Hydrazone Bond Research Articles

Hydrazone bond-oriented molecularly imprinted nanocomposites for the selective separation of protein via the well-defined recognition sites.

The development of hydrazone bond-oriented epitope imprinting strategy is reported to synthesize the polymeric binders for the selective recognition of a protein-β2-microglobulin through either its N- or C-terminal epitope. The dynamic reversibility of hydrazone bond facilitated not only the oriented assembly of the template peptide hydrazides onto the substrate but also the efficient removal of them from the imprinted cavities. The well-defined surface imprinted layer was successfully constructed through the precise control over the polymerization of silicate esters. Binding performance of the C-terminal peptide imprinted nanocomposite was significantly improved after tuning the non-covalent interactions using the sequence-matching aromatic co-monomers. The dissociation constant (Kd) between the optimized nanocomposite and epitope peptide was 0.5µmol L-1. The nanomaterial was utilized for the selective extraction and determination of β2-microglobulin from human urine by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and HPLC-UV with satisfied recoveries of 93.1-112.3% in a concentration range 1.0-50.0μg⋅mL-1.

Hydrazone-linked luminescent covalent organic frameworks based on AIE-active unit for acid vapour sensing

Many two-dimensional (2D) covalent organic frameworks (COFs) exhibit weak fluorescence in the solid state or relatively strong fluorescence only in their suspensions. So it is significant to develop a COF with high luminescence in its as-synthesized solid-state for the better practical applications such as fluorescence sensor. We constructed a 2D COF of TPE-DHZ-COF with the hydrazone bond as the linkage and the monomers of triphenylbenzene (TPE) units with aggregation-induced emission (AIE) characteristics, and also synthesized an analogue of TPB-DHZ-COF without AIE-active unit as a comparison. Compared with TPB-DHZ-COF, the COF with TPE unit show excellent solid-state luminescence properties, demonstrating that introducing of AIE-active unit in COF can significantly improve the solid-state luminescence performance of hydrazone-linked COFs. In addition, all of these COFs could weaken or quench their fluorescence when exposure to strong-acid vapour. We regarded the response of TPE-DHZ-COF to trifluoroacetic acid (TFA) vapour as the research object, and found that TPE-DHZ-COF exhibited a fast response speed, strong adsorption capacity, excellent stability and recycling performance in the detection of TFA vapour. These results indicated that COFs would be a good candidate in solid-state fluorescence sensing.

Brush-like Polymer Prodrug with Aggregation-Induced Emission Features for Precise Intracellular Drug Tracking.

In this study, a brush-like polymer with aggregation-induced emission (AIE) features was synthesized for drug delivery and intracellular drug tracking. The polymer consisting of tetraphenylethene (TPE) chain-end as well as oligo-poly (ethylene glycol) (PEG) and hydrazine functionalities was successfully synthesized through copper (0)-mediated reversible-deactivation radical polymerization (Cu0-mediated RDRP). Anticancer drug doxorubicin (DOX) was conjugated to the polymer and formed a prodrug named TPE-PEGA-Hyd-DOX, which contains 11% DOX. The hydrazone between DOX and polymer backbone is a pH-sensitive linkage that can control the release of DOX in slightly acidic conditions, which can precisely control the DOX release rate. The drug release of 10% after 96 h in normal cell environments compared with about 40% after 24 h in cancer cell environments confirmed the influence of the hydrazone bond. The ratiometric design of fluorescent intensities with peaks at 410 nm (emission due to AIE feature of TPE) and 600 nm (emission due to ACQ feature of DOX) provides an excellent opportunity for this product as a precise intracellular drug tracker. Cancer cells confocal microscopy showed negligible DOX solution uptake, but an intense green emission originated from prodrug uptake. Moreover, a severe red emission in the DOX channel confirmed a promising level of drug release from the prodrug in the cytoplasm. The merged images of cancer cells confirmed the high performance of the TPE-PEGA-Hyd-DOX compound in the viewpoints of cellular uptake and drug release. This polymer prodrug successfully demonstrates low cytotoxicity in healthy cells and high performance in killing cancer cells.

