Nano-sized Polymeric Micelles Research Articles

Micelle encapsulated curcumin and piperine-laden 3D printed calcium phosphate scaffolds enhance in vitro biological properties

Limitations in the current clinical management of critical-sized osseous defects have driven the need for multifunctional bone constructs. The ideal bone scaffold should possess advanced microarchitecture, well-defined pore interconnectivity, and supply biological signals, which actively guide and control tissue regeneration while simultaneously preventing post-implantation complications. Here, a natural medicine-based localized drug delivery from 3D printed scaffold is presented, which offers controlled release of curcumin, piperine from nano-sized polymeric micelles, and burst release of antibacterial carvacrol from the coating endowing the scaffold with their distinct, individual biological properties. This functionalized scaffold exhibits improved osteoblast (hFOB) cell attachment, 4-folds higher hFOB proliferation, and 73% increased hFOB differentiation while simultaneously providing cytotoxicity towards osteosarcoma cells with 61% lesser viability compared to control. In vitro, early tube formation (p < 0.001) indicates that the scaffolds can modulate the endothelial cellular network, critical for faster wound healing. The scaffold also exhibits 94% enhanced antibacterial efficacy (p < 0.001) against gram-positive Staphylococcus aureus, the main causative bacteria for osteomyelitis. Together, the multifunctional scaffolds provide controlled delivery of natural biomolecules from the nano-sized micelle-loaded 3D printed matrix for significant improvement in osteoblast proliferation, endothelial formation, osteosarcoma, and bacterial inhibition, guiding better bone regeneration for post-traumatic defect repair.

Oligo(Lactic Acid)8-Docetaxel Prodrug-Loaded PEG-b-PLA Micelles for Prostate Cancer.

Docetaxel (DTX) is among the most frequently prescribed chemotherapy drugs and has recently been shown to extend survival in advanced prostate cancer patients. However, the poor water solubility of DTX prevents full exploitation of this potent anticancer drug. The current marketed formulation, Taxotere®, contains a toxic co-solvent that induces adverse reactions following intravenous injection. Nano-sized polymeric micelles have been proposed to create safer, water-soluble carriers for DTX, but many have failed to reach the clinic due to poor carrier stability in vivo. In this study, we aimed to improve micelle stability by synthesizing an ester prodrug of DTX, oligo(lactic acid)8-docetaxel (o(LA)8-DTX), for augmented compatibility with the core of poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) micelles. Due to the enhancement of drug-carrier compatibility, we were able to load 50% (w/w) prodrug within the micelle, solubilize 20 mg/mL o(LA)8-DTX (~12 mg/mL DTX-equivalent) in aqueous media, and delay payload release. While the micelle core prohibited premature degradation, o(LA)8-DTX was rapidly converted to parent drug DTX through intramolecular backbiting (t1/2 = 6.3 h) or esterase-mediated degradation (t1/2 = 2.5 h) following release. Most importantly, o(LA)8-DTX micelles proved to be as efficacious but less toxic than Taxotere® in a preclinical mouse model of prostate cancer.

Biomedical Applications of Nano-Sized Polymeric Micelles and Polyion Complexes

Biomedical Applications of Nano-Sized Polymeric Micelles and Polyion Complexes

Reduction-active polymeric prodrug micelles based on α-cyclodextrin polyrotaxanes for triggered drug release and enhanced cancer therapy

As one of the medical polymers approved by US Food and Drug Administration (FDA), poly(ethylene glycol) has low toxicity, high stability, good biocompatibility, unique physical and chemical properties. Cyclodextrin is an ideal candidate as a drug carrier due to its special structures and characteristics. These two materials were successfully assembled through chemosynthesis in combination with the hydrophilic poly(ethylene glycol) methyl ether methacrylate (OEGMA) chain and hydrophobic polymeric camptothecin (CPT) chain by atom transfer radical polymerization (ATRP). The introduction of disulfide bond of monomer was aimed to realize reduction agent-triggered release of active CPT. The obtained amphipathic prodrug [(Denoted as PC-PCPT-b-POEGMA (PCCO)] could form nano-sized polymeric micelles, which could release more than 85% of the loaded CPT via triggered cleavage of the disulfide linker. The cellular co-localization study revealed the potential pathway of drug internalization. Moreover, the PCCO micelles showed good biocompatibility in vivo after intravenous injection on a mouse model. This new CPT-loaded prodrug system could be prepared with low cost, and showed efficient and controlled drug release and favorable biocompatibility, demonstrating a promising potential as a stimuli-responsive polymeric prodrug for future clinical applications.

