Micellar Encapsulation Research Articles

Improved Photodynamic Cancer Treatment by Folate-Conjugated Polymeric Micelles in a KB Xenografted Animal Model.

Photodynamic therapy (PDT) is a light-induced chemical reaction that produces localized tissue damage for the treatment of cancers and various nonmalignant conditions. In the clinic, patients treated with PDT should be kept away from direct sunlight or strong indoor lighting to avoid skin phototoxicity. In a previous study, it was demonstrated that the skin phototoxicity of meta-tetra(hydroxyphenyl)chlorin (m-THPC), a photosensitizer used in the clinic, can be significantly reduced after micellar encapsulation; however, no improvement in antitumor efficacy was observed. In this work, a folate-conjugated polymeric m-THPC delivery system is developed for improving tumor targeting of the photosensitizer, preventing photodamage to the healthy tissue, and increasing the effectiveness of the photosensitizers. The results demonstrate that folate-conjugated m-THPC-loaded micelles with particle sizes around 100 nm are taken up and accumulated by folate receptor-overexpressed KB cells in vitro and in vivo, and their PDT has no significant adverse effects on the body weight of mice. After an extended delivery time, a single dose of folate-conjugated m-THPC-loaded micelles has higher antitumor effects (tumor growth inhibition = 92%) through inhibition of cell proliferation and reduction of vessel density than free m-THPC or m-THPC-loaded micelles at an equivalent m-THPC concentration of 0.3 mg kg(-1) after irradiation. Furthermore, folate-conjugated m-THPC-loaded micelles at only 0.2 mg kg(-1) m-THPC have a similar antitumor efficacy to m-THPC or m-THPC-loaded micelles with the m-THPC concentration at 0.3 mg kg(-1) , which indicates that the folate conjugation on the micellar photosensitizer apparently reduces the requirement of m-THPC for PDT. Thus, folate-conjugated m-THPC-loaded micelles with improved selectivity via folate-folate receptor interactions have the potential to reduce, not only the skin photosensitivity, but also the drug dose requirement for clinical PDT.

Glycine molecules in ionic liquid based reverse micelles: Investigation of structure and dynamics using molecular dynamics simulations

Abstract Amino acids, the building blocks of proteins, are probed in reverse micellar encapsulation processes of biological molecules. To achieve a theoretical picture of the effect of confinement of amino acids on the structure and dynamics of reverse micellar aqueous core, a water/[C 1 C 10 Im][Br] reverse micelles containing variable number of glycine molecules (0 to 8), dispersed in pure nonane has been studied using atomistic molecular dynamics simulations. The size of the central water pool was found to become stable with increase in the number of glycine molecules. Glycine molecules associate together through H-bonding interaction within the aqueous core of the reverse micelles. The radial density profile of glycine molecules from the center of mass of the reverse micellar aqueous core shows the preferential presence of glycine molecules near the center. Confinement in nano-space region stabilizes the H-bonds formed between glycine molecules compared to bulk aqueous solution. Increase in the number of glycine molecules within the reverse micellar aqueous core increases the survival time of H-bonds among glycine molecules as well as among water molecules. Translational and reorientational motion of glycine and water molecules are found to be directly related to the survival probability of intermolecular glycine–glycine and water–water H-bonds suggesting the correlation between the mobility of molecules with the rearrangement of the H-bonding network.

Connectivity pattern modifies excited state relaxation dynamics of fluorophore-photoswitch molecular dyads.

In order to modulate the emission of BODIPY fluorophores, they were connected to a diarylethene (DAE) photoswitch via phenylene-ethynylene linkers of different lengths and orientations. The latter allowed for modulation of the electronic coupling in the prepared four BODIPY-DAE dyads, which were compared also to appropriate BODIPY and DAE model compounds by steady state as well as time-resolved spectroscopies. In their open isomers, all dyads show comparable luminescence behavior indicative of an unperturbed BODIPY fluorophore. In strong contrast, in the closed isomers the BODIPY emission is efficiently quenched but the deactivation mechanism depends on the nature of the linker. The most promising dyad was rendered water-soluble by means of micellar encapsulation and aqueous suspensions were investigated by fluorescence spectroscopy and microscopy. Our results (i) illustrate that the electronic communication between the BODIPY and DAE units can indeed be fine-tuned by the nature of the linker to achieve fluorescence modulation while maintaining photoswitchability and (ii) highlight potential applications to image and control biological processes with high spatio-temporal resolution.

