biotin-PEG-b-P(NIPAAm-co-HMAAm) copolymer did not exhibit obvious cytotoxicity. The block copolymer was capable of self-assembling into micelle in water. Transmission electron microscopy showed that the self-assembled micelles were regularly spherical in shape. The anticancer drug methotrexate (MTX) was loaded in the micelles and the in vitro release behaviors of MTX at different temperatures were investigated. The association of biotin molecule with the copolymer was confirmed by a unique capillary electrophoresis immunoassay (CEIA) method based on enhanced chemiluminescence (CL) detection. The fluorescence spectroscopy analysis as well as confocal microscopy studies confirmed the DHBC drug carriers could specifically and efficiently bind to cancer cells with pretreatment of biotin-transferrin, suggesting that the multifunctionalized DHBC micelle may be a useful drug carrier for tumor targeting.     

Self-assembled thermosensitive micelles based on poly(L-lactide-star block-N-isopropylacrylamide) for drug delivery

A novel seven-arm star block copolymer poly(L-lactide-star block-N-isopropylacrylamide) (PLLA-sb-PNIPAAm), comprised of a hydrophobic poly(L-lactide) (PLLA) arm and an average of six hydrophilic poly(N-isopropylacrylamide) (PNIPAAm) arms, was designed and synthesized. The amphiphilic PLLA-sb-PNIPAAm copolymer was capable of self-assembling into nano-sized micelle in water, which was confirmed by FT-IR, 1H NMR and fluorescence spectroscopy. Transmission electron microscopy images showed that these nano-sized micelles were regularly spherical in shape. Micelle size determined by size analysis was around 100 nm in diameter. The micelles showed reversible dispersion/aggregation in response to temperature changes through an outer polymer shell of PNIPAAm at around 31 degrees C, observed by optical absorbance measurements. The anticancer drug methotrexate (MTX) as model drug was loaded in the polymeric nano-sized micelles. In vitro release behavior of MTX was investigated, which showed a drastic thermoresponsive fast/slow switching behavior according to the temperature-responsive structural changes of a micellar shell structure. The reversible and sensitive thermoresponse of this micelle might provide opportunities to construct a novel drug delivery system in conjunction with localized hyperthermia.     

Design and synthesis of pH-sensitive polymeric micelles for oral delivery of poorly water-soluble drugs

pH-sensitive polymer poly (polylactide-co-methacrylic acid)–b-poly (acrylic acid) was synthesized using atom transfer radical polymerization and ring-opening polymerization and characterized by gel permeation chromatography and ¹H NMR. The polymers can self-assemble to form micelles in aqueous medium, which respond rapidly to pH change within the gastrointestinal relevant pH range. Critical micelle concentrations and pH response behavior of the polymeric micelle were investigated. Water-insoluble drug nifedipine was loaded and the drug-loading content can be controlled by tuning the composition of the polymers. The in vitro release studies indicate pH sensitivity enabled rapid drug release at the environment of simulated intestinal fluid (pH 7.36), the cumulative released amount of NFD reached more than 80% within 24 h, while only 35% in the simulated gastric fluid (pH 1.35). All the results showed that the pH-sensitive P(PLAMA-co-MAA)–b-PAA micelle may be a prospective candidate as oral drug delivery carrier for hydrophobic drugs with controlled release behavior.     

Nanoporous Gold Film Prepared by the Epoxidation of Poly(styrene‐b‐butadiene) Diblock Copolymer Templated Micelles

A new approach is developed for the preparation of nanoporous gold (Au) films using diblock copolymer micelles as templates. Stable Au nanoparticles (NPs) with a narrow distribution are prepared by modifying NPs functionalized with 4‐(dimethylamino)pyridine ligands (DMAP Au NPs) and a spherical micelle formed through the epoxidation of poly(styrene‐b‐butadiene) diblock copolymer to produce poly(styrene‐b‐vinyl oxirane) (PS‐b‐PBO) in tetrahydrofuran–acetonitrile solution. The exchange reaction of 4‐aminothiophenol of PS‐b‐PBO diblock copolymer micelles with DMAP Au NPs can produce block copolymer–Au NPs composite films. After the pyrolysis of the diblock copolymer templates at a specific temperature to avoid the collapse of the Au NPs, a nanoporous Au film is prepared.     