In vitro and in vivo assessment of delivery of hydrophobic molecules and plasmid DNAs with PEO–PPO–PEO polymeric micelles on cornea

The stability and bio-distribution of genes or drug complexes with poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO–PPO–PEO, Pluronic F-68) polymeric micelles (PM) are essential for an effective nanosized PM delivery system. We used Förster resonance energy transfer (FRET) pairs with PM and measured the FRET ratio to assess the stability of PM in vitro and in vivo on the cornea. The FRET ratio reached a plateau at 0.8 with 3% PM. Differential scanning calorimetry measurement confirmed the complex formation of FRET pairs with PM. Confocal imaging with the fluorophores fluorescein isothiocyanate isomer I (FITC) and rhodamine B base (RhB) also showed the occurrence of FRET pairs in vitro. The fluorophores were mixed with 3% PM solution or the FITC-labeled PEO–PPO–PEO polymers (FITC-P) were mixed with RhB-labeled plasmids (RhB–DNA). In addition, the in vitro corneal permeation of FRET pair complexes with PM reached a 0.8 FRET ratio. One hour after eye drop administration, FRET pairs colocalized in the cytoplasm, and surrounded and entered the nuclei of cells in the cornea, and the polymers were located in the corneal epithelial layers, as detected through anti-PEG immunohistochemistry. Furthermore, fluorescence colocalization in the cytoplasm and cell nucleus of the corneal epithelium was confirmed in tissues where RhB or RhB–DNA complexed with FITC-P was found to accumulate. We demonstrate that at a concentration of 3%, PM can encapsulate FRET pairs or RhB–DNA and retain their integrity within the cornea 1 h after administration, suggesting the feasibility and stability of PEO–PPO–PEO polymers as a vehicle for drug delivery.

Poly(ε-benzyloxycarbonyl-L-lysine)-grafted branched polyethylenimine as efficient nanocarriers for indomethacin with enhanced oral bioavailability and anti-inflammatory efficacy.

The use of polyethylenimine (PEI) as an oral drug delivery carrier is limited because it is not biodegradable and the use of higher molecular weight PEI leads to improved efficiency but also increased cytotoxicity. The design of functionalized PEIs with low cytotoxicity and high efficiency is crucial for developing a successful oral drug delivery system. In our study, poly(ε-benzyloxycarbonyl-L-lysine) (PZLL)-grafted branched PEI (PEI-g-PZLL) was reported as an oral nanocarrier for indomethacin (IND). The low cytotoxicity and biodegradability, well-defined self-assembled nano-sized polymeric micelles, high loading capacity and loading efficiency, amorphous state of the encapsulated IND, as well as the enhanced oral bioavailability of IND, makes the copolymer PEI-g-PZLL a promising nanocarrier for the oral administration of IND and possibly other poorly water-soluble drugs.

Mixed Nanosized Polymeric Micelles as Promoter of Doxorubicin and miRNA-34a Co-Delivery Triggered by Dual Stimuli in Tumor Tissue.

Dual stimuli-sensitive mixed polymeric micelles (MM) are developed for co-delivery of the endogenous tumor suppressor miRNA-34a and the chemotherapeutic agent doxorubicin (Dox) into cancer cells. The novelty of the system resides in two stimuli-sensitive prodrugs, a matrix metalloproteinase 2 (MMP2)-sensitive Dox conjugate and a reducing agent (glutathione, GSH)-sensitive miRNA-34a conjugate, self-assembled in a single particle decorated with a polyethylene glycol corona for longevity, and a cell-penetrating peptide (TATp) for enhanced intracellular delivery. The MMP2-sensitivity of the system results in threefold higher cytotoxicity in MMP2-overexpressing HT1080 cells compared to low MMP2-expressing MCF7 cells. Cellular internalization of Dox increases by more than 70% after inclusion of TATp to the formulation. MMP2-sensitive MM also inhibits proliferation and migration of HT1080 cells. Moreover, GSH-sensitive MM allows for an efficient downregulation of Bcl2, survivin, and notch1 (65%, 55%, and 46%, respectively) in HT1080 cells. Combination of both conjugates in dual sensitive MM reduces HT1080 cell viability to 40% and expression of Bcl2 and survivin. Finally, 50% cell death is observed in 3D models of tumor mass. The results confirm the potential of the MM to codeliver miRNA-34a and doxorubicin triggered by dual stimuli inherent of tumor tissues.