A Lipid Base Formulation for Intramuscular Administration of a Novel Sulfur Donor for Cyanide Antagonism.

This study represents a new formulation of the novel Cyanide (CN) antidote, Dimethyl trisulfide (DMTS), for intramuscular administration. This is a naturally occurring organosulfur molecule with the capability of reacting with CN more efficiently than the present sulfur donor type CN therapy of Thiosulfate (TS). Two types of micelles (PEG2000-DSPE and PEG2000-DSPE/TPGS) were prepared and tested for their ability to encapsulate the liquid, highly lipophilic and volatile drug, DMTS. The micellar encapsulation for DMTS does not only eliminate the possible muscle necrosis at the injection sites, but the rate of evaporation within the micelles is suppressed, that can provide a level of stability for the formulation. The method of micelle preparation was optimized and it was demonstrated that the PEG2000-DSPE preparation can dissolve up to 2.0 mg/ml of the antidote candidate. Keeping the injection volume minimized this could provide a maximum DMTS dose of 12.5 mg/kg. However, even this low dose of DMTS showed a remarkable in vivo therapeutic efficacy (2 X LD50 protection) in a mice model when injected intramuscularly. These in vitro and in vivo findings proved the efficacy of DMTS in combating CN intoxication, and the presented work gives valuable insight to micelle preparation and sets the bases for a more advanced future formulation of DMTS.

The reversal of multidrug resistance in ovarian carcinoma cells by co-application of tariquidar and paclitaxel in transferrin-targeted polymeric micelles

In this study, a transferrin (Tf)-modified polyethylene glycol-phosphatidyl ethanolamine (PEG-PE)-based micellar delivery system containing paclitaxel (PTX) and tariquidar (TRQ), a potent third generation P-gp inhibitor, was prepared. The nanoformulation was evaluated by targeting efficiency, cellular association, cellular internalization pathway and cytotoxicity for reversal of PTX resistance on two multidrug resistant (MDR) ovarian carcinoma cell lines, SKOV-3TR and A2780-Adr. PTX and TRQ are both hydrophobic compounds. They were successfully encapsulated into the micellar structure containing vitamin E as the encapsulation enhancer. The Tf-targeted micelles were internalized mainly via clathrin-dependent endocytosis by both cell lines. For SKOV-3TR, additional mechanisms including caveolin-dependent endocytosis and macropinocytosis were found to play a significant role. The PTX cytotoxicity against the SKOV-3TR and A2780-Adr MDR cells was increased significantly in the presence of micellar encapsulation. However, unlike the A2780-Adr cell line, the Tf-targeting effect was significant on SKOV-3TR cells when co-administrated with TRQ. Penetration of the Tf-targeted micelles in a cancer cell spheroid culture was also investigated.

Enhanced Nuclear Localization of Photosensitizer Using Artificial Oil Bodies for Photodynamic Therapy

Photodynamic therapy (PDT) is a light-activated photochemical reaction that induces localized tissue damage for the treatments of cancers and other nonmalignant conditions through the generation of reactive oxygen species. In the clinic, patients treated with PDT reveal strong skin photosensitivity and thus should be kept away from direct sunlight. In our previous study, we demonstrated that the skin phototoxicity of meta-tetra(hydroxyphenyl)chlorin (m-THPC), a photosensitizer used in the clinic, can be significantly reduced after micellar encapsulation. In this present work, m-THPC was loaded into artificial oil bodies (AOBs) to improve its biocompatibility with self-aggregation. Our results show that the m-THPC-loaded oil bodies with particle size around 100 nm significantly enhanced the nuclear localization of m-THPC, whereas m-THPC-loaded Pluronic® F68 micelles were only observed in the cytosol. In addition, m-THPC-loaded oil bodies had better PDT efficacy than those m-THPC-loaded polymeric micelles. It is speculated that the nuclear accumulation of m-THPC using AOBs as drug carriers significantly enhanced the PDT effects in cancer cells. Thus, m-THPC-loaded oil bodies with improved anticancer efficacy have a great potential for developing nanotechnology-based PDT.

