Diselenide-Bridged Doxorubicin Dimeric Prodrug: Synthesis and Redox-Triggered Drug Release.

The diselenide bond has attracted intense interest in redox-responsive drug delivery systems (DDSs) in tumor chemotherapy, due to its higher sensitivity than the most investigated bond, namely the disulfide bond. Here, a diselenide-bridged doxorubicin dimeric prodrug (D-DOXSeSe) was designed by coupling two doxorubicin molecules with a diselenodiacetic acid (DSeDAA) molecule via α-amidation, as a redox-triggered drug self-delivery system (DSDS) for tumor-specific chemotherapy. The drug release profiles indicated that the D-DOXSeSe could be cleaved to release the derivatives selenol (DOX-SeH) and seleninic acid (DOX-SeOOH) with the triggering of high GSH and H2O2, respectively, indicating the double-edged sword effect of the lower electronegativity of the selenide atom. The resultant solubility-controlled slow drug release performance makes it a promising candidate as a long-acting DSDS in future tumor chemotherapy. Moreover, the interaction between the conjugations in the design of self-immolation traceless linkers was also proposed for the first time as another key factor for a desired precise tumor-specific chemotherapy, besides the conjugations themselves.

Coordination and Redox Dual-Responsive Mesoporous Organosilica Nanoparticles Amplify Immunogenic Cell Death for Cancer Chemoimmunotherapy.

Amplifying the chemotherapy-driven immunogenic cell death (ICD) for efficient and safe cancer chemoimmunotherapy remains a challenge. Here, a potential ICD nanoamplifier containing diselenide-bridged mesoporous organosilica nanoparticles (MONs) and chemotherapeutic ruthenium compound (KP1339) to achieve cancer chemoimmunotherapy is tailored. KP1339-loaded MONs show controlled drug release profiles via glutathione (GSH)-responsive competitive coordination and matrix degradation. High concentration of MONs selectively evoked reactive oxygen species production, GSH depletion, and endoplasmic reticulum stress in cancer cells, thus amplifying the ICD of KP1339 and boosting robust antitumor immunological responses. After the combination of PD-L1 checkpoint blockade, cancer cell membrane-cloaked KP1339-loaded MONs not only regress primary tumor growth with low systemic toxicity, but also inhibit distant tumor growth and pulmonary metastasis of breast cancer. The results have shown the potential of coordination and redox dual-responsive MONs boosting amplified ICD for cancer chemoimmunotherapy.

Healable and Rearrangeable Networks of Liquid Crystal Elastomers Enabled by Diselenide Bonds.

Based on liquid crystal elastomer (LCE) materials, hierarchically structured soft actuators can meet some requirements for "human-friendly" working mode and execute complex tasks with intelligent adaptation to environmental changes. However, few researchers have paid much attention to the preparation methods of multicomponent/hierarchical LCE actuators. In this communication, we demonstrate the successful integration of an exchangeable diselenide chain extender for the preparation of dynamic LCEs, which could be reprogrammed on heating or under visible light illumination. Moreover, the rearrangeable polydiselenide networks could be applied to develop the self-welding technology toward fabricating hierarchically structured LCE actuators with sophisticated deformability without using any auxiliary reagent (adhesive, tape, catalysts or initiator) during the assembling process.

Probing the Superiority of Diselenium Bond on Docetaxel Dimeric Prodrug Nanoassemblies: Small Roles Taking Big Responsibilities.

The current state of chemotherapy is far from satisfaction, restricted by the inefficient drug delivery and the off-target toxicity. Prodrug nanoassemblies are emerging as efficient platforms for chemotherapy. Herein, three docetaxel dimeric prodrugs are designed using diselenide bond, disulfide bond, or dicarbide bond as linkages. Interestingly, diselenide bond-bridged dimeric prodrug can self-assemble into stable nanoparticles with impressive high drug loading (≈70%, w/w). Compared with disulfide bond and dicarbide bond, diselenide bond greatly facilitates the self-assembly of dimeric prodrug, and then improves the colloidal stability, blood circulation time, and antitumor efficacy of prodrug nanoassemblies. Furthermore, the redox-sensitive diselenide bond can specifically respond to the overexpressed reactive oxygen species and glutathione in tumor cells, leading to tumor-specific drug release. Therefore, diselenide bond bridged prodrug nanoassemblies exhibit discriminating cytotoxicity between tumor cells and normal cells, significantly alleviating the systemic toxicity of docetaxel. The present work gains in-depth insight into the impact of diselenide bond on the dimeric prodrug nanoassemblies, and provides promising strategies for the rational design of the high efficiency-low toxicity chemotherapeutical nanomedicines.

Structural reorganization and crack-healing properties of hydrogels based on dynamic diselenide linkages.

