Glycoconjugation of Quinoline Derivatives Using the C-6 Position in Sugars as a Strategy for Improving the Selectivity and Cytotoxicity of Functionalized Compounds.

Based on the Warburg effect and the increased demand for glucose by tumor cells, a targeted drug delivery strategy was developed. A series of new glycoconjugates with increased ability to interact with GLUT transporters, responsible for the transport of sugars to cancer cells, were synthesized. Glycoconjugation was performed using the C-6 position in the sugar unit, as the least involved in the formation of hydrogen bonds with various aminoacids residues of the transporter. The carbohydrate moiety was connected with the 8-hydroxyquinoline scaffold via a 1,2,3-triazole linker. For the obtained compounds, several in vitro biological tests were performed using HCT-116 and MCF-7 cancer cells as well as NHDF-Neo healthy cells. The highest cytotoxicity of both cancer cell lines in the MTT test was noted for glycoconjugates in which the triazole-quinoline was attached through the triazole nitrogen atom to the d-glucose unit directly to the carbon at the C-6 position. These compounds were more selective than the analogous glycoconjugates formed by the C-1 anomeric position of d-glucose. Experiments with an EDG inhibitor have shown that GLUTs can be involved in the transport of glycoconjugates. The results of apoptosis and cell cycle analyses by flow cytometry confirmed that the new type of glycoconjugates shows pro-apoptotic properties, without significantly affecting changes in the distribution of the cell cycle. Moreover, glycoconjugates were able to decrease the clonogenic potential of cancer cells, inhibit the migration capacity of cells and intercalate with DNA.

Synthesis and Preliminary Evaluation of the Cytotoxicity of Potential Metabolites of Quinoline Glycoconjugates.

The design of prodrugs is one of the important strategies for selective anti-cancer therapies. When designing prodrugs, attention is paid to the possibility of their targeting tumor-specific markers such as proteins responsible for glucose uptake. That is why glycoconjugation of biologically active compounds is a frequently used strategy. Glycoconjugates consisting of three basic building blocks: a sugar unit, a linker containing a 1,2,3-triazole ring, and an 8-hydroxyquinoline fragment was described earlier. It is not known whether their cytotoxicity is due to whole glycoconjugates action or their metabolites. To check the biological activity of products that can be released from glycoconjugates under the action of hydrolytic enzymes, the synthetically obtained potential metabolites were tested in vitro for the inhibition of proliferation of HCT-116, MCF-7, and NHDF-Neo cell lines using the MTT assay. Research shows that for the full activity of glycoconjugates, the presence of all three building blocks in the structure of a potential drug is necessary. For selected derivatives, additional tests of targeted drug delivery to tumor cells were carried out using polymer nanocarriers in which they are encapsulated. This approach significantly lowered the determined IC50 values of the tested compounds and improved their selectivity and effectiveness.

Towards Advances in Molecular Understanding of Boric Acid Biocatalyzed Ring-Opening (Co)Polymerization of δ-Valerolactone in the Presence of Ethylene Glycol as an Initiator.

Following our previous studies on the molecular level structure of (co)oligoesters obtained via anionic homo- and co-polymerization of novel ß-substituted ß-lactones, prepared by the atmospheric pressure carbonylation reaction of respective epoxides, the boric acid biocatalyzed ring-opening (co)polymerization of δ-valerolactone has been studied. As a co-monomer the 6-methy-ε-caprolactone, prepared by the one-pot oxidation of respective alcohol, and ethylene glycol as polymerization initiator were used. The obtained copolymers were characterized by 1H-NMR, GPC and ESI-MS, respectively in order to confirm their chemical structures and identity. Subsequently, tandem mass spectrometry (MS-MS studies) via collision-induced dissociation were utilized to characterize the fragmentation pattern. ESI-MS and NMR analyses confirmed the formation of random linear copolymer chains composed of different polyester repeat units. MS-MS experiments showed that fragmentation proceeds via ester bound cleavage along the (co)polyester chains. The innovative aspect of this contribution is related to the elaboration of the telechelic (co)polymers end-capped with hydroxyl end groups and well-defined molecular architectures, which could facilitate the development of new flexible macromolecular systems for potential biomedical applications.