Nanomedicine based curcumin and doxorubicin combination treatment of glioblastoma with scFv-targeted micelles: In vitro evaluation on 2D and 3D tumor models

NF-κB is strongly associated with poor prognosis of different cancer types and an important factor responsible for the malignant phenotype of glioblastoma. Overcoming chemotherapy-induced resistance caused by activation of PI3K/Akt and NF-κB pathways is crucial for successful glioblastoma therapy. We developed an all-in-one nanomedicine formulation for co-delivery of a chemotherapeutic agent (topoisomerase II inhibitor, doxorubicin) and a multidrug resistance modulator (NF-κB inhibitor, curcumin) for treatment of glioblastoma due to their synergism. Both agents were incorporated into PEG-PE-based polymeric micelles. The glucose transporter-1 (GLUT1) is overexpressed in many tumors including glioblastoma. The micellar system was decorated with GLUT1 antibody single chain fragment variable (scFv) as the ligand to promote blood brain barrier transport and glioblastoma targeting. The combination treatment was synergistic (combination index, CI of 0.73) against U87MG glioblastoma cells. This synergism was improved by micellar encapsulation (CI: 0.63) and further so with GLUT1 targeting (CI: 0.46). Compared to non-targeted micelles, GLUT1 scFv surface modification increased the association of micelles (>20%, P<0.01) and the nuclear localization of doxorubicin (∼3-fold) in U87MGcells, which also translated into enhanced cytotoxicity. The increased caspase 3/7 activation by targeted micelles indicates successful apoptosis enhancement by combinatory treatment. Moreover, GLUT1 targeted micelles resulted in deeper penetration into the 3D spheroid model. The increased efficacy of combination nanoformulations on the spheroids compared to a single agent loaded, or to non-targeted formulations, reinforces the rationale for selection of this combination and successful utilization of GLUT1 scFv as a targeting agent for glioblastoma treatment.

Gastrointestinal behavior of nano- and microsized fenofibrate: In vivo evaluation in man and in vitro simulation by assessment of the permeation potential

IntroductionThe purpose of this study was (i) to evaluate the gastrointestinal behavior of micro- and nanosized fenofibrate in humans and (ii) to develop a simple yet qualitatively predictive in vitro setup that simulates the observed absorption-determining factors. Materials and methodsCommercially available micro- and nanoparticles of fenofibrate (Lipanthyl® and Lipanthylnano®, respectively) were administered orally to five healthy volunteers in fasting and postprandial conditions. Intraluminal and systemic drug concentrations were determined as reference data for the development of a predictive in vitro setup. To capture the observed solubility/permeability interplay, in vitro dissolution testing was performed in the presence of a permeation bag with sink conditions. ResultsIn fasting conditions, intake of nanosized fenofibrate generated increased duodenal concentrations compared to microsized fenofibrate, which was reflected in an improved systemic exposure. In postprandial conditions, duodenal concentrations were greatly enhanced for both formulations, however without an accompanying increase in systemic exposure. It appeared that micellar encapsulation of the highly lipohilic fenofibrate limited its potential to permeate from fed state intestinal fluids. To capture these in vivo observations in an in vitro setup, classic dissolution testing was combined with permeation assessment into a permeation bag with sink conditions. In case of fasting conditions, the dissolution/permeation approach allowed for an improved discriminative power between micro- and nanosized fenofibrate by better simulating the dynamic interplay of dissolution and absorption. In case of postprandial conditions, the observed solubility–permeability interplay could be simulated using the dissolution/permeation approach in combination with biorelevant media (FeSSGFFortimel and FeSSIF-V2) to mimic micellar entrapment and reduced permeation potential of fenofibrate. ConclusionFor the first time, reduced permeation of a lipophilic drug despite increased intraluminal concentrations, was demonstrated in humans. Dissolution testing using biorelevant media in combination with permeation assessment into a sink permeation bag appeared to be a simple yet pragmatic approach to capture this solubility–permeability interplay in early formulation evaluation.