We report the dynamic behavior of diselenide-containing hydrophilic polyurethanes and hydrogels based on diselenide exchange reactions in an aqueous media. Diselenide-containing linear and cross-linked polyurethanes were synthesized via polyaddition reactions using diselenide-containing diol in combination with pyridinium diol that enhances the hydrophilicity of the polymer chains. The obtained linear polyurethanes underwent photo-induced diselenide exchange reactions with small diselenide compounds and degraded to smaller fragments, confirming the dynamicity of the obtained hydrophilic polyurethanes. The prepared hydrogels displayed characteristic large swelling behavior based on the structural reorganization through diselenide exchange either under photo-irradiation at 365 nm or even in the dark at room temperature. The diselenide-containing hydrogels also showed crack-healing behavior under the same exchanging conditions, presenting the utility of diselenide linkages as simple and useful units to offer high dynamicity to hydrogels.

Doxorubicin-loaded Polymeric Biotin-PEG-SeSe-PBLA Micelles with surface Binding of Biotin-Mediated Cancer Cell Targeting and Redox-Responsive Drug release for enhanced anticancer efficacy.

Biotin receptors are overexpressed in various cancer cell types, essential in tumor development, metabolism, and metastasis. Chemotherapeutic agents may be more effective and have fewer adverse effects if they specifically target the biotin receptors on cancer cells. Polymeric micelles (PMs) with nanoscale size via the EPR effect to accumulate near tumor tissue. We utilized the solvent exchange technique to crate polymeric Biotin-PEG-SeSe-PBLA micelles. This underwent self-assembly to create uniformly dispersed PMs with a hydrodynamic diameter of 81.54 ± 0.23 nm. The resulting PMs characterized by 1HNMR, 13CNMR, FTIR, and Raman spectroscopy. PMs exhibited a high efficacy of Doxorubicin encapsulation (EE) and loading content (DLC), with values of 5.93 wt% and 74.32 %, respectively. DOX@Biotin-PEG-SeSe-PBLA micelles showed optimal DOX release, around 89 % and 74 % in 10 mM glutathione and 0.1 % H2O2, respectively, within 72 hours, in the simulated cancer redox pool. Fascinatingly, the blank Biotin-PEG-SeSe-PBLA micelles did not affect the HaCaT or HeLa cell lines; approximately 85 % of the cells were metabolically active. Contrarily, at a 5 µg/ml concentration, DOX@Biotin-PEG-SeSe-PBLA specifically inhibited the proliferation of roughly 76 % of HeLa cells and 11 % of HaCaT cells. The fluorescence microscopy results demonstrated that biotin-decorated micelles were more successfully internalized by HeLa cells, which overexpress the biotin receptor, than by non-targeted micelles in vitro. In summary, the diselenide-linked Biotin-PEGSeSe-PBLA formed smart PMs that could offer DOX specific to cancer cells with precision and are physiologically durable.

Necroptosis-Mediated Synergistic Photodynamic and Glutamine-Metabolic Therapy Enabled by a Biomimetic Targeting Nanosystem for Cholangiocarcinoma.

Targeted delivery of glutamine metabolism inhibitors holds promise for cholangiocarcinoma therapy, yet effective delivery vehicles remain a challenge. This study reports the development of a biomimetic nanosystem, termed R-CM@MSN@BC, integrating mesoporous organosilicon nanoparticles with reactive oxygen species-responsive diselenide bonds for controlled release of the glutamine metabolism inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and the photosensitizer Ce6. Erythrocyte membrane coating, engineered with Arg-Gly-Asp (RGD) peptides, not only enhanced biocompatibility but also improved tumor targeting and tissue penetration. Upon laser irradiation, R-CM@MSN@BC executed both photodynamic and glutamine-metabolic therapies, inducing necroptosis in tumor cells and triggering significant immunogenic cell death. Time-of-flight mass cytometry analysis revealed that R-CM@MSN@BC can remodel the immunosuppressive tumor microenvironment by polarizing M1-type macrophages, reducing infiltration of M2-type and CX3CR1+ macrophages, and decreasing T cell exhaustion, thereby increasing the effectiveness of anti-programmed cell death ligand 1 immunotherapy. This strategy proposed in this study presents a viable and promising approach for the treatment of cholangiocarcinoma.

Mesoscopic Simulations of Diselenide-Containing Crosslinked Doxorubicin-Loaded Micelles and Their Tumor Microenvironment Responsive Release Behaviors.