Polymeric micellar nanocarriers of benzoyl peroxide as potential follicular targeting approach for acne treatment

The aim of this work was to optimize polymeric nano-sized micellar carriers of the anti-acne compound benzoyl peroxide (BPO) and to examine the ability of these carriers to deposit into hair follicles with the objective of improving skin delivery of BPO. BPO loaded polymeric micelles composed of Pluronic® F127 were prepared by the thin film hydration method and characterized in terms of size, loading capacity, morphology and physical stability. The optimized micelle formulation was then selected for skin delivery studies. The penetration of BPO loaded micellar carriers into skin and skin appendages across full thickness porcine skin was examined in vitro. Confocal microscopy images confirmed the penetration of Nile Red into hair follicles, which was loaded into micellar carriers as a model fluorescent compound. The relative safety of the polymeric micelles was evaluated with the MTT viability test using mouse embryonic fibroblasts. The results indicated that nano-sized polymeric micelles of BPO composed of Pluronic® F127 offer a potential approach to enhance skin delivery of BPO and that targeting of micelles into hair follicles may be an effective and safe acne treatment.

PH-responsive copolymers based on pluronic P123-poly(β-amino ester): Synthesis, characterization and application of copolymer micelles

A novel amphiphilic and pH-responsive copolymer, pluronie P123-poly(β-amino ester) (P123-PAE), was firstly designed and synthesized using a Michael-type step polymerization. Nano-sized polymeric micelles based on P123-PAE block copolymer were prepared by self-assembly. Curcumin (Cur), a potential cancer therapy drug, was efficiently encapsulated into the P123-PAE micelles to enhance anticancer efficacy. The obtained Cur loaded P123-PAE micelles (Cur-P123-PAE) presented a spherical shape and high drug loading (18.4%). Interestingly, when the media pH decreased from 7.4 to 5.5, the particle size of the micelles shrank from 152.5nm to 122.1nm due to the protonation of PAE blocks, and the zeta potential of the P123-PAE micelles changed from weakly positive (1.5mV) to highly positive (9.0mV) over a pH range from 7.4 to 5.5. In vitro drug release studies demonstrated that the release rate of Cur was markedly influenced by pH. In vitro cytotoxicity tests showed that all the blank micelles were non-toxic. Cur-P123-PAE exhibited similar antitumor effect against MCF-7 and HepG2 cells compared to solubilized Cur solution. Using Coumarin-6 as a fluorescence probe, it was observed that Cur-P123-PAE micelles experienced longer circulation followed by accumulation at tumor tissues with stronger fluorescence intensity. The results of pharmacokinetics studies showed that the P123-PAE micelles could significantly prolong the retention time of Cur in vivo.

Amphiphilic polyallylamine based polymeric micelles for siRNA delivery to the gastrointestinal tract: In vitro investigations

Targeting the gastrointestinal (GI) tract represents a promising strategy for local or systemic delivery of nucleic acid-based therapeutics. The development of a nano-carrier for siRNA delivery via the GI tract would enable localised therapy for a range of gastrointestinal diseases. Previously, nano-sized polymeric micelles (PM) formed by a variety of amphiphilic poly(allylamine) (PAA) derivatives have shown potential for oral delivery of hydrophobic drugs and bioactive peptides. The aim of this study was to evaluate the ability of these amphiphilic PAA-based PM for siRNA delivery via the GI tract. The physicochemical characteristics of PAA·siRNA transfection complexes and their biological efficacy in vitro were investigated. Physicochemical profiles demonstrated that PAAs and siRNA self-assembled into complexes with nano-sized diameters (150-300 nm) and cationic surface charge (+ 20 to 30 mV). The PAA·siRNA complexes were stable in the presence of salt solutions and simulated gastric/intestinal fluids. In undifferentiated Caco-2 cells, PAA·siRNA complexes achieved up to 35% cellular uptake, with successful siRNA release from endosomes/lysosomes and significant luciferase gene knockdown. These results highlight the potential of these nano-sized PM for siRNA oral delivery via the GI tract for treatment of gastrointestinal diseases.