8-Hydroxyquinoline Glycoconjugates: Modifications in the Linker Structure and Their Effect on the Cytotoxicity of the Obtained Compounds.

Small molecule nitrogen heterocycles are very important structures, widely used in the design of potential pharmaceuticals. Particularly, derivatives of 8-hydroxyquinoline (8-HQ) are successfully used to design promising anti-cancer agents. Conjugating 8-HQ derivatives with sugar derivatives, molecules with better bioavailability, selectivity, and solubility are obtained. In this study, 8-HQ derivatives were functionalized at the 8-OH position and connected with sugar derivatives (D-glucose or D-galactose) substituted with different groups at the anomeric position, using copper(I)-catalyzed 1,3-dipolar azide-alkyne cycloaddition (CuAAC). Glycoconjugates were tested for inhibition of the proliferation of cancer cell lines (HCT 116 and MCF-7) and inhibition of ß-1,4-galactosyltransferase activity, which overexpression is associated with cancer progression. All glycoconjugates in protected form have a cytotoxic effect on cancer cells in the tested concentration range. The presence of additional amide groups in the linker structure improves the activity of glycoconjugates, probably due to the ability to chelate metal ions present in many types of cancers. The study of metal complexing properties confirmed that the obtained glycoconjugates are capable of chelating copper ions, which increases their anti-cancer potential.

Shell-Sheddable Micelles Based on Poly(ethylene glycol)-hydrazone-poly[R,S]-3-hydroxybutyrate Copolymer Loaded with 8-Hydroxyquinoline Glycoconjugates as a Dual Tumor-Targeting Drug Delivery System.

The development of selective delivery of anticancer drugs into tumor tissues to avoid systemic toxicity is a crucial challenge in cancer therapy. In this context, we evaluated the efficacy of a combination of nanocarrier pH-sensitivity and glycoconjugation of encapsulated drugs, since both vectors take advantage of the tumor-specific Warburg effect. Herein, we synthesized biodegradable diblock copolymer, a poly(ethylene glycol)-hydrazone linkage-poly[R,S]-3-hydroxybutyrate, which could further self-assemble into micelles with a diameter of ~55 nm. The hydrazone bond was incorporated between two copolymer blocks under an acidic pH, causing the shell-shedding of micelles which results in the drug's release. The micelles were stable at pH 7.4, but decompose in acidic pH, as stated by DLS studies. The copolymer was used as a nanocarrier for 8-hydroxyquinoline glucose and galactose conjugates as well as doxorubicin, and exhibited pH-dependent drug release behavior. In vitro cytotoxicity, apoptosis, and life cycle assays studies of blank and drug-loaded micelles were performed on Normal Human Dermal Fibroblasts-Neonatal (NHDF-Neo), colon carcinoma (HCT-116), and breast cancer (MCF-7) for 24, 48, and 72 h. A lack of toxicity of blank micelles was demonstrated, whereas the glycoconjugates-loaded micelles revealed enhanced selectivity to inhibit the proliferation of cancer cells. The strategy of combining pH-responsive nanocarriers with glycoconjugation of the drug molecule provides an alternative to the modus operandi of designing multi-stimuli nanocarriers to increase the selectivity of anticancer therapy.

Co-Delivery of 8-Hydroxyquinoline Glycoconjugates and Doxorubicin by Supramolecular Hydrogel Based on α-Cyclodextrin and pH-Responsive Micelles for Enhanced Tumor Treatment.

The sustained release of multiple anti-cancer drugs using a single delivery carrier to achieve a synergistic antitumor effect remains challenging in biomaterials and pharmaceutics science. In this study, a supramolecular hydrogel based on the host-guest complexes between pH-responsive micelle derived poly(ethylene glycol) chains and α-cyclodextrin was designed for codelivery of two kinds of anti-cancer agents, hydrophilic 8-hydroxyquinoline glycoconjugate and hydrophobic doxorubicin. The host-guest interactions were characterized using X-ray diffraction and differential scanning calorimetry techniques. The resultant supramolecular hydrogel showed thixotropic properties, which are advantageous to drug delivery systems. In vitro release studies revealed that the supramolecular hydrogel exhibited faster drug release profiles in acidic conditions. The MTT assay demonstrated a synergistic cancer cell proliferation inhibition of DOX/8HQ-Glu mixture. In vitro cytotoxicity studies indicated excellent biocompatibility of the supramolecular hydrogel matrix, whereas the DOX/8HQ-Glu-loaded supramolecular hydrogel showed a sustained inhibition efficacy against cancer cells. The codelivery of hydrophobic anti-cancer drugs and hydrophilic anti-cancer drug glycoconjugates via a pH-responsive supramolecular hydrogel opens up new possibilities for the development of an effective cancer treatment based on the tumor-specific Warburg effect.

