Fluorescent Polymeric Micelles Research Articles

Trackable Water-Soluble Prodrug Micelles Capable of Rapid Mitochondrial-Targeting and Alkaline pH-Responsive Drug Release for Highly Improved Anticancer Efficacy.

A trackable water-soluble prodrug conjugate possessing high contents of chlorambucil (Cb) and triphenylphosphonium cation (TPP) was designed and developed after TPP modification on the "branch" of amphipathic prodrugs based on convenient synthesis of heterobifunctional clickable poly(ethylene glycol) (PEG). The aqueous self-assembly of fluorescent polymeric micelles along precise composition can be easily prepared after directly dissolved (DD) in aqueous solution, and exhibit superior cytotoxicity to cancer cells along with highly improved selectivity and sensitivity because of their rapid mitochondrial-targeting and alkaline pH-responsive drug release capabilities. Notably, efficient codelivery of doxorubicin (DOX) for synergistic targeted drug delivery and cancer therapy was achieved.

Abstract A118: Efflux of paclitaxel nanoformulation in cell culture model of human placental barrier

Abstract Background: Breast cancer affects 1 of every 3000 pregnancies, and is treated with chemotherapeutics including paclitaxel. Chemotherapy administration in pregnancy is associated with fetal morbidity. Purpose: Here, we investigated the transplacental transfer of both paclitaxel and new paclitaxel nanoformulations that are entering clinical studies or are commercially available for use in breast cancer. In addition, we examined the transfer of fluorescent albumin-based and polymeric micellar nanoformulations with similar properties to those paclitaxel nanoformulations. Methods: Transport studies were performed using BeWo b30 cells (human placental trophoblast cells) seeded in TranswellTM plates coated with human placental collagen. Cells were treated with 20 μg/mL of paclitaxel from marketed formulations. Since paclitaxel undergoes efflux by P-glycoprotein (P-gp) substrate, 100 μM of verapamil was used as a competitive P-gp inhibitor to prevent efflux of free paclitaxel released from the nanoformulations. In order to determine the role of nanomaterials in transport and uptake of paclitaxel, we synthesized fluorescent albumin nanoparticles and fluorescent polymeric micelles with similar properties to the paclitaxel nanoformulations for use in transport studies. Samples were analyzed by high-performance liquid chromatography or fluorometer. Uptake measurements were corrected for protein content. Particle size and polydispersity index were determined using dynamic light scattering. Results: There were no formulation-dependent differences in paclitaxel permeability between the formulations of paclitaxel, nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and paclitaxel-loaded polymeric micelles. In the presence of verapamil, nab-paclitaxel showed a twofold increase in permeability, in contrast to the other formulations. The size of fluorescent albumin nanoparticles (130.3nm) was matched with nab-Paclitaxel (156.2 nm), and the fluorescent micelles (27.6 nm) with paclitaxel-loaded polymeric micelles (27.7nm). The apparent permeability of the fluorescent albumin nanoparticles across the BeWo cells was 1.98 x 10-6 ± 0.81 x 10-6 cm/s, whereas the apparent permeability of the fluorescent micelles was 59.5 x 10-6 ± 10.5 x 10-6 cm/s. Conclusion: These data suggest that paclitaxel-encapsulated micelles may evade efflux by P-gp and cross the trophoblast to a significant extent, while paclitaxel albumin nanoparticles behave like free paclitaxel. Therefore, choice of formulation may have a significant impact on fetal exposure to paclitaxel. We anticipate that these findings will have an impact on future pharmaceutical design and rational development of safe treatment strategies for pregnancy-associated breast cancer and other diseases. Citation Format: Shariq Ali, Sanaalarab Alenazy, Mansi Shah, Luke Bourner, Erik Rytting. Efflux of paclitaxel nanoformulation in cell culture model of human placental barrier [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A118.

Fabrication of Water-soluble Fluorescent Polymeric Micelles for Selective Detection of Hg<sup>2+</sup> in Blood Serum

In this study, amphiphilic diblock copolymers were designed and synthesized via the incorporation of reversible addition-fragmentation chain transfer radical polymerization (RAFT) and a subsequent grafting technique. Subsequently, Hg2+-sensitive water-soluble fluorescent polymeric micelles (FNs) were prepared by a reprecipitation strategy. The spectroscopic characteristics demonstrate that the fluorescein isothiocyanate (FITC) was successfully linked into the polymer. Due to the promoted reaction of desulfurization cyclization by Hg2+, the fluorescence of fluorescein in FNs was obviously quenched. The as-prepared FNs showed admirable Hg2+-sensitivity (detection limit: 54 nM), excellent water-solubility and high selectivity. In addition, FNs were successfully used to determine Hg2+ in blood serum. We expected that the as-prepared FNs could perform potential applications in imaging, sensing, and bioanalytic chemistry.