Biostable Poly(ethylene oxide)-b-poly(methacrylic acid) Micelles forpH-triggered Release of Doxorubicin

ABSTRACT − pH-sensitive cross-linked polymeric micelles were synthesized by using block ionomer complexes of poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMA) with calcium ions as micellar templates. An anticancer drug, doxorubicin (DOX) was conjugated on the cross-linked ionic cores of micelles via acid-labile hydrozone bonds. The result-ing DOX-conjugated, pH-sensitive micelles are stable at physiological conditions, whereas the release of DOX was sig-nificantly increased at the acidic pH. Such micelles were internalized to lysosomes, and acidic pH in lysosomes triggers the release of DOX upon internalization in MCF-7 breast cancer cells. The released DOX entered the cell nucleus and even-tually killed cancer cells. Therefore, these data demonstrate that the pH-sensitive micelles could be a promising nanocarrier for delivery of anticancer drug, DOX.Key words− Doxorubicin, Block ionomer, Calcium, Cross-linked, Polymeric micelles Self-assembled polymeric micelles formed by amphilphilic block copolymers have been utilized as potential drug delivery vehicles for anti-cancer drugs (Allen et al., 1999; Cohy, 2005; Croy et al., 2006; Duncan, 2003; Kabanov et al., 2009; Lavasanifara et al., 2002; Riess, 2003; Rosler, 2001). They are nanoparticles prepared by self-assembly of block copolymers consisted of two different blocks, which are hydrophilic and hydrophobic blocks. Advantages of polymeric micelles for tumor targeting include core-shell type architecture with nanoscale size (10 to 100 nm in diameter), which prolong cir-culation time of polymeric micelles in the body. Hydrophilic nonionic shell such as poly(ethylene oxide) allows for long-cir -culation of nanocarriers by reducing non-specific uptake and clearance by the macrophages of the reticuloendothelial sys-tem (RES). Interestingly, such polymeric nanocarriers have been shown to accumulate in tumors and improve anti-tumor activity of anti-cancer drugs (Alakhov et al., 1999; Yokoyama et al., 1999; Lavasanifara et al., 2002; Duncan, 2003; Davis et al., 2008), by the enhanced permeability and retention effect (EPR effect) (Maeda, 2001). Nanofabrication of the polymeric micelles has been exten-sively advanced through employment of double hydrophilic diblock copolymers, one of which is hydrophilic ionic block and the other is hydrophilic nonionic block. These copolymers spontaneously form nanoparticles called “block ionomer com-plexes (BIC)” or “polyion complex micelles (PIC)”, through electrostatic interaction with oppositely charged molecules. However, the stability of polymeric micelles can be signif-icantly affected by environmental factors such as pH, ionic strength, dilution and shear forces after administration in the blood stream, which may lead to loss of their ability to deliver chemotherapeutic drugs to target tissues.In order to address this problem, nano-sized polymeric micelles based on a cross-linked network of amphiphilic block copolymers have been developed for delivery of anti-cancer drugs (Bronich et al., 2005; Bontha et al., 2006; Kim et al., 2009; Kim et al., 2010). It contains several key features such as cross-linked ionic core, a hydrophilic PEO shell and nanos-cale size. Due to cross-linked ionic cores of micelles, these micelles exhibited distinctive properties as drug delivery carriers, such as their high loading capacity, high stability, and responses to environmental stimuli, such as ionic strength, pH, and temperature (Bontha et al., 2006; Kim et al., 2009).Furthermore, the entry of the cross-linked micelles is inhibited in tight junctions in normal epithelial cells but permitted in cancer cells that do not form tight junctions, via caveolae-mediated endocytosis (Sahay et al., 2010). These favorable characteristics of cross-linked micelles can lead to develop-

Effect of Local Dual Frequency Sonication on Drug Distribution from Nanomicelles

Abstract — The nanosized polymeric micelles release the drug due to acoustic cavitation, which is enhanced in dual frequency ultrasonic fields. In this study, adult female Balb/C mice were transplanted with spontaneous breast adenocarcinoma tumors and were injected with a dose of 1.3 mg/kg doxorubicin in one of three forms: free doxorubicin, micellar doxorubicin without sonication and micellar doxorubicin with sonication. To increase cavitation yield, the tumor region was sonicated with low level dual frequency of 3 MHz and 28 kHz. The animals were sacrificed 24 h after injection, and their tumor, heart, spleen, liver, kidneys and plasma were separated and homogenized. The drug content in their tumor, heart, spleen, liver, kidneys and plasma was determined using tissue fluorimetry. The results show that in the group that received micellar doxorubicin with sonication, the drug concentration in the tumor tissue was nine and three times higher than in the free doxorubicin group and the micellar doxorubicin without sonication group, respectively. In the micellar doxorubicin with sonication group, the drug concentration in other tissues was lower than other groups (p<0.05). We conclude that dual frequency sonication improves drug release from micelles and increases the drug uptake by tumors due to sonoporation.