Combination of chemotherapy and immune checkpoint therapy by the immunoconjugates-based nanocomplexes synergistically improves therapeutic efficacy in SCLC

Although the etoposide and carboplatin (EP) combination strategy has been the first-line chemotherapy, patients with extensive-stage disease small-cell lung cancer (SCLC) still have poor survival outcomes. Our retrospective analysis revealed that 46 patients with SCLC only achieved medium overall survival (OS) of 11.6 months after treated by EP. Recently, it was demonstrated that combination therapy of PD1/PD-L1 immune checkpoint blocker and EP could significantly improve the OS of SCLC patients. However, the serious treatment-related toxicity leaded to a high rate of treatment-discontinuation or even death. In the present study, we have developed a novel TPP1-conjugated nanocomplex, abbreviated as TPP1NP-EP, which was co-loaded with carboplatin (CBP) and etoposide (VP16). The TPP1 was a PD-L1 targeting peptide and conjugated on the surface of nanocomplex by a matrix metalloproteinase (MMP-2/9)-cleavable peptide linker sequence PLGLAG. For dual-loading of CBP and VP16, the CBP was chemically conjugated with poly(ethylene glycol) (PEG)–poly(caprolactone) (PCL) by pH-sensitive hydrazone bond and the VP16 was physically encapsulated by emulsion-solvent evaporation method. In vitro and in vivo experiments demonstrated an excellent anti-tumor effect of TPP1NP-EP on SCLC and improved safety. In conclusion, the present study has provided a promising strategy for treatment of malignant SCLC.

Synthesis and solution properties of hydrophobically associating water-soluble copolymer with dynamic covalent bond

The hydrophobically associating water-soluble terpolymer was synthesized by free-radical copolymerization of acrylamide (AM), diacetone acrylamide (DAAM), and cetyl dimethylallyl ammonium chloride (ACD), and then was crosslinked by acyl hydrazone bonds. The viscosity properties, surface activity, interfacial activity, and the emulsifying ability of the copolymer solution were characterized by the rotational viscometer, tensiometer, interface rheometer, optical microscope, and Formulaction Turbiscan Expert Lab optical analyzer. The dynamism, salt resistance, shear tolerance, and temperature resistance were investigated by viscosity analysis and rheometer measurements. The results showed that the copolymer solution combined chemical with physical cross-linking had high viscosity maintained at high salinity and shear rate. This understanding of the contribution of dynamic covalent bonds and hydrophobic association to the viscosity properties should be informative for the design of oil agents.

Mechanically interlocked molecular architectures of valinomycin as cancer targeted prodrugs

AbstractMacrocyclic drugs are promising agents for treating a variety of diseases. However, these compounds usually present delivery limitations, such as low tissue selectivity and poor cellular uptake, which may impair efficacy and clinical translation. Here, we propose a molecular machine approach for delivering macrocyclic drugs based on their assembly into bioactive rotaxanes. To prove this concept, we use the extremely toxic macrocycle valinomycin (Val) as the host molecule, and identify dihydralazine (Dihyd) as a guest molecule after screening several guest compounds. The Val‐Dihyd complex is mechanically interlocked by capping one hydrazide group in Dihyd with fluorescein isothiocyanate (FITC) and the other with a Y‐shape branched poly(ethylene glycol) (PEG) via a pH‐sensitive hydrazone bond. Thus, the Val‐loaded rotaxanes (Vrot) are stable at physiological pH, but release Val at mild acidic conditions mimicking intratumoral and endosomal environments. In vitro studies revealed Vrot is less cytotoxic than free Val in pancreatic cancer cells, while modifying Vrot with cyclic arginine‐glycine‐aspartic acid (cRGD) peptides promotes the cytotoxicity by enhancing cellular uptake. These results indicate the potential of rotaxanes of macrocyclic drugs for generating cancer targeted prodrugs.

