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.

The Influence of Hydrophobic Blocks of PEO-Containing Copolymers on Glyceryl Monooleate Lyotropic Liquid Crystalline Nanoparticles for Drug Delivery.

The investigation of properties of amphiphilic block copolymers as stabilizers for non-lamellar lyotropic liquid crystalline nanoparticles represents a fundamental issue for the formation, stability and upgraded functionality of these nanosystems. The aim of this work is to use amphiphilic block copolymers, not studied before, as stabilizers of glyceryl monooleate 1-(cis-9-octadecenoyl)-rac-glycerol (GMO) colloidal dispersions. Nanosystems were prepared with the use of poly(ethylene oxide)-b-poly(lactic acid) (PEO-b-PLA) and poly(ethylene oxide)-b-poly(5-methyl-5-ethyloxycarbonyl-1,3-dioxan-2-one) (PEO-b-PMEC) block copolymers. Different GMO:polymer molar ratios lead to formulation of nanoparticles with different size and internal organization, depending on the type of hydrophobic block. Resveratrol was loaded into the nanosystems as a model hydrophobic drug. The physicochemical and morphological characteristics of the prepared nanosystems were investigated by dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), fast Fourier transform (FFT) analysis and X-ray diffraction (XRD). The studies allowed the description of the lyotropic liquid crystalline nanoparticles and evaluation of impact of copolymer composition on these nanosystems. The structures formed in GMO:block copolymer colloidal dispersions were compared with those discussed previously. The investigations broaden the toolbox of polymeric stabilizers for the development of this type of hybrid polymer/lipid nanostructures.

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.

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.

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.