Micellar Encapsulation of Some Polycyclic Aromatic Hydrocarbons by Glucose Derived Non-Ionic Gemini Surfactants in Aqueous Medium

Abstract Novel glucose-based non-ionic gemini surfactants consisting of two sugar head groups, two hydrophobic tails having chain length of C8, C10, C12, C14, C16, C18 and –CH2-C6H4-CH2– as a rigid spacer were synthesized and investigated for their micellar encapsulation properties. The head groups of the geminis consist of glucose entities (with reducing function blocked in cyclic acetal group) connected through C-6 to tertiary amines. These surfactants were explored for micellar encapsulation of some polynuclear aromatic hydrocarbons (PAHs) viz. fluorene, anthracene, triptycene and pyrene in 20% ethanol–water mixture. Micellar studies revealed that PAHs were encapsulated in the sequence fluorene &gt; anthracene &gt; triptycene &gt; pyrene and the better efficiency of gemini surfactant was dependent on longer alkyl tail but lesser HLB value.

Inhibition mechanism of hydroxypropyl methylcellulose acetate succinate on drug crystallization in gastrointestinal fluid and drug permeability from a supersaturated solution

The effects of drug-crystallization inhibitor in bile acid/lipid micelles solution on drug permeation was evaluated during the drug crystallization process. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was used as a drug-crystallization inhibitor, which efficiently suppressed dexamethasone (DEX) crystallization in a gastrointestinal fluid model containing sodium taurocholate (NaTC) and egg-phosphatidylcholine (egg-PC). Changes of molecular state of supersaturated DEX during the DEX crystallization process was monitored in real time using proton nuclear magnetic resonance (1H NMR). It revealed that DEX distribution to bulk water and micellar phases formed by NaTC and egg-PC was not changed during the DEX crystallization process even in the presence of HPMC-AS. DEX permeation during DEX crystallization was evaluated using dissolution/permeability system. The combination of crystallization inhibition by HPMC-AS and micellar encapsulation by NaTC and egg-PC led to considerably higher DEX concentrations and improvement of DEX permeation at the beginning of the DEX crystallization process. Crystallization inhibition by HPMC-AS can efficiently work even in the micellar solution, where NaTC/egg-PC micelles encapsulates some DEX. It was concluded that a crystallization inhibitor contributed to improvement of permeation of a poorly water-soluble drug in gastrointestinal fluid.

Reverse Micellar Encapsulation of d‐ and l‐Enantiomers of Some Aromatic α‐Amino Acids and Nucleobases by Glucose‐Derived Non‐ionic Gemini Surfactants in Neat n‐Hexane

AbstractNovel carbohydrate‐based non‐ionic gemini surfactants consisting of two sugar head groups, two hydrophobic tails having chain lengths of C12, C14, and C16 and a flexible –(CH2)6– spacer were synthesized and investigated for their reverse micellar encapsulation properties. The head groups of the geminis comprise glucose entities (with reducing function blocked in a cyclic acetal group) connected through C‐6 to tertiary amines. These surfactants were explored for reverse micellar encapsulation of d‐ and l‐enantiomers of aromatic α‐amino acids viz. histidine (His), phenylalanine (Phe), tyrosine (Tyr) and tryptophan (Trp) in neat n‐hexane. Similar studies were carried out for encapsulation of nucleobases viz. adenine (Ade), guanine (Gua), thymine (Thy), cytosine (Cyt) and Uracil (Ura). Reverse micellar studies revealed that aromatic α‐amino acids were encapsulated in the sequence His&gt;Tyr&gt;Phe&gt;Trp. In most cases, a difference in the degree of encapsulation of d‐ and l‐enantiomers of aromatic amino acids in reverse micellar phases of gemini amphiphiles in neat n‐hexane, was revealed. For Tyr, l‐enantiomer was better encapsulated than its antipode, i.e., d‐enantiomer but for Trp, d‐enantiomer was better encapsulated then l‐enantiomer. In the case of nucleobases, Ura was found selectively encapsulated by reverse micelles formed by these new amphiphiles.