Tumor targetable and pH-sensitive polymer nanoparticles for simultaneously improve the Type 2 Diabetes Mellitus and malignant breast cancer

ABSTRACT In the recent study, we have developed novel tumor targetable and pH-sensitive PLGA nanoparticles co-loaded with camptothecin (CPT) and metformin (Metf) to simultaneously improve the Type 2 Diabetes Mellitus (T2DM) and malignant breast cancer. To improve the drug loading efficiency, the hydrophobic CPT was conjugated with PLGA polymer by the pH-sensitive hydrazone bonds (hyd). Then, the Metf was physically loaded into the hydrophobicity inner core of CPT-conjugated PLGA nanocomplex to form the dual drugs-loaded nanoparticles (NP/CPT-Metf). Furthermore, on the surface of NP/CPT-Metf was modified with tumor-homing CGKRK peptides to obtain the tumor targetable and pH-sensitive polymer nanoparticles (CNP/CPT-Metf). It was demonstrated that the developed CNP/CPT-Metf displayed sufficient sensitivity to the weak acidic tumor microenvironment. Besides, excellent ability of CNP/CPT-Metf to mediate accumulation of drugs in cells and tumor tissues finally in turn resulted in a signal enhanced anti-tumor effect. Furthermore, it was demonstrated as well that CNP/CPT-Metf was able of significantly alleviating the type 2 diabetes mellitus in diabetic mice. In summary, the developed multifunctional polymer nanoparticles might represent a promising strategy for simultaneously improve the T2DM and treat malignant breast cancer.

Sticking Together: Injectable Granular Hydrogels with Increased Functionality via Dynamic Covalent Inter-Particle Crosslinking.

Granular hydrogels are an exciting class of microporous and injectable biomaterials that are being explored for many biomedical applications, including regenerative medicine, 3D printing, and drug delivery. Granular hydrogels often possess low mechanical moduli and lack structural integrity due to weak physical interactions between microgels. This has been addressed through covalent inter-particle crosslinking; however, covalent crosslinking often occurs through temporal enzymatic methods or photoinitiated reactions, which may limit injectability and material processing. To address this, a hyaluronic acid (HA) granular hydrogel is developed with dynamic covalent (hydrazone) inter-particle crosslinks. Extrusion fragmentation is used to fabricate microgels from photocrosslinkable norbornene-modified HA, additionally modified with either aldehyde or hydrazide groups. Aldehyde and hydrazide-containing microgels are mixed and jammed to form adhesive granular hydrogels. These granular hydrogels possess enhanced mechanical integrity and shape stability over controls due to the covalent inter-particle bonds, while maintaining injectability due to the dynamic hydrazone bonds. The adhesive granular hydrogels are applied to 3D printing, which allows the printing of structures that are stable without any further post-processing. Additionally, the authors demonstrate that adhesive granular hydrogels allow for cell invasion in vitro. Overall, this work demonstrates the use of dynamic covalent inter-particle crosslinking to enhance injectable granular hydrogels.

Viscoelastic Chondroitin Sulfate and Hyaluronic Acid Double-Network Hydrogels with Reversible Cross-Links.