Recent Progress in Phthalocyanine-Polymeric Nanoparticle Delivery Systems for Cancer Photodynamic Therapy.

This perspective article summarizes the last decade's developments in the field of phthalocyanine (Pc)-polymeric nanoparticle (NP) delivery systems for cancer photodynamic therapy (PDT), including studies with at least in vitro data. Moreover, special attention will be paid to the various strategies for enhancing the behavior of Pc-polymeric NPs in PDT, underlining the great potential of this class of nanomaterials as advanced Pcs' nanocarriers for cancer PDT. This review shows that there is still a lot of research to be done, opening the door to new and interesting nanodelivery systems.

From Anionic Ring-Opening Polymerization of ß-Butyrolactone to Biodegradable Poly(hydroxyalkanoate)s: Our Contributions in This Field.

The feasibility of synthesis of functionalized poly(3-hydroxybutanoic acid) analogue and its copolymers via ring-opening polymerization of ß-butyrolactone mediated by activated anionic initiators is presented. Using these new synthetic approaches, polyesters with a defined chemical structure of the end groups, as well as block, graft, and random copolymers, have been obtained and characterized by modern instrumental techniques, with special emphasis on ESI-MS. The relationship between the structure and properties of the prepared polymeric materials is also discussed.

The Effect of Alkyl Substitution of Novel Imines on Their Supramolecular Organization, towards Photovoltaic Applications.

Three novel conjugated polyazomethines have been obtained by polycondensation of diamines consisting of the diimine system, with either 2,5-bis(octyloxy)terephthalaldehyde or 9-(2-ethylhexyl)carbazole-3,6-dicarboxaldehyde. Partial replacement of bulky solubilizing substituents with the smaller side groups has allowed to investigate the effect of supramolecular organization. All obtained compounds have been subsequently identified using the NMR and FTIR spectroscopies and characterized by the thermogravimetric analysis, differential scanning calorimetry, cyclic voltammetry, UV-Vis spectroscopy, and X-ray diffraction. Investigated polymers have shown a good thermal stability and high glass transition temperatures. X-ray measurements have proven that partial replacement of octyloxy side chains with smaller methoxy groups induced a better planarization of macromolecule. Such modification has tuned the LUMO level of this molecule and caused a bathochromic shift of the lowest energy absorption band. On the contrary, imines consisting of N-ethylhexyl substituted carbazole units have not been so clearly affected by alkyl chain length modification. Photovoltaic activity of imines (acting as a donor) in bulk-heterojunction systems has been observed for almost all studied compounds, blended with the fullerene derivative (PCBM) in various weight ratios.

Stimuli-Responsive Aliphatic Polycarbonate Nanocarriers for Tumor-Targeted Drug Delivery.

Nanoparticles based on amphiphilic copolymers with tunable physicochemical properties can be used to encapsulate delicate pharmaceutics while at the same time improving their solubility, stability, pharmacokinetic properties, reducing immune surveillance, or achieving tumor-targeting ability. Those nanocarriers based on biodegradable aliphatic polycarbonates are a particularly promising platform for drug delivery due to flexibility in the design and synthesis of appropriate monomers and copolymers. Current studies in this field focus on the design and the synthesis of new effective carriers of hydrophobic drugs and their release in a controlled manner by exogenous or endogenous factors in tumor-specific regions. Reactive groups present in aliphatic carbonate copolymers, undergo a reaction under the action of a stimulus: e.g., acidic hydrolysis, oxidation, reduction, etc. leading to changes in the morphology of nanoparticles. This allows the release of the drug in a highly controlled manner and induces a desired therapeutic outcome without damaging healthy tissues. The presented review summarizes the current advances in chemistry and methods for designing stimuli-responsive nanocarriers based on aliphatic polycarbonates for controlled drug delivery.