Chemical control of channel interference in two-photon absorption processes.

The two-photon absorption (TPA) process is the simplest and hence the most studied nonlinear optical phenomenon, and various aspects of this process have been explored in the past few decades, experimentally as well as theoretically. Previous investigations have shown that the two-photon (TP) activity of a molecular system can be tuned, and at present, performance-tailored TP active materials are easy to develop by monitoring factors such as length of conjugation, dimensionality of charge-transfer network, strength of donor-acceptor groups, polarity of solvents, self-aggregation, H-bonding, and micellar encapsulation to mention but a few. One of the most intriguing phenomena affecting the TP activity of a molecule is channel interference. The phrase "channel interference" implies that if the TP transition from one electronic state to another involves more than one optical pathway or channel, characterized by the corresponding transition dipole moment (TDM) vectors, the channels may interfere with each other depending upon the angles between the TDM vectors and hence can either increase (constructive interference) or decrease (destructive interference) the overall TP activity of a system to a significant extent. This phenomenon was first pointed out by Cronstrand, Luo, and Ågren [Chem. Phys. Lett. 2002, 352, 262-269] in two-dimensional systems (i.e., only involving two components of the transition moment vectors). For three-dimensional molecules, an extended version of this idea was required. In order to fill this gap, we developed a generalized model for describing and exploring channel interference, valid for systems of any dimensionality. We have in particular applied it to through-bond (TB) and through-space (TS) charge-transfer systems both in gas phase and in solvents with different polarities. In this Account, we will, in addition to briefly describing the concept of channel interference, discuss two key findings of our recent work: (1) how to control the channel interference by chemical means, and (2) the role of channel interference in the anomalous solvent dependence of certain TP chromophores. For example, we will show that simple structurally induced changes in certain dihedral angles of the well-known betaine dye (TB type) will help fine-tune the constructive channel interference and hence increase the overall TP activity of molecules with this general TP channel structure. Another intriguing result we will discuss is observed for a tweezer-trinitrofluorinone complex (TS type) where, on moving from polar to essentially nonpolar solvents, the nature of the channel interference switches from destructive to constructive, leading to a net abnormal solvent dependence of the TP activity of the system. The present Account highlights the usefulness of the channel interference effect and establishes it as a new and unique way of controlling the TP transition probability in different types of three-dimensional molecules.

Linear-dendrimer type methoxy-poly (ethylene glycol)-b-poly (ɛ-caprolactone) copolymer micelles for the delivery of curcumin