Viscoelastic hydrogels are gaining interest as they possess necessary requirements for bioprinting and injectability. By means of reversible, dynamic covalent bonds, it is possible to achieve features that recapitulate the dynamic character of the extracellular matrix. Dually cross-linked and double-network (DN) hydrogels seem to be ideal for the design of novel biomaterials and bioinks, as a wide range of properties required for mimicking advanced and complex tissues can be achieved. In this study, we investigated the fabrication of chondroitin sulfate/hyaluronic acid (CS/HA)-based DN hydrogels, in which two networks are interpenetrated and cross-linked with the dynamic covalent bonds of very different lifetimes. Namely, Diels–Alder adducts (between methylfuran and maleimide) and hydrazone bonds (between aldehyde and hydrazide) were chosen as cross-links, leading to viscoelastic hydrogels. Furthermore, we show that viscoelasticity and the dynamic character of the resulting hydrogels could be tuned by changing the composition, that is, the ratio between the two types of cross-links. Also, due to a very dynamic nature and short lifetime of hydrazone cross-links (∼800 s), the DN hydrogel is easily processable (e.g., injectable) in the first stages of gelation, allowing the material to be used in extrusion-based 3D printing. The more long-lasting and robust Diels–Alder cross-links are responsible for giving the network enhanced mechanical strength and structural stability. Being highly charged and hydrophilic, the cross-linked CS and HA enable a high swelling capacity (maximum swelling ratio ranging from 6 to 12), which upon confinement results in osmotically stiffened constructs, able to mimic the mechanical properties of cartilage tissue, with the equilibrium moduli ranging from 0.3 to 0.5 MPa. Moreover, the mesenchymal stromal cells were viable in the presence of the hydrogels, and the effect of the degradation products on the macrophages suggests their safe use for further translational applications. The DN hydrogels with dynamic covalent cross-links hold great potential for the development of novel smart and tunable viscoelastic materials to be used as biomaterial inks or bioinks in bioprinting and regenerative medicine.

Enzyme-assisted ReMALDI-MS assay for quantification of cholesterol in food

Cholesterol is a vital building block for animal cell membranes and participates in the synthesis of various hormones. Accurate quantitation of cholesterol in food is crucial for healthy diets. Here, we describe an enzyme-assisted reactive matrix-assisted laser desorption/ionization mass spectrometry (ReMALDI-MS) assay for the quantification of cholesterol in food. First, cholesterol was converted to 4-cholesten-3-one using the cholesterol oxidase, and then reacted with a reactive matrix, 4-hydrazinoquinazoline (4-HQ), to form a hydrazone bond. Utilizing 4-HQ significantly improved the ionization efficiency of cholesterol, which possesses poor ionization efficiency in MALDI-MS, and no additional tedious derivatization/purification steps were needed. Thus, the proposed assay was successfully used for the quantification of cholesterol in bovine milk and cream. The standard recovery tests show a recovery range of 95.3–103.0% with a relative standard deviation of 0.3–3.1%. Therefore, the proposed enzyme-assisted ReMALDI-MS assay has great potential for quantification of cholesterol in other foods.

Adsorption-Based Detoxification of Endotoxins by Porous Flexible Organic Frameworks.

Bacterial lipopolysaccharides (LPS, endotoxins) cause sepsis that is responsible for a huge amount of mortality globally. However, their neutralization or detoxification remains an unmet medical need. We envisaged that cationic organic frameworks with persistent hydrophobic porosity may adsorb and thus neutralize LPS through a combination of cooperative ion-pairing electrostatic attraction and hydrophobicity. We here report the preparation of two water-soluble flexible organic frameworks (FOF-1 and FOF-2) from tetratopic and ditopic precursors through quantitative formation of hydrazone bonds at room temperature. The two FOFs are revealed to possess hydrodynamic diameters, which range from 20 to 120 nm, depending on the concentrations. Dynamic light scattering and isothermal titration calorimetric and chromogenic limulus amebocyte lysate experiments indicate that both frameworks are able to adsorb and thus reduce the concentration of free LPS molecules in aqueous solution, whereas cytokine inhibition experiments with RAW264.7 support that this adsorption can significantly decrease the toxicity of LPS. In vivo experiments with mice (five males per group) show that the injection of FOF-1 at a dose of 0.6 mg/kg realizes the survival of all of the mice administrated with LPS of the d-galactosamine (d-Gal)-sensitized absolute lethal dose (LD100, 0.05 mg/kg), whereas its maximum tolerated dose for mice is determined to be 10 mg/kg. These findings provide a new promising sequestration strategy for the development of porous agents for the neutralization of LPS.