The effects of acyl chain length on the micelle properties of poly(ethylene oxide)-block-poly(N-hexylL-aspartamide)-acyl conjugates

Derivatives of poly(ethylene oxide)-block-poly(β-benzyl-aspartate), 12 :25 have been prepared via aminolysis of the benzyl protecting group with 6-amino-1-hexanol, followed by subsequent acylation with acetic anhydride, hexanoic acid, lauric acid, or stearic acid. A series of amphiphilic diblock copolymers based on poly(ethylene oxide)-block-poly(N-hexyl-aspartamide)-acyl conjugates with various acyl chain lengths have been prepared. The extent of esterification was determined by ¹H-NMR. Aqueous micelle solutions were prepared by a dialysis method and the polymer series was characterized as a function of the acyl chain length. Transmission electron microscopy and dynamic light scattering revealed micelle-like structures of nanoscopic dimensions (< 100 nm). Environmentally sensitive fluorescent probes were loaded into the micelles in order to study the properties of the hydrophobic microdomain and to determine the critical micelle concentration (CMC). Steady-state fluorescence measurements indicated that the relative apparent core viscosity and polarity are modulated by the relative length of the attached acyl chains, as is the CMC. Increasing the acyl chain length results in a decreased CMC and a more viscous and less polar core region. Carefully chosen chemical moieties can be introduced in order to influence the properties of the poly(L-Asp) blocks of the micelles. As a result, the micellar properties can be altered via chemical modification in order to impact several key properties relevant to drug delivery.     

Influence of the block length on the structure of micelles formed by polystyrene-block-poly(ethylene-co-propene) in octane and 5-methyl-2-hexanone

The influence of molar mass and chemical composition of the copolymer on the structural parameters of copolymer micelles was investigated. Two polystyrene-block-poly(ethylene-co-propene) copolymers with the same polystyrene block length but different poly(ethylene-co-propene) length were used. The micelles were studied in solutions of octane and 5-methyl-2-hexanone, selective solvents for poly(ethylene-co-propene) (PEP) and polystyrene (PS) blocks, respectively. Static light scattering and viscosity measurements were carried out in order to determine the weight-average molar mass, radius of gyration, second virial coefficient and hydrodynamic radius of the micelles. The association number of the micelles depends on the location of the largest copolymer block in the micelle structure. An influence of the copolymer structure on the micelle dimensions was also found.     

siRNA delivery from triblock copolymer micelles with spatially-ordered compartments of PEG shell,siRNA-loaded intermediate layer,and hydrophobic core

Hydrophobized block copolymers have widely been developed for construction of polymeric micelles for stable delivery of nucleic acids as well as anticancer drugs. Herein, we elaborated an A-B-C type of triblock copolymer featuring shell-forming A-segment, nucleic acid-loading B-segment, and stable core-forming C-segment, directed toward construction of a three-layered polymeric micelle as a small interfering RNA (siRNA) vehicle. The triblock copolymer was prepared with nonionic and hydrophilic poly(ethylene glycol) (PEG), cationic poly(l-lysine) (PLys), and poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [PAsp(DET)] bearing a hydrophobic dimethoxy nitrobenzyl ester (DN) moiety in the side chain [PEG-PLys-PAsp(DET-DN)]. The resulting triblock copolymers spontaneously formed sub-100 nm-sized polymeric micelles with a hydrophobic PAsp(DET-DN) core as well as PEG shell in an aqueous solution. This micelle was able to incorporate siRNA into the intermediate PLys layer, associated with slightly reduced size and a narrow size distribution. The triblock copolymer micelles (TCMs) stably encapsulated siRNA in serum-containing medium, whereas randomly hydrophobized triblock copolymer [PEG-PLys(DN)-PAsp(DET-DN)] control micelles (RCMs) gradually released siRNA with time and non-PEGylated diblock copolymer [PLys-PAsp(DET-DN)] control micelles (DCMs) immediately formed large aggregates. The TCMs thus induced appreciably stronger sequence-specific gene silencing in cultured cancer cells, compared to those control micelles. The siRNA delivery with TCMs was further examined in terms of cellular uptake and intracellular trafficking. The flow cytometric analysis revealed that the cellular uptake of TCMs was more efficient than that of RCMs, but less efficient than that of DCMs. The intracellular trafficking study using confocal laser scanning microscopy combined with fluorescence resonance energy transfer (FRET) revealed that the TCMs could readily release the siRNA payload within cells, which was in contrast to the DCMs exhibiting much slower release profile. This result indicates that PEG shell contributed to the smooth release of siRNA from TCMs within the cells, presumably due to avoiding irreversible aggregate formation. The obtained results demonstrated that the design of separately functionalized polymer segments expanded the performance of polymeric micelles for successful siRNA delivery.     