Purpose: To improve curcumin’s pharmacokinetic, in vitro cytotoxicity and release property.Methods: A novel linear-dendrimer methoxy-poly (ethylene glycol)-b-poly (ɛ-caprolactone) copolymer was synthesized through O-alkylation, basic hydrolysis and ring-opening polymerization reaction with methoxy-poly (ethylene glycol), epichlorohydrin and ɛ-caprolactone as raw materials. Its structure was characterized by 1H-NMR and GPC. The copolymer’s hemolysis and micellar encapsulation for curcumin by thin-film hydration were studied. Curcumin-loaded micelles were evaluated by use of in vitro release, FT-IR and X-ray diffraction. Curcumin-loaded micelles’ in vitro cytotoxic activities against Hela and HT-29 cells were done, and its pharmacokinetic parameters were also carried out.Results: Curcumin was encapsulated into the micelles with 92.54% of entrapment efficiency and 12.84% of drug loading in amorphous forms. The dissolubility of nanoparticulate curcumin was 1.70 × 105 times higher than that of curcumin in water. The obtained copolymer showed no hemolysis. In vitro drug release study indicated that, in all cases, the kinetics was adjusted well to the Makoid–Banakar model ( = 0.9984). In addition, data were analyzed by the Korsmeyer–Peppas model, n values were 0.43, indicating that the drug release was accomplished by the combination diffusion and polymer chain relaxation. The cytotoxicity experiment indicated that the nanoparticulate curcumin kept up its potent anti-cancer activities. The pharmacokinetic results showed that the MRT0–∞, t1/2z and AUC0–∞ of Curcumin-loaded micelles were 1.64, 6.54 and 4.67 times higher than that of CUR control solution.Conclusions: The copolymeric micelles loading curcumin might act as a delivery vehicle for CUR.

Solubility enhancement of paclitaxel using a linear-dendritic block copolymer

The solubilising capacities of micelles of a linear-dendritic copolymer (BE-PAMAM), formed by conjugating the poly(butylene oxide) (B)-poly(ethylene oxide) (E) block copolymer B16E42 (BE) with a G2 PAMAM dendrimer, have been compared with those of the diblock copolymer B16E42 for the anti-cancer drug paclitaxel. The BE-PAMAM copolymer showed a greater solubility enhancement than BE under equivalent conditions. Drug-loading efficiency was improved using a solvent-loading method compared with the conventional solution-loading method. The solubility of paclitaxel was increased 3700-fold by micellar encapsulation in a 2% (w/v) BE-PAMAM copolymer solution at 37°C using this solubilisation technique. Dynamic light scattering and transmission electron microscopy studies indicated a transition of spherical to worm-like micelles of the BE copolymer induced by the encapsulation of drug molecules. A sustained release of encapsulated drug was observed, with approximately 80% and 60% paclitaxel being released from 2% (w/v) solutions of BE and BE-PAMAM respectively after 24h of dialysis at 37°C.

Water-Soluble Upconversion Nanoparticles by Micellar Route

Upconversion nanoparticles (UCNs) have been of interest in applications such as biological imaging and sensing because of properties like low autofluorescence and negligible photobleaching. In this paper, a micellar encapsulation route was worked upon to make hydrophilic UCNs that are compatible with biological systems and enable conjugation of biomolecules. Phospholipid micelles cannot be easily synthesized with chemical recognition groups of biological interest so synthetic amphiphiles with suitable functional head groups were used to encapsulate and solubilize the hydrophobic UCNs. The encapsulated nanoparticles were characterized using transmission electron microscopy, fluorescence spectroscopy, and dynamic light scattering. The micelle-encapsulated UCNs had an average diameter of 125 nm and the fluorescence emission at 540/660 nm of the bare UCNs did not show any shift after encapsulation. The cytotoxicity of the micelle-encapsulated UCNs was tested using lactose dehydrogenase/MTS (tetrazole salt) assays. The cell viability was estimated to be 80 % at the working concentration of the micelle-encapsulated UCNs. Finally, the micelle-encapsulated UCNs bearing Arg-Gly-Asp tripeptidic RGD surface functionalization were tested on cancer cells expressing integrins for specificity. The micelle-encapsulated UCNs were found to be suitable for cellular targeting and imaging.