Hydrazone bond enhance the mechanical properties, heating resistance, and water resistance of imine-based thermosets

The development of dynamic imine bonds offers a solution to the recycling and repair issues related to conventional petroleum-based thermosetting resins and provides a closed-loop method for utilization towards a circular thermosetting materials economy. Despite recent advances, however, the poor mechanical properties, low heat resistance, and bad water-resistance of imine-based thermosets limit their application. In this study, the biomass dynamic hydrazone bonds were introduced into imine thermosets networks that can enhance the mechanical properties and heating resistance by hydrogen bonding. The prepared biomass hydrazone-imine thermosets exhibit excellent heat resistance (Tg = 215 °C) and tensile strength (56.1 MPa). The properties of the hydrazone-imine thermosets can be readily adjusted by controlling the number of hydrazone bonds. Molecular dynamics calculation of hydrazone-imine thermosets model provides mechanistic insights to how the number of hydrazone bonds manipulating the performance of the themosets. Moreover, the introduction of hydrazone bonds does not affect to the recyclability and repairability of the hydrazone-imine thermosets. Additionally, incorporating hydrazone bonds can enhance the water resistance of imine-based thermosets. Comprehensively, this work provide a sustainable way to design and prepared high-value intelligence thermosets.

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.

Stimuli-Sensitive Linear-Dendritic Block Copolymer-Drug Prodrug as a Nanoplatform for Tumor Combination Therapy.

Linear-dendritic block copolymer (LDBCs) are highly attractive candidates for smart drug-delivery vehicles. Herein, an amphiphilic poly[(ethylene glycol) methyl ether methacrylate] (POEGMA) linear-peptide dendritic prodrug of doxorubicin (DOX) prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization is reported. The hydrophobic-dye-based photosensitizer chlorin e6 (Ce6) is employed for encapsulation in the prodrug nanoparticles (NPs) to obtain an LDBCs-based drug-delivery system (LD-DOX/Ce6) that offers a combination cancer therapy. Due to the presence of Gly-Phe-Leu-Gly peptides and hydrazone bonds in the prodrug structure, LD-DOX/Ce6 is degraded into small fragments, thus specifically triggering the intracellular release of DOX and Ce6 in the tumor microenvironment. Bioinformatics analysis suggests that LD-DOX/Ce6 with laser irradiation treatment significantly induces apoptosis, DNA damage, and cell cycle arrest. The combination treatment can not only suppress tumor growth, but also significantly reduce tumor metastasis compared with treatments with DOX or Ce6 through regulating EMT pathway, TGFβ pathway, angiogenesis, and the hypoxia pathway. LD-DOX/Ce6 displays a synergistic chemo-photodynamic antitumor efficacy, resulting in a high inhibition in tumor growth and metastasis, while maintaining an excellent biosafety. Therefore, this study demonstrates the potential of the biodegradable and tumor-microenvironment-responsive LDBCs as an intelligent multifunctional drug-delivery vehicle for high-efficiency cancer combination therapy.

Amino‐Modified Poly (l–lactic Acid) Nanofibers Enable pH‐Stimulated Drug Release and NIR Real‐Time Detection

AbstractStimulus‐responsive nanofibers can adjust the speed of drug delivery, and real‐time monitoring elucidates the relationship between drug release and therapeutic efficacy. Both of these advantages have great potential in clinical therapy. However, the complex preparation of current stimulus‐responsive drug‐loaded nanofibers leads to low drug‐loading levels, limiting their widespread applications. In this study, we prepared pH‐responsive drug‐loaded nanofibers with fluorescence monitoring properties using the electrospinning method. A representative drug of DOX was loaded onto the nanofibers. The degradable flexible nanofibers modified by amino groups attained higher drug loading and controlled drug release. Precisely, the rate of drug release varies with different pH. Faster release speed occurs in the tumor microenvironment with faintly acidic conditions than in healthy tissues with neutral conditions. The pH‐responsive mechanism was due to hydrazone bonds between the amino groups and DOX molecules, which FTIR confirmed. In addition, these pH‐responsive nanofibers with intense upconversion fluorescence enable more sensitive monitoring, whereas weak luminescence cannot achieve.

