Thermally irreversible photochromic dithienylethenes

Abstract. A lot of previously unknown derivatives of dithienylperfluorocyclopentene (DTPFCP) were synthesized. It was shown that 2, 2 -dialkylsubstituted DTPFCP'S are phtochromes. The quantum yields of forward and backward photochemical reactions and spectral parameters of open and cyclic forms of the photochromes synthesized were measured. An attempt to obtain fluorescing phtochromes by means of introduction of benzoxazolyl, benzthiazolyl and 1,2,4-oxadiazolyl moieties in 5 and 5 positions of DTPFCP failed; these compounds were synthesized but they do not fluoresce

Safe approaches for camptothecin delivery: Structural analogues and nanomedicines

[EN] Twenty-(S)-camptothecin is a strongly cytotoxic molecule with excellent antitumor activity over a wide spectrum of human cancers. However, the direct formulation is limited by its poor water solubility, low plasmatic stability and severe toxicity, which currently limits its clinical use. As a consequence, two strategies have been developed in order to achieve safe and efficient delivery of camptothecin to target cells: structural analogues and nanomedicines. In this review, we summarize recent advances in the design, synthesis and development of camptothecin molecular derivatives and supramolecular vehicles, following a systematic classification according to structure-activity relationships (structural analogues) or chemical nature (nanomedicines). A series of organic, inorganic and hybrid materials are presented as nanoplatforms to overcome camptothecin restrictions in administration, biodistribution, pharmacokinetics and toxicity. Nanocarriers which respond to a variety of stimuli endogenously (e.g., pH, redox potential, enzyme activity) or exogenously (e.g., magnetic field, light, temperature, ultrasound) seem the best positioned therapeutic materials for optimal spatial and temporal control over drug release. The main goal of this review is to be used as a source of relevant literature for others interested in the field of camptothecin-based therapeutics. To this end, final remarks on the most important formulations currently under clinical trial are provided. (C) 2016 Elsevier B.V. All rights reserved.Financial support of the Spanish Ministry of Economy and Competitiveness (projects MAT2012-39290-C02-02 and SEV-2012-0267) is gratefully acknowledged. Dr. E.M. Rivero thanks the Cursol Foundation for a post-doctoral scholarship.Botella Asuncion, P.; Rivero-Buceta, EM. (2017). Safe approaches for camptothecin delivery: Structural analogues and nanomedicines. Journal of Controlled Release. 247:28-54. https://doi.org/10.1016/j.jconrel.2016.12.023S285424

Click Hybridization of Immune Cells and Polyamidoamine Dendrimers

Immobilizing highly branched polyamidoamine (PAMAM) dendrimers to the cell surface represents an innovative method of enhancing cell surface loading capacity to deliver therapeutic and imaging agents. In this work, hybridized immune cells, that is, macrophage RAW264.7 (RAW), with PAMAM dendrimer G4.0 (DEN) on the basis of bioorthogonal chemistry are clicked. Efficient and selective cell surface immobilization of dendrimers is confirmed by confocal microscopy. Viability and motility of RAW-DEN hybrids remain the same as untreated RAW cells according to WST-1 assay and wound closure assay. Furthermore, Western blot analysis reveals that there are no significant alterations in the expression levels of signaling molecules AKT, p38, and NFκB (p65) and their corresponding activated (phosphorylated) forms in RAW cells treated with azido sugar and dendrimer, indicating that the hybridization process neither induced cell stress response nor altered normal signaling pathways. Taken together, this work shows the feasibility of applying bioorthogonal chemistry to create cell-nanoparticle hybrids and demonstrates the noninvasiveness of this cell surface engineering approach

Poly(Ethylene Glycol)-Armed Hyperbranched Polyoxetanes for Anticancer Drug Delivery

A facile method for synthesis of poly ethylene glycol (PEG)-armed hyperbranched polyoxetanes is presented along with characterization and use in drug delivery. A series of hyperbranched polyoxetanes with multiple PEG arms were synthesized via a one-pot cationic ring-opening polymerization of 3-ethyl-3-hydroxymethyl oxetane (EHMO) and its PEGylated derivative (EPMO), in which the feed mass ratio of EHMO to EPMO was 98:2, 96:4, 74:26, or 17:83. Characterization methods included nuclear magnetic resonance, dynamic light scattering, Fourier transform infrared, differential scanning calorimetry, and scanning electron microscopy. Toxicity of the synthesized polymers to human dermal fibroblasts was evaluated using the MTT assay. Formulation into particles was carried out to encapsulate the anticancer drug camptothecin using the single oil-in-water solvent evaporation method. The resulting drug encapsulated particles were evaluated for antitumor activity using HN12 cells