Glutathione-dependent micelles based on carboxymethyl chitosan for delivery of doxorubicin

Novel glutathione (GSH)-dependent micelles based on carboxymethyl chitosan (CMCS) were developed for triggered intracellular release of doxorubicin (DOX). DOX-33′-Dithiobis (N-hydroxysuccinimidyl propionate)-CMCS (DOX-DSP-CMCS) prodrugs were synthesized. DOX was attached to the amino group on CMCS via disulfide bonds and drug-loaded micelles were formed by self-assembly. The micelles formed core–shell structure with CMCS and DOX as the shell and core, respectively, in aqueous media. The structure of the prodrugs was confirmed by IR and proton nuclear magnetic resonance (¹H NMR) spectroscopy. The drug-loading capacity determined by UV spectrophotometry was 4.96% and the critical micelle concentration of polymer prodrugs determined by pyrene fluorescence was 0.089 mg/mL. Micelles were spherical and the mean size of the nanoparticles was 174 nm, with a narrow polydispersity index of 0.106. Moreover, in vitro drug release experiments showed that the micelles were highly GSH-sensitive owing to the reductively degradable disulfide bonds. Cell counting kit (CCK-8) assays revealed that DOX-DSP-CMCS micelles exhibited effective cytotoxicity against HeLa cells. Moreover, confocal laser scanning microscopy (CLSM) demonstrated that DOX-DSP-CMCS micelles could efficiently deliver and release DOX in the cancer cells. In conclusion, the DOX-DSP-CMCS nanosystem is a promising drug delivery vehicle for cancer therapy.     

Small‐Angle Neutron Scattering Study of Onion‐Type Micelles

Onion‐type block copolymer micelles were prepared from polystyrene‐block‐poly(2‐vinylpyridine) (PS‐b‐PVP) inner micelles in an acidic solution by basifying in the presence of poly(2‐vinylpyridine)‐block‐poly‐(ethylene oxide) (PVP‐b‐PEO). This has the effect of depositing the PVP‐b‐PEO onto the collapsed corona of the PS‐b‐PVP micelle. These core PS‐b‐PVP micelles, the small micelles formed by PVP‐b‐PEO, and the resulting onion micelles were studied by small angle neutron scattering (SANS) techniques. Two recently developed evaluation techniques were employed: 1.Bare‐core approximation, which utilizes the data at larger scattering angles and provided information about the size and polydispersity of the micelle cores. 2. Application of the Pedersen and Gerstenberg micelle model, which utilizes the whole scattering curve. Due to their polyelectrolyte nature, the core micelles had very extended coronas corresponding to rather large statistical segment lengths. The SANS data at large scattering angles for the solution of onion‐type micelles revealed the presence of a significant number of the small PVP‐b‐PEO micelles. The contribution of the small micelles to the total scattering was subtracted and the properties and polydispersities of onion cores and stabilizing PEO coronas were obtained.     