There is currently limited research on the structure-property relationship of reduction stimuli-responsive polymeric crosslinked micelles using mesoscopic simulations. Herein, dissipative particle dynamics (DPD) simulations were used to simulate the self-assembly process of the blank non-crosslinked micelle, the structure and doxorubicin (DOX) distribution of diselenide crosslinked micelle with different crosslinker contents (CCs) based on the nearest-neighbor bonding principle. The results revealed that the formation of a three-layer spherical micelle and the loaded DOX mainly distributed in the polycaprolactone (PCL) core and hydroxyethyl methacrylate (HEMA) mesosphere. The larger the dosage of DOX, the more DOX encapsulated, but the encapsulation of DOX in the hydrophobic domain would reach saturation when the dosage increased to 6.0 %. In micelles with lower CCs or crosslinking levels (CLs), DOX entered the middle layer and the inner core faster. Then, based on the nearest media-bead bond breaking principle and subsequently DPD simulation, the effects of different CCs on the micelle structure and DOX release properties were investigated. Low CC could cause fast drug release. With the increase of CCs, the micelle showed a slower DOX release trend. The multilayer crosslinked network system also affected the DOX release rate. Hence, this work can provide some mesoscale guidance for the structural design and structure-property relationship of stimuli-responsive reversible crosslinked micelles for drug delivery.

pH/redox-responsive core cross-linked based prodrug micelle for enhancing micellar stability and controlling delivery of chemo drugs: An effective combination drug delivery platform for cancer therapy.

Core-crosslinking of micelles (CCMs) appears to be a favorable strategy to enhance micellar stability and sustained release of the loaded drug. In this study, the DOX-conjugated pH-sensitive polymeric prodrug Methoxy Poly (ethylene oxide)-b-Poly (Aspartate-Hydrazide) (mPEG-P [Asp-(Hyd-DOX)] was created using ring-opening polymerization. To further enhance the micellar system, 3,3'-diselanediyldipropanoic acid (DSeDPA) was applied to link the hydrophobic segment via click reaction to form pH/redox-responsive CCMs. Dual anti-cancer drugs, DOX as a pro-drug and SN-38 as a targeting drug, were used to enhance inhibition. DLS confirmed that the non-cross-linked micelle (NCMs) showed a higher (96.43 nm) particle size compared to the CCMs (72.63 nm). Due to micellar shrinkage after crosslinking, CCMs displayed SN-38 drug loading (7.32 %) and encapsulation efficiency (86.23 %). The mPEG-P(Asp-Hyd) copolymer's in vitro cytotoxicity on HeLa and HaCaT cell lines found that 84.52 % of the cells are alive, and zebrafish (Danio rerio) embryos and larvae are highly biocompatible. The DOX/SN-38@CCMs had a sustained discharge profile in vitro, unlike the DOX/SN-38@NCMs. In DOX/SN-38@CCMs, HeLa cells were inhibited 50.90 % more than HaCaT (14.25 %) at the maximum drug dose (10 µg/mL). The CCMs successfully targeted and supplied DOX/SN-38 in HeLa cells rather than HaCaT cells, based on cellular uptake of 2D cell culture. CCMs, unlike NCMs, inhibit the growth of spheroids for extended periods of time due to the prolonged release of the loaded drug. Overall, CCMs are good-looking for use as regulated delivery of DOX/SN-38 in cancer cells because of all of these appealing characteristics.

Laser-Induced Remote Healing of Stretchable Diselenide-Containing Conductive Composites.

Remotely controlled on-demand functional healing is vital to components that are difficult to access and repair in distance such as satellites and unmanned cruising aircrafts. Compared with other stimuli, a blue laser is a better choice to input energy to the damaged area in distance because of its high energy density and low dissipation through the air. Herein, diselenide-containing polyurethane (PUSe) is first employed to fabricate visible light-responsive stretchable conductive composites with multiwalled carbon nanotubes (MWCNTs). Then, laser-induced remote healing was realized based on the characteristics of long-distance propagation of lasers and the dynamic properties of diselenide bonds. Moreover, the PUSe/MWCNT composite film can be used to transfer an electrical signal in the circuit containing a signal generator. This laser-induced remote healing of conductivity paves the way for developing healing conductors which are difficult to access and repair.

Small changes in the length of diselenide bond-containing linkages exert great influences on the antitumor activity of docetaxel homodimeric prodrug nanoassemblies.

Homodimeric prodrug-based self-assembled nanoparticles, with carrier-free structure and ultrahigh drug loading, is drawing more and more attentions. Homodimeric prodrugs are composed of two drug molecules and a pivotal linkage. The influence of the linkages on the self-assembly, in vivo fate and antitumor activity of homodimeric prodrugs is the focus of research. Herein, three docetaxel (DTX) homodimeric prodrugs are developed using different lengths of diselenide bond-containing linkages. Interestingly, compared with the other two linkages, the longest diselenide bond-containing linkage could facilitate the self-delivery of DTX prodrugs, thus improving the stability, circulation time and tumor targeting of prodrug nanoassemblies. Besides, the extension of linkages reduces the redox-triggered drug release and cytotoxicity of prodrug nanoassemblies in tumor cells. Although the longest diselenide bond-containing prodrug nanoassemblies possessed the lowest cytotoxicity to 4T1 cells, their stable nanostructure maintained intact during circulation and achieve the maximum accumulation of DTX in tumor cells, which finally "turned the table". Our study illustrates the crucial role of linkages in homodimeric prodrugs, and gives valuable proposal for the development of advanced nano-DDS for cancer treatment.