Amphiphilic, cross-linkable diblock copolymers for multifunctionalized nanoparticles as biological probes

Nanoparticles (NPs) play an increasingly important role in biological labeling and imaging applications. However, preserving their useful properties in an aqueous biological environment remains challenging, even more as NPs therein have to be long-time stable, biocompatible and nontoxic. For in vivo applications, size control is crucial in order to route excretion pathways, e.g. renal clearance vs. hepato-biliary accumulation. Equally necessary, cellular and tissue specific targeting demands suitable linker chemistry for surface functionalization with affinity molecules, like peptides, proteins, carbohydrates and nucleotides. Herein, we report a three stage encapsulation process for NPs comprised of (1) a partial ligand exchange by a multidentate polyolefinic amine ligand, PI-N3, (2) micellar encapsulation with a precisely tuned amphiphilic diblock PI-b-PEG copolymer, in which the PI chains intercalate to the PI-N3 prepolymer and (3) radical cross-linking of the adjacent alkenyl bonds. As a result, water-soluble NPs were obtained, which virtually maintained their primal physical properties and were exceptionally stable in biological media. PEG-terminal functionalization of the diblock PI-b-PEG copolymer with numerous functional groups was mostly straightforward by chain termination of the living anionic polymerization (LAP) with the respective reagents. More complex affinity ligands, e.g. carbohydrates or biotin, were introduced in a two-step process, prior to micellar encapsulation. Advantageously, this pre-assembly approach opens up rapid access to precisely tuned multifunctional NPs, just by using mixtures of diverse functional PI-b-PEG polymers in a combinatorial manner. All constructs showed no toxicity from 0.001 to 1 μM (particle concentration) in standard WST and LDH assays on A549 cells, as well as only marginal unspecific cellular uptake, even in serum-free medium.

Synthesis, characterization, drug-loading capacity and safety of novel pH-independent amphiphilic amino acid copolymer micelles.

A novel block copolymer containing two polymeric components, poly(L-aspartic acid)-b-poly (L-phenylalanine) (PAA-PPA), was synthesized and its potential for the preparation of copolymer micelles with a poorly water-soluble drug was investigated in this study. The chemical structure and physical properties of PAA-PPA were characterized by FTIR, 1H NMR and TG. The degree of polymerization of PAA-PPA was calculated by analyzing the relative area of N-CH signal and C-CH3 of 1H NMR spectra. The critical micelle concentration (CMC) of the PAA-PPA achieved a minimum of 11.1 mg/L. Studies on the drug-free PAA-PPA solutions showed PAA-PPA aggregation into micellar type in the sub-150 nm size range. Furthermore, the size of the PAA-PPA micelles was found to be pH-independent between the pH range of 4.0 and 8.0, which could be favorable to avoid the limitation of the size change at the specified pH value seeking drug stability. 4-amino-2-trifluoromethyl-phenyl retinate (ATPR) was studied as a poorly water-soluble model drug. The drug-loading and entrapment efficiency of the ATPR-loaded PAA-PPA micelles were 30.9 wt% and 87.9 %, respectively. The high drug-loading and entrapment efficiency were due to the synergistic effect of the micellar encapsulation and the binding interaction between drug and PAA-PPA. The ATPR-loaded PAA-PPA micelles showed a narrow size distribution, low zeta potential, high drug-loading capacity and good stable. The PAA-PPA was safer than Tween-80 and Cremophor EL (CrmEL) as an injectable pharmaceutical adjuvant for ATPR as indicated by the hemolysis and cytotoxicity studies. The novel amphiphilic amino acid copolymer can be considered as a prospective injectable delivery system for ATPR in terms of the pH-independent, greater drug-loading capacity and safety.

Improved Photodynamic Cancer Treatment by Folate‐Conjugated Polymeric Micelles in a KB Xenografted Animal Model