Amphiphilic cellulose: Surface activity and aqueous self-assembly into nano-sized polymeric micelles

The aim of the present study was to design amphiphilic cellulose that can self-assemble into polymeric vesicle or as nontoxic surfactants. Sulfate was firstly introduced as hydrophilic groups, then the hydrophobic groups for three cellulose derivatives. Effects of the hydrophobic length on the surface tension and critical aggregate concentration (cac) were investigated by the conventional Wilhelmy plate method. Results showed that the cac value decreased from 0.28 to 0.08 wt% and the corresponding surface tension increased from 44 to 55 mN/m when the hydrophobic chain length changed from C 8 to C 18. The aqueous self-assembly of the modified polymer was investigated using transmission electron microscopy (TEM) and dynamic laser scattering (DLS). Results showed that three cellulose derivatives were capable of forming polymeric micelles in water with an average particle diameter ranging from 20 to 67 nm. And the diameter of the nano-micelles was proportional to the length of hydrophobic chain under the experimental conditions. These amphiphilic polymers showed more remarkable shear shinning rheological behavior as expected since higher shear rates lead to disruptions of hydrophobic associations. These data suggest that the amphiphilic cellulose derivative may form nano-micelles and might find use as surfactant or a potential drug carrier.

Hydrophobically Modified Hydroxyethyl Starch: Synthesis, Characterization and Aqueous Self-Assembly into Nano-Sized Polymeric Micelles and Vesicles

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionORIGINAL ARTICLEThis notice is a correctionHydrophobically Modified Hydroxyethyl Starch: Synthesis, Characterization and Aqueous Self-Assembly into Nano-Sized Polymeric Micelles and VesiclesAhmed Besheer, Gerd Hause, Jörg Kressler, and Karsten MäderCite this: Biomacromolecules 2007, 8, 6, 2045Publication Date (Web):May 18, 2007Publication History Published online18 May 2007Published inissue 1 June 2007https://doi.org/10.1021/bm078003sCopyright © 2007 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views745Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (11 KB) Get e-Alerts Get e-Alerts

Hydrophobically Modified Hydroxyethyl Starch: Synthesis, Characterization, and Aqueous Self-Assembly into Nano-Sized Polymeric Micelles and Vesicles

Hydroxyethyl starch (HES) is a water soluble semisynthetic polysaccharide that is used as a plasma volume expander and cryoprotectant. In order to produce a fully biodegradable amphiphilic polymer, HES was esterified with lauric, palmitic, and stearic acids under mild reaction conditions using dicyclohexyl carbodiimide (DCC) and dimethylaminopyridine (DMAP). The molar substitution of the acyl chains (MSfatty acid) was determined with 1H NMR spectroscopy, while the conformational state of the hydrocarbon chains in the graft copolymer was determined using Raman spectroscopy. Furthermore, the aqueous self-assembly of the modified polymer was studied using dynamic light scattering (DLS) and transmission electron microscopy (TEM). Results show the formation of 20 to 30 nm micelles, and 250 to 350 nm polymeric vesicles. Electron spin resonance (ESR) spectroscopy was used to study the microenvironment of a hydrophobic spin probe loaded inside the formed nanodispersion. It was possible to identify the location of the probe and its distribution between the micelles and vesicles. Finally, the hydrophobically modified HES might find use as a potential drug carrier, warranting the future investigation of its ability to encapsulate and deliver drug candidates.

Bioaffinitive and Nanosized Polymeric Micelles Based on a Reactive Block Copolymer

AbstractSummary: Bio‐affinitive, nanosized polymeric micelles with glucosamine in their corona have a specific interaction with Concanavalin A. They are prepared by a substitution reaction of p‐nitrophenol groups in the poly(p‐nitrophenyl acrylate) (PNPA) corona of stable micelles with glucosamine. The nanosized, stable, and reactive micelles are formed by self‐assembly of the diblock copolymer, poly(p‐nitrophenyl acrylate)‐block‐polystyrene (PNPA‐b‐PSt) in nitromethane, followed by a shell cross‐linking reaction. This method may be useful in the preparation of targeted drugs.A schematic of the formation of stable glucosamine‐carrying micelles from the diblock copolymer, PNPA‐b‐PSt.magnified imageA schematic of the formation of stable glucosamine‐carrying micelles from the diblock copolymer, PNPA‐b‐PSt.