Characterization of the thermo- and pH-responsive assembly of triblock copolymers based on poly(ethylene glycol) and functionalized poly(ε-caprolactone)

A series of novel triblock copolymers composed of poly(ethylene glycol) (PEG) and poly(ε-caprolactone)-bearing benzyl carboxylate on the α-carbon of ε-caprolatone were synthesized through ring opening polymerization of α-benzyl carboxylate-ε-caprolactone by dihydroxylated PEG. The debenzylation of the synthesized copolymer, i.e., poly(α-benzyl carboxylate-ε-caprolactone)-b-PEG-b-poly(α-benzyl-carboxylate-ε-caprolactone) (PBCL-b-PEG-b-PBCL), in the presence of hydrogen gas using different levels of catalyst, was carried out to achieve copolymers with various degrees of free α-carboxyl to α-benzyl-ε-carboxylate groups on the hydrophobic block. Incomplete reduction of PBCL led to the formation of poly(α-carboxyl-co-benzyl caboxylate-ε-caprolactone) PCBCL in the lateral blocks at 27%, 50% and 75% carboxyl group substitution. The molecular weight and polydispersity of the resultant copolymers were estimated by ¹H NMR and MALDI-TOF. Synthesized triblock copolymers formed stable micelles at low concentrations (critical micellar concentrations (CMC) of 0.34–12.5 μg ml⁻¹). Polymers containing carboxyl groups in their structure showed a pH-dependent increase in CMC. As the pH was raised from 4.0 to 9.0, CMC increased from 0.76 to 1.06 μg ml⁻¹, for 27% debenzylated polymer, and from 1.30 to 2.20 μg ml⁻¹, for 50% debenzylated polymers. In contrast, the CMC in polymers without carboxyl group was independent of pH (0.55 μg ml⁻¹). Different changes in micellar size as a function of temperature was observed depending on the degree of debenzylation on the PCBCL block: polymers with 27% degree of debenzylation illustrated a rise in micelle size from ∼38 to 55 nm as the temperature increased above 29 °C, while polymers with 50% debenzylation showed a decrease in micelle size, from ∼52 to 38 nm, with increase in temperature. A similar trend was observed at pH 4.5, 7.0 and 9.0 for polymers containing carboxyl groups on their hydrophobic block. The temperature for the onset of size change and/or the extent of aggregate size change was found to be dependent on the pH of the medium and the polymer concentration. The results point to a potential for the formation of thermo- and pH-responsive micelles from triblock copolymers of PEG and carboxyl substituted caprolactone. The results also imply a potential for the 27% debenzylated PCBCL-b-PEG-b-PCBCL copolymers to form a biodegradable thermoreversible gel with a transition temperature a few degrees below 37 °C.     

Biodegradable cationic PEG-PEI-PBLG hyperbranched block copolymer: synthesis and micelle characterization

A novel amphiphilic biodegradable cationic hyperbranched poly(ethylene glycol)-polyethylenimine-poly(gamma-benzyl L-glutamate) (PEG-PEI-PBLG) block copolymer was successfully synthesized by ring-opening polymerization (ROP) of N-carboxyanhydride of gamma-benzyl-L-glutamate (BLG-NCA) with PEG-PEI as a macroinitiator. PEG-PEI was firstly prepared by coupling of PEG and PEI using hexamethylene diisocyanate (HMDI). The structural properties of PEG-PEI-PBLG copolymers were confirmed by 1H NMR and GPC. The copolymers were found to be self-assembled in water with critical micelle concentration (CMC) in the range of 0.00368-0.0125 g/l and high hydrophobic micelle core. The micelle size and CMC obviously depended on the hydrophobic block content in the copolymer and the ionic state of the PEI block. The CMC decreased with the increase in the PBLG block content. The decrease of micelle size and the increase of CMC simultaneously occurred with the protonated degree of PEI block by addition of HCl solution. ESEM and Gel retardation assay showed that the cationic micelles had ability to encapsulate plasmid DNA. The copolymer has potential medical applications in drug and gene delivery.     