Novel biocompatible fluorescent polymeric micelles based on 1,8-naphthalimide derivatives for cell imaging

A new type of fluorescent polymeric micelle was developed by the aqueous self-assembly from amphiphilic block copolymers via click chemistry and showed good potential for application in cell imaging with good biocompatibility. Notably, P1 can readily serve as an excellent intracellular pH sensor in whole living cells based on PET inhibition

Fluorescent polymeric micelles containing fluorene derivatives for monitoring drug encapsulation and release

In this study, we demonstrate a new series of fluorescent polymeric micelles self-assembled from two amphiphilic block copolymers, poly(ethylene glycol)-block-poly[styrene-co-[4-tri(9,9-dihexylfluoren-2,7-yl)styrene]] [PEG-b-P(S-co-TFS), P1] and poly(ethylene glycol)-block-poly[styrene-co-[4-(2-(4-benzo-[2,1,3]-thiadiazole)-9,9-dihexylfluoren-7-yl)styrene]] [PEG-b-P(S-co-BTFS), P2], with fluorescent moieties based on two different fluorene derivatives. The weight fraction and the chemical structure of these two fluorene derivatives could be correlated to the nanostructures and photophysical properties of the corresponding polymeric micelles. In particular, facile adjustment on the emission color of micelles enables the delicate design of drug carriers for the drug with specific photophysical properties. Two fluorescent drugs, curcumin (CUM) and doxorubicin (DOX), are chosen as model drugs for P1 and P2 micelles. Due to the spectral overlap between fluorescent micelles and drugs and their close proximity in the core of micelles, Forster resonance energy transfer (FRET) from micelles to drugs is observed for both the CUR-loaded P1-1 micelles and DOX-loaded P2-1 micelles, which could serve as an indication of successful encapsulation of drug in these micelles. Furthermore, the subsequent decrement of FRET resulting from the increasing distance between fluorene moieties and drugs could be used as an optical approach for monitoring the drug release from the drug carriers.

Dual effect of thiol addition on fluorescent polymeric micelles: ON-to-OFF emissive switch and morphology transition.

The morphology transition from micelles to vesicles of a solution-state self-assembled block copolymer, containing a fluorescent dye at the core-shell interface, has been induced by an addition-elimination reaction using a thiol, and has been shown to be coupled to a simultaneous ON-to-OFF switch in particle fluorescence.

PH-sensitive unimolecular fluorescent polymeric micelles: from volume phase transition to optical response

Unimolecular fluorescent micelles of star polyelectrolytes with a perylenediimide core are very sensitive to changes in pH values. The pH-responsive behavior relies on the ionization or deionization of the star polyelectrolytes, which causes a reversible volume phase transition and optical response.

Self-assembled magnetic fluorescent polymeric micelles for magnetic resonance and optical imaging

Stable and cytocompatible hybrid PEGylated micelles with multimodal imaging capabilities are described. The F3O4-encapsulated polymeric micelles composed of cores containing magnetic nanoparticles and polyethylene glycol (PEG) shells are synthesized by self-assembly of amphiphilic poly(HFMA-co-VBK)-g-PEG copolymers and oleic acid stabilized Fe3O4 nanoparticles. The Fe3O4 magnetic nanoparticles in the core produce T2-weighted MR imaging functionalities, whereas the small fluorescent monomer carbazole in the polymer shell introduces good fluorescent properties. The multifunctional micelles exhibit excellent paramagnetic properties with the maximum saturation magnetization of 9.61 emu/g and transverse relaxivity rate of 157.44 mm−1 S−1. In vivo magnetic resonance imaging (MRI) studies reveal enhanced contrast between the liver and spleen. Fluorescence spectra show characteristic emission peaks from carbazole at 350 nm and 365 nm and vivid blue fluorescence can be observed by 2-photon confocal scanning laser microscopy (CLSM). In vivo optical imaging demonstrates the unique fluorescent characteristics of the Fe3O4-encapsulated polymeric micelles in the liver and spleen and the excellent multifunctional properties suggest potential clinical use as nanocarriers in magnetic resonance imaging and optical imaging.