Photodynamic therapy (PDT) is a light-induced chemical reaction that produces localized tissue damage for the treatment of cancers and various nonmalignant conditions. In the clinic, patients treated with PDT should be kept away from direct sunlight or strong indoor lighting to avoid skin phototoxicity. In a previous study, it was demonstrated that the skin phototoxicity of meta-tetra(hydroxyphenyl)chlorin (m-THPC), a photosensitizer used in the clinic, can be significantly reduced after micellar encapsulation; however, no improvement in antitumor efficacy was observed. In this work, a folate-conjugated polymeric m-THPC delivery system is developed for improving tumor targeting of the photosensitizer, preventing photodamage to the healthy tissue, and increasing the effectiveness of the photosensitizers. The results demonstrate that folate-conjugated m-THPC-loaded micelles with particle sizes around 100 nm are taken up and accumulated by folate receptor-overexpressed KB cells in vitro and in vivo, and their PDT has no significant adverse effects on the body weight of mice. After an extended delivery time, a single dose of folate-conjugated m-THPC-loaded micelles has higher antitumor effects (tumor growth inhibition = 92%) through inhibition of cell proliferation and reduction of vessel density than free m-THPC or m-THPC-loaded micelles at an equivalent m-THPC concentration of 0.3 mg kg(-1) after irradiation. Furthermore, folate-conjugated m-THPC-loaded micelles at only 0.2 mg kg(-1) m-THPC have a similar antitumor efficacy to m-THPC or m-THPC-loaded micelles with the m-THPC concentration at 0.3 mg kg(-1) , which indicates that the folate conjugation on the micellar photosensitizer apparently reduces the requirement of m-THPC for PDT. Thus, folate-conjugated m-THPC-loaded micelles with improved selectivity via folate-folate receptor interactions have the potential to reduce, not only the skin photosensitivity, but also the drug dose requirement for clinical PDT.

Application of simulated intestinal fluid on the phospholipid vesicle-based drug permeation assay

The compatibility of fasted state simulated intestinal fluid (FaSSIF) in drug permeation studies employing the phospholipid vesicle-based permeation assay (PVPA) model was confirmed by a set of different integrity indicators. Neither calcein permeability nor electrical resistance were found significantly changed indicating unaffected barrier tightness. Furthermore, the release of phospholipid from the barriers in contact with FaSSIF was negligible, although sodium taurocholate disappeared from the donor – possibly due to transfer into the barrier. Visual examination of the barrier structure by confocal laser scanning microscopy (CLSM) revealed no changes. The model drugs, cimetidine, nadolol, ketoprofen and griseofulvin showed either slightly enhanced or unchanged permeability values in the presence of FaSSIF. This may be attributed to micellar encapsulation and/or slight changes in barrier characteristics. Particularly for poorly soluble drugs, FaSSIF appeared favourable in terms of markedly improved recovery. Moreover, utilisation of BSA in the receiver compartment seems to augment this beneficial effect on recovery rate. It is likely that this experimental set-up affords better sink conditions in the receiver phase, which results in higher fluxes. Overall, a combination of FaSSIF in the donor phase and BSA in the receiver phase facilitates improved experimental output.

Tailoring the efficacy of nimodipine drug delivery using nanocarriers based on A 2B miktoarm star polymers

We report a nanocarrier based on A 2B type miktoarm polymers (A = polyethylene glycol (PEG); B = polycaprolactone (PCL)) for nimodipine (NIM), a hydrophobic drug with very poor aqueous solubility that is commonly prescribed for the prevention and treatment of delayed ischemic neurological disorders. The A 2B star polymers were constructed on a core with orthogonal functionalities that facilitated the performance of “click” chemistry followed by ring-opening polymerization. These star polymers assemble into spherical micelles into which NIM can be easily loaded by the co-solvent evaporation method. The micelles obtained from the star polymer PEG775 2–PCL5800 showed NIM encapsulation efficiency of up to 78 wt% at a feed weight ratio of 5.0%. The loading efficiency of the micelles was dependent on the length of the PCL arm in the A 2B miktoarm polymers. Aqueous solubility of NIM was increased by ∼200 fold via micellar encapsulation. The in vitro release of NIM from the micelles was found to occur at a much slower rate than from its solution. Lipopolysaccharide induced nitric oxide production in N9 microglia cells was reduced in the presence of micelle-encapsulated NIM, as well as in the presence of micelles alone. The treatment of microglia with micelle-encapsulated NIM reduced the release of TNF-α, a pro-inflammatory cytokine. These results suggest that NIM-loaded miktoarm micelles could be useful in the treatment of neuroinflammation.