Increased Drug-Loading Enhances the Activity of Ellipticine in Poly(N-(2-hydroxypropyl) Methacrylamide) PHPMA-Based Polymeric Micelles in 2D and 3D Cancer Cell Models

Polymeric micelles are widely used as multifunctional drug carriers of poorly water-soluble drugs, but the role of drug loading content is often overlooked. The purpose of this study is to investigate the cellular uptake and penetration of polymeric micelles with different drug loading contents and their effects on biological activities. In this study, poly(N-(2-hydroxypropyl) methacrylamide-co-methacrylic acid)-block-poly methyl methacrylate P(HPMA-co-MAA)-b-PMMA micelles are used as a nanocarrier for the encapsulation of the potent anticancer agent ellipticine (EPT). The micelles are loaded with various amounts of EPT and the physicochemical characteristics such as particle size, morphology, and zeta potential of blank and EPT loaded nanoparticles are studied. Moreover, fluorescent lifetime studies confirm that hydrophobic EPT is indeed in the PMMA micelle core. In vitro cytotoxicity tests using the glioma cell line U87MG reveal lower IC₅₀ values when the cells are incubated with micelle with high drug loading content. The higher toxicity in micelles with higher drug loading content is associated with higher cellular uptake, which is monitored using laser scanning confocal microscopy and flow cytometry. Moreover, higher activity of micelles with higher drug loading is also observed in U87MG multicellular tumor spheroids although the difference is not significant.     

Synthesis and Micellization of Star‐Shaped Poly(ethylene glycol)‐block‐Poly(ε‐caprolactone)

Summary: The relationship between the architecture of block copolymers and their micellar properties was investigated. Diblock, 3‐arm star‐shaped and 4‐arm star‐shaped block copolymers based on poly(ethylene glycol) and poly(ε‐caprolactone) were synthesized. Micelles of star‐shaped block copolymer in an aqueous solution were then prepared by a solvent evaporation method. The critical micelle concentration and the size of the micelles were measured by the steady‐state pyrene fluorescence method and dynamic light scattering, respectively. The CMC decreased in the order di‐, 3‐arm star‐shaped and 4‐arm star‐shaped block copolymer. The size of the micelles increased in the same order as the CMC. Theory also predicts that the formation of micelles becomes easier for 4‐arm star‐shaped block copolymers than for di‐ and 3‐arm star‐shaped block copolymers, which qualitatively agrees with the experiments.

     

Constructing doxorubicin-loaded polymeric micelles through amphiphilic graft polyphosphazenes containing ethyl tryptophan and PEG segments

By changing the molar ratio of hydrophilic and hydrophobic segments, a series of novel amphiphilic graft polyphosphazenes (PEG/EtTrp-PPPs) was synthesized via thermal ring-opening polymerization and a subsequent two-step substitution reaction of hydrophilic methoxyl polyethylene glycol (MPEG) and hydrophobic ethyl tryptophan (EtTrp). ¹H-Nuclear magnetic resonance and Fourier transform infrared studies validated the expected synthesis of copolymers. The copolymer composition was also confirmed by UV–visible spectrophotometry. The molar ratio of the segment PEG to group EtTrp was 1.33:0.67, 1.01:0.99 and 0.78:1.22, respectively. Micellization behavior of PEG/EtTrp-PPPs in an aqueous phase was characterized by fluorescence technique, dynamic light scattering and transmission electron microscopy. The critical micelle concentration (CMC) of the graft copolymer in aqueous solution was 0.158, 0.033 and 0.020 g l^?1, which decreased as the hydrophobic content in amphiphilic copolymers increased. Doxorubicin (DOX) was physically loaded into micelles prepared by an O/W emulsion method with a drug loading content increasing with DOX feeding. In vitro release of DOX from micelles can be accelerated in weak acidic solution. The results of cytotoxicity study using an MTT assay method with HeLa cell showed that amphiphilic graft polyphosphazenes were biocompatible while DOX-loaded micelles achieved comparable cytotoxicity with that of free DOX. In summary, these novel amphiphilic copolymers exhibited potential to be used as injectable drug carriers for tumor treatment.