A pH-responsive hyaluronic acid hydrogel for regulating the inflammation and remodeling of the ECM in diabetic wounds.

Diabetes is a universal disease in the world. In the wounds of diabetic individuals, chronic inflammation and an inefficient fibrogenic process hinder the formation and deposition of the ECM, which delays the process of wound healing. To reconstruct the ECM of a diabetic patient's wound, in this work, we designed a pH-responsive "Double H-bonds" (hydrogen bond and hydrazone bond) hyaluronic acid-collagen hydrogel. This hydrogel can be self-gelled quickly in neutral and alkaline environments. But the weakly acidic inflammatory environment of diabetic wounds may accelerate the degradation of the hydrogel and the release of metformin. The in vitro results showed that the hydrogel can enhance the adhesion and infiltration of fibroblasts while inhibiting the growth of macrophages. Meanwhile, metformin could be released and polarize macrophages from M1 to M2, thereby accelerating the migration of fibroblasts and the production of collagen in a high glucose environment. The in vivo results proved that this hydrogel could remodel the ECM in diabetic mice wounds.

Dynamic covalent chemistry in live cells for organelle targeting and enhanced photodynamic action.

Organelle-specific targeting enables increasing the therapeutic index of drugs and localizing probes for better visualization of cellular processes. Current targeting strategies require conjugation of a molecule of interest with organelle-targeting ligands. Here, we propose a concept of dynamic covalent targeting of organelles where the molecule is conjugated with its ligand directly inside live cells through a dynamic covalent bond. For this purpose, we prepared a series of organelle-targeting ligands with a hydrazide residue for reacting with dyes and drugs bearing a ketone group. We show that dynamic hydrazone bond can be formed between these hydrazide ligands and a ketone-functionalized Nile Red dye (NRK) in situ in model lipid membranes or nanoemulsion droplets. Fluorescence imaging in live cells reveals that the targeting hydrazide ligands can induce preferential localization of NRK dye and an anti-cancer drug doxorubicin in plasma membranes, mitochondria and lipid droplets. Thus, with help of the dynamic covalent targeting, it becomes possible to direct a given bioactive molecule to any desired organelle inside the cell without its initial functionalization by the targeting ligand. Localizing the same NRK dye in different organelles by the hydrazide ligands is found to affect drastically its photodynamic activity, with the most pronounced phototoxic effects in mitochondria and plasma membranes. The capacity of this approach to tune biological activity of molecules can improve efficacy of drugs and help to understand better their intracellular mechanisms.

A pH-responsive complex based on supramolecular organic framework for drug-resistant breast cancer therapy

Chemotherapy is one of the main ways to treat breast cancer clinically. However, the multidrug resistance to anti-tumor drugs limits their clinical use. To overcome these drawbacks, development of drug delivery systems (DDSs) has attracted more and more attention in cancer therapy. At present, the preparation and purification process are complicated for many reported DDSs, while clinic calls for new DDSs that are more convenient for preparation. Here, a new pH-responsive supramolecular organic framework drug delivery complex loading doxorubicin (DOX) is fabricated. Anti-tumor activity of the system in vitro was investigated by cell cytotoxicity, uptake assay, and cell apoptosis analysis. The anti-tumor activity in vivo was investigated by inspecting nude mice body weight, tumor volume, and weight, also a preliminary mechanism probe was conducted by HE and TUNEL staining. The DOX@SOF displayed high stability, good biocompatibility, and pH regulated drug release. At acid condition, the hydrazone bonds would be broken, which result in the dissociation of SOF, and then the drugs would be released from the system. Furthermore, DOX@SOF enhanced cellular internalization. Both in vitro and in vivo experiments reflected that DOX@SOF could enhance the anti-tumor activity of DOX for the MCF-7/ADR tumor cells and tumors. This study provides a highly efficient strategy to prepare stimulus-responsive supramolecular drug delivery complex for treatment of drug-resistant cancer, the results presented inspiring scientific interests in exploring new drug delivery strategy and reversing multi-drug resistance for clinical chemotherapy.