Fluorescent Polymeric Micelles with Aggregation‐Induced Emission Properties for Monitoring the Encapsulation of Doxorubicin

A new type of fluorescent polymeric micelles is developed by self-assembly from a series of amphiphilic block copolymers, poly(ethylene glycol)-b-poly[styrene-co-(2-(1,2,3,4,5-pentaphenyl-1H-silol-1-yloxy)ethyl methacrylate)] [PEG-b-P(S-co-PPSEMA)]. Their capability of loading doxorubicin (DOX) is investigated by monitoring the loading content, encapsulation efficiency, and photophysical properties of micelles. Förster resonance energy transfer from PPSEMA to DOX is observed in DOX-loaded micelles, which can serve as an indication of successful encapsulation of DOX in these micelles. The application of this new type of fluorescent polymeric micelles as a fluorescent probe and an anticancer drug carrier simultaneously is explored by studying the intracellular uptake of DOX-loaded micelles.

Fluorescent Polymeric Micelles with Tetraphenylethylene Moieties and Their Application for the Selective Detection of Glucose

By linking TPE moieties that exhibit aggregation-induced (enhanced) emission to the amphiphilic copolymer 1, fluorescent micelles are prepared and characterized. The polymeric micelles exhibit relatively strong fluorescence which can be tuned by heating and cooling. By combining cascaded enzymatic (oxidation of D-glucose with GOx) and chemical (oxidation of I(-) by H(2) O(2) ) reactions, the fluorescent micelles of copolymer 1 are successfully utilized for the selective detection of D-glucose in aqueous solution. The influences of proteins (e.g., bovine serum albumin) and reductants (e.g., ascorbic acid) on this fluorescence detection of D-glucose are also discussed.

Mobility of fluorescently labeled polymer micelles in living cells

Stabilized fluorescent polymeric micelles were made that are spontaneously taken up into the cytoplasm of human cells. The mobility of these micelles in living cells was probed on a molecular level for the first time with FCS. Importantly, the present micelles do not interact with proteins, membranes or cellular organelles. This system provides a new nanotechnological tool which is biocompatible, versatile and easy to use, especially since after further chemical modification, they could be targeted to specific subcellular locations.

Thermally sensitive dual fluorescent polymeric micelles for probing cell properties

Dual fluorescent micelles with a hydrophobic probe (HMA) embedded in the micelle core and a hydrophilic probe (TRITC) attached on the micelle corona were prepared. These micelles can act as nanometre-sized thermal sensors. Within a short temperature range, the fluorescent emission of the micelles changes strongly and reversibly as a function of temperature. These micelles can be easily taken up by human HeLa cells and can potentially be used as intracellular thermometers.

Self-assembled, fluorescent polymeric micelles of a graft copolymer containing carbazole for thermo-controlled drug deliveryin vitro

A novel thermosensitive amphiphilic graft copolymer PNIPAAm-g-PCbzEA appending carbazole group was successfully designed and synthesized by the free radical copolymerization of N-isopropylacrylamide with hydrophobic precursor polymers of vinyl-functionalized poly(2-(N-carbazolyl)ethyl acrylate) (PCbzEA) in DMF. The PNIPAAm-g-PCbzEA copolymer was characterized by FTIR, (1)H NMR, GPC analysis, UV-vis spectroscopy and fluorescence spectroscopy. The TEM observation shows that the graft copolymer may self-assemble into polymeric micelles exhibiting a nanospheric morphology within a narrow size range of 30-60 nm in aqueous solution. From the (1)H NMR and FTIR analysis, the polymer micelles are composed of hydrophobic PCbzEA segments as the cores and the hydrophilic PNIPAAm segements as outer shells. The resulting micelles exhibited the temperature sensitivity with a lower critical solution temperature (LCST) of 31.5 degrees C and a critical micelle concentration (CMC) of 12.9 mg/L in water. In the study of drug release, an "on-off" drug release profile was found in response to stepwise temperature changes between 20 and 40 degrees C. The cytotoxicity assays for vero cells shows good biocompatibility of the graft copolymer in vitro.