Synthesis and Characterization of Clickable Cytocompatible Poly(Ethylene Glycol)-Grafted Polyoxetane Brush Polymers

We report a new family of clickable poly(ethylene glycol) (PEG)-grafted polyoxetane brush polymers as a potential modular platform for delivery of drugs and imaging agents. 3-Ethyl-3-hydroxymethyloxetane (EHMO) monomer reacted with propargyl benzenesulfonate in the presence of sodium hydride to yield alkyne-substituted monomer (EAMO). Subsequently, cationic ring-opening polymerization using boron trifluoride diethyl etherate catalyst and 1,4-butanediol initiator produced P(EAMO) homopolymer with a DP of ∼30 (30 alkynes per chain). Methoxypoly(ethylene glycol) azide (mPEG750-azide) prepared from mPEG750 (750 g mol-1) was grafted to P(EAMO) via copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click chemistry. Water-soluble cytocompatible P(EAMO)-g-PEG brush polymers with controlled degrees of PEGylation were synthesized by varying the feed molar ratio of mPEG750-azide to alkyne (25:100, 50:100, 75:100, and 100:100). 1H NMR, GPC, end-group analysis, FTIR, and DSC were applied for polymer characterization. The utility of P(EAMO)-g-PEG for carrying imaging agents was demonstrated by preparing fluorescently labeled P(EAMO)-g-PEG. 5-(Aminoacetamido)fluorescein (AAF) was used as a model compound. Fluorescein-carrying P(EAMO)-g-PEG was synthesized by click coupling bifunctional spacer 6-azidohexanoic acid (AHA) to P(EAMO)-g-PEG and subsequently coupling of AAF to AHA with EDC/NHS chemistry

Nanoconjugated NAP as a Potent and Periphery Selective Mu Opioid Receptor Modulator to Treat Opioid-Induced Constipation

Opioids are the mainstay for cancer and noncancer pain management. However, their use is often associated with multiple adverse effects. Among them, the most common and persistent one is probably opioid-induced constipation (OIC). Periphery selective opioid antagonists may alleviate the symptoms of OIC without compromising the analgesic effects of opioids. Recently our laboratories have identified one novel lead compound, 17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6ß-[(4′-pyridyl)acetamido]-morphinan (NAP), as a peripherally selective mu opioid receptor ligand carrying subnanomolar affinity to the mu opioid receptor and over 100-folds of selectivity over both the delta and kappa opioid receptors, with reasonable oral availability and half-life, and potential to treat OIC. Nanoparticle-based drug delivery systems are now widely considered due to their technological advantages such as good stability, high carrier capacity, low therapeutic side effects, etc. Herein we report nanoparticle supported NAP as a potential candidate for OIC treatment with improved peripheral selectivity over the original lead compound NAP

Synthesis and Characterization of Clickable Cytocompatible Poly(ethylene glycol)-Grafted Polyoxetane Brush Polymers

We report a new family of clickable poly­(ethylene glycol) (PEG)-grafted polyoxetane brush polymers as a potential modular platform for delivery of drugs and imaging agents. 3-Ethyl-3-hydroxymethyloxetane (EHMO) monomer reacted with propargyl benzenesulfonate in the presence of sodium hydride to yield alkyne-substituted monomer (EAMO). Subsequently, cationic ring-opening polymerization using boron trifluoride diethyl etherate catalyst and 1,4-butanediol initiator produced P­(EAMO) homopolymer with a DP of ∼30 (30 alkynes per chain). Methoxypoly­(ethylene glycol) azide (mPEG750-azide) prepared from mPEG750 (750 g mol^–1) was grafted to P­(EAMO) via copper­(I)-catalyzed alkyne–azide cycloaddition (CuAAC) click chemistry. Water-soluble cytocompatible P­(EAMO)-<i>g</i>-PEG brush polymers with controlled degrees of PEGylation were synthesized by varying the feed molar ratio of mPEG750-azide to alkyne (25:100, 50:100, 75:100, and 100:100). ¹H NMR, GPC, end-group analysis, FTIR, and DSC were applied for polymer characterization. The utility of P­(EAMO)-<i>g</i>-PEG for carrying imaging agents was demonstrated by preparing fluorescently labeled P­(EAMO)-<i>g</i>-PEG. 5-(Aminoacetamido)­fluorescein (AAF) was used as a model compound. Fluorescein-carrying P­(EAMO)-<i>g</i>-PEG was synthesized by click coupling bifunctional spacer 6-azidohexanoic acid (AHA) to P­(EAMO)-<i>g</i>-PEG and subsequently coupling of AAF to AHA with EDC/NHS chemistry