Biodegradable pH-responsive micelles loaded with 8-hydroxyquinoline glycoconjugates for Warburg effect based tumor targeting.

Biodegradable triblock copolymer poly(ethylene glycol)-b-polycarbonate-b-oligo([R]-3-hydroxybutyrate) was prepared via metal-free ring-opening polymerization of ketal protected six-membered cyclic carbonate followed by esterification with bacterial oligo([R]-3-hydroxybutyrate) (oPHB). Amphiphilic triblock copolymer self-organizes into micelles with a diameter of ~25 nm. Acid-triggered hydrolysis of ketal groups to two hydroxyl groups causes an increase in hydrophilicity of the hydrophobic micelle core, resulting in the micelles swell and drug release. oPHB was added as core-forming block to increase the stability of prepared micelles in all pH (7.4, 6.4, 5.5) studied. Doxorubicin and 8-hydroxyquinoline glucose- and galactose conjugates were loaded in the micelles. In vitro drug release profiles in PBS buffers with different pH showed that a small amount of loaded drug was released in PBS at pH 7.4, while the drug was released much faster at pH 5.5. MTT assay showed that the blank micelles were non-toxic to different cell lines, while glycoconjugates-loaded micelles, showed significantly increased ability to inhibit the proliferation of MCF-7 and HCT-116 cells compared to free glycoconjugates. The glycoconjugation of anti-cancer drugs and pH-responsive nanocarriers have separately shown great potential to increase the tumor-targeted drug delivery efficiency. The combination of drug glycoconjugation and the use of pH-responsive nanocarrier opens up new possibilities to develop novel strategies for efficient tumor therapy.

α-Cyclodextrin-Based Polypseudorotaxane Hydrogels.

Supramolecular hydrogels that are based on inclusion complexes between α-cyclodextrin and (co)polymers have gained significant attention over the last decade. They are formed via dynamic noncovalent bonds, such as host-guest interactions and hydrogen bonds, between various building blocks. In contrast to typical chemical crosslinking (covalent linkages), supramolecular crosslinking is a type of physical interaction that is characterized by great flexibility and it can be used with ease to create a variety of "smart" hydrogels. Supramolecular hydrogels based on the self-assembly of polypseudorotaxanes formed by a polymer chain "guest" and α-cyclodextrin "host" are promising materials for a wide range of applications. α-cyclodextrin-based polypseudorotaxane hydrogels are an attractive platform for engineering novel functional materials due to their excellent biocompatibility, thixotropic nature, and reversible and stimuli-responsiveness properties. The aim of this review is to provide an overview of the current progress in the chemistry and methods of designing and creating α-cyclodextrin-based supramolecular polypseudorotaxane hydrogels. In the described systems, the guests are (co)polymer chains with various architectures or polymeric nanoparticles. The potential applications of such supramolecular hydrogels are also described.

Anionic Polymerization of ß-Butyrolactone Initiated with Sodium Phenoxides. The Effect of the Initiator Basicity/Nucleophilicity on the ROP Mechanism.

It was shown that selected sodium phenoxide derivatives with different basicity and nucleophilicity, such as sodium p-nitrophenoxide, p-chlorophenoxide, 1-napthoxide, phenoxide and p-methoxyphenoxide, are effective initiators in anionic ring-opening polymerization (AROP) of ß-butyrolactone in mild conditions. It was found that phenoxides as initiators in anionic ring-opening polymerization of ß-butyrolactone behave as strong nucleophiles, or weak nucleophiles, as well as Brønsted bases. The resulting polyesters possessing hydroxy, phenoxy and crotonate initial groups are formed respectively by the attack of phenoxide anion at (i) C2 followed by an elimination reaction with hydroxide formation, (ii) C4 and (iii) abstraction of acidic proton at C3. The obtained poly(3-hydroxybutyrate) possesses carboxylate growing species. The ratio of the observed initial groups strongly depends on the basicity and nucleophilicity of the sodium phenoxide derivative used as initiator. The proposed mechanism of this polymerization describes the reactions leading to formation of observed end groups. Moreover, the possibility of formation of a crotonate group during the propagation step of this polymerization is also discussed.