A pH-responsive complex based on supramolecular organic framework for drug-resistant breast cancer therapy

Chemotherapy is one of the main ways to treat breast cancer clinically. However, the multidrug resistance to anti-tumor drugs limits their clinical use. To overcome these drawbacks, the development of drug delivery systems (DDSs) has attracted more and more attention in cancer therapy. At present, the preparation and purification process are complicated for many reported DDSs, while the clinic calls for new DDSs that are more convenient for preparation. Here a new pH-responsive supramolecular organic framework drug delivery complex loading doxorubicin (DOX) is fabricated. Anti-tumor activity of the system in vitro was investigated by cell cytotoxicity, uptake assay, and cell apoptosis analysis. The anti-tumor activity in vivo was investigated by inspecting nude mice body weight, tumor volume and weight, also a preliminary mechanism probe was conducted by HE and TUNEL staining. The DOX@SOF displayed high stability, good biocompatibility and pH-regulated drug release. At acid condition, the hydrazone bonds would be broken, which result in the dissociation of SOF, and then the drugs would be released from the system. Furthermore, DOX@SOF enhanced cellular internalization. Both in vitro and in vivo experiments reflected that DOX@SOF could enhance the anti-tumor activity of DOX. for the MCF-7/ADR tumor cells and tumors. This study provides a highly efficient strategy to prepare a stimulus-responsive supramolecular drug delivery complex for the treatment of drug-resistant cancer, the results presented inspiring scientific interests in exploring new drug delivery strategies and reversing multi-drug resistance for clinical chemotherapy.

Stimuli-responsive, dual-function prodrug encapsulated in hyaluronic acid micelles to overcome doxorubicin resistance

Multidrug resistance (MDR) is the main challenge faced by cancer chemotherapy. Drug-conjugate offers a promising strategy for breast cancer therapy. In this regard, we developed a DNVM multifunctional drug delivery system by crosslinking doxorubicin (DOX) and vitamin E succinate (VES) with a pH-sensitive hydrazone bond and then encapsulated the DOX-NN-VES prodrug into pH-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine (HOD) micelles. DOX resistant MCF-7/ADR cell were adopted as a model to study the capability and mechanism of MDR reversal. DNVM exhibited much higher cytotoxicity and cell uptake efficiency compared with that of acid-insensitive DOX-VES loaded HOD micelles (DVSM) and DOX loaded HOD micelles (DOXM), indicating the better capacity of DNVM for the reversal of MDR. Moreover, DNVM prevented drug efflux more effectively, inhibited the expression of P-gp, induced excessive production of reactive oxygen species and affected the expression of apoptosis-related proteins. In vivo experiments showed that DNVM significantly inhibited the tumor growth with no obvious changes in the body weight of MCF-7/ADR cells-bearing nude mice. The results suggested that the “double gain” DNVM can synergistically enhance the efficacy of chemotherapeutics for DOX resistant tumor cells and has the potential to overcome tumor MDR. Statement of SignificanceA dual-functional pH-sensitive doxorubicin - vitamin E succinate prodrug was developed and loaded into tumor microenvironment-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine micelle system (DNVM) for sequencing stimuli-release and overcoming doxorubicin resistance. The “double gain” DNVM can synergistically enhance the efficacy of chemotherapeutics for doxorubicin resistant tumor cells and has the potential to overcome tumor multiple drug resistance.