Synthesis of Water-Soluble Camptothecin-Polyoxetane Conjugates via Click Chemistry

Water-soluble camptothecin (CPT)-polyoxetane conjugates were synthesized using a clickable polymeric platform P(EAMO) that was made by polymerization of acetylene-functionalized 3-ethyl-3-(hydroxymethyl)oxetane (i.e., EAMO). CPT was first modified with a linker 6-azidohexanoic acid via an ester linkage to yield CPT-azide. CPT-azide was then click coupled to P(EAMO) in dichloromethane using bromotris(triphenylphosphine)copper(I)/N,N-diisopropylethylamine. For water solubility and cytocompatibility improvement, methoxypolyethylene glycol azide (mPEG-azide) was synthesized from mPEG 750 g mol-1 and click grafted using copper(II) sulfate and sodium ascorbate to P(EAMO)-g-CPT. 1H NMR spectroscopy confirmed synthesis of all intermediates and the final product P(EAMO)-g-CPT/PEG. CPT was found to retain its therapeutically active lactone form. The resulting P(EAMO)-g-CPT/PEG conjugates were water-soluble and produced dose-dependent cytotoxicity to human glioma cells and increased γ-H2AX foci formation, indicating extensive cell cycle-dependent DNA damage. Altogether, we have synthesized CPT-polymer conjugates able to induce controlled toxicity to human cancer cells

PEAMOtecan, a Novel Chronotherapeutic Polymeric Drug for Brain Cancer

Glioblastoma multiforme (GBM) is an aggressive and difficult to treat form of brain cancer. In this work, we report on a novel chronotherapeutic polymeric drug, PEAMOtecan, for GBM therapy. PEAMOtecan was synthesized by conjugating camptothecin, a topoisomerase I inhibitor, to our proprietary, \u27clickable\u27 and modular polyoxetane polymer platform consisting of acetylene-functionalized 3-ethyl-3-(hydroxymethyl)oxetane (EAMO) repeat units (Patent No.: US 9,421,276) via the linker 3,3′-dithiodipropionic acid (DDPA) with a disulfide bond (S[sbnd]S) extended by short-chain polyethylene glycol (PEG). We show that PEAMOtecan is a highly modular polymer nanoformulation that protects covalently bound CPT until slowly being released over extended periods of time dependent on the cleavage of the disulfide and ester linkages. PEAMOtecan kills glioma cells by mitotic catastrophe with p53 mutant/knockdown cells being more sensitive than matched wild type cells potentially providing cancer-specific targeting. To establish proof-of-principle therapeutic effects, we tested PEAMOtecan as monotherapy for efficacy in a mouse orthotopic glioma model. PEAMOtecan was administered by one-time, convection-enhanced delivery (CED) intra-tumorally to achieve superior distribution and extended drug release over time. In addition, the near-infrared (NIR) dye Cy5.5 was coupled to the polymer providing live-animal imaging capability to track tissue distribution and clearance of the injected polymer over time. We show that PEAMOtecan significantly improves the survival of mice harboring intra-cranial tumors (p = .0074 compared to untreated group). Altogether, these results support further development and testing of our nanoconjugate platform

Thermally irreversible photochromic dithienylethenes

A lot of previously unknown derivatives of dithienylperfluorocyclopentene (DTPFCP) were synthesized. It was shown that 2,2′-dialkylsubstituted DTPFCP'S are phtochromes. The quantum yields of forward and backward photochemical reactions and spectral parameters of open and cyclic forms of the photochromes synthesized were measured. An attempt to obtain fluorescing phtochromes by means of introduction of benzoxazolyl, benzthiazolyl and 1,2,4-oxadiazolyl moieties in 5 and 5′ positions of DTPFCP failed; these compounds were synthesized but they do not fluoresce