X-ray-responsive polypeptide nanogel for concurrent chemoradiotherapy.

Concurrent chemoradiotherapy (CCRT) is a standard treatment regimen for medically inoperable stage III non-small-cell lung carcinoma (NSCLC) owing to its superior prognostics compared with the sequential modality. Nevertheless, the current pattern of CCRT still fails to provide satisfactory survival outcome. Furthermore, CCRT is always accompanied by a higher risk of severe side effects, limiting the dose escalation. Herein, an X-ray-responsive polypeptide nanogel (PNG) was developed for on-demand delivery of chemotherapeutic agent triggered by radiotherapy to synergistically improve the efficacy of CCRT with reduced side effects. The smart PNG was formed by crosslinking methoxy poly(ethylene glycol)-block-poly(L-glutamic acid-co-γ-2-chloroethyl-L-glutamate) (mPEG-b-P(LG-co-CELG)) with a diselenide (Se-Se) bond. The doxorubicin (DOX)-loaded polypeptide nanogel (PNG/DOX) exhibited accelerated drug release when exposed to X-ray irradiation as a result of Se-Se bond degradation. With prolonged circulation and enhanced intratumoral accumulation in vivo, PNG/DOX combined with X-ray irradiation exhibited better synergistic antitumor efficacy and fewer side effects toward human A549 lung carcinoma-bearing nude mice. The smart X-ray-responsive nanogel provides a promising bridge between chemotherapy and radiotherapy and enhances the potential application of CCRT in clinic.

Diselenide Core Cross-Linked Micelles of Poly(Ethylene Oxide)-b-Poly(Glycidyl Methacrylate) Prepared through Alkyne-Azide Click Chemistry as a Near-Infrared Controlled Drug Delivery System.

In this article, a drug delivery system with a near-infrared (NIR) light-responsive feature was successfully prepared using a block copolymer poly(ethylene oxide)-b-poly(glycidyl methacrylate)-azide (PEO-b-PGMA-N3) and a cross-linker containing a Se-Se bond through "click" chemistry. Doxorubicin (DOX) was loaded into the core-cross-linked (CCL) micelles of the block copolymer along with indocyanine green (ICG) as a generator of reactive oxygen species (ROS). During NIR light exposure, ROS were generated by ICG and attacked the Se-Se bond of the cross-linker, leading to de-crosslinking of the CCL micelles. After NIR irradiation, the CCL micelles were continuously disrupted, which can be a good indication for effective drug release. Photothermal analysis showed that the temperature elevation during NIR exposure was negligible, thus safe for normal cells. In vitro drug release tests demonstrated that the drug release from diselenide CCL micelles could be controlled by NIR irradiation and affected by the acidity of the environment.

Fabrication of Core Crosslinked Polymeric Micelles as Nanocarriers for Doxorubicin Delivery: Self-Assembly, In Situ Diselenide Metathesis and Redox-Responsive Drug Release.

Polymeric micelles (PMs) have been used to improve the poor aqueous solubility, slow absorption and non-selective biodistribution of chemotherapeutic agents (CAs), albeit, they suffer from disassembly and premature release of payloads in the bloodstream. To alleviate the thermodynamic instability of PMs, different core crosslinking approaches were employed. Herein, we synthesized the poly(ethylene oxide)-b-poly((2-aminoethyl)diselanyl)ethyl l-aspartamide)-b-polycaprolactone (mPEG-P(LA-DSeDEA)-PCL) copolymer which self-assembled into monodispersed nanoscale, 156.57 ± 4.42 nm, core crosslinked micelles (CCMs) through visible light-induced diselenide metathesis reaction between the pendant selenocystamine moieties. The CCMs demonstrated desirable doxorubicin (DOX)-loading content (7.31%) and encapsulation efficiency (42.73%). Both blank and DOX-loaded CCMs (DOX@CCMs) established appreciable colloidal stability in the presence of bovine serum albumin (BSA). The DOX@CCMs showed redox-responsive drug releasing behavior when treated with 5 and 10 mM reduced glutathione (GSH) and 0.1% H2O2. Unlike the DOX-loaded non-crosslinked micelles (DOX@NCMs) which exhibited initial burst release, DOX@CCMs demonstrated a sustained release profile in vitro where 71.7% of the encapsulated DOX was released within 72 h. In addition, the in vitro fluorescent microscope images and flow cytometry analysis confirmed the efficient cellular internalization of DOX@CCMs. The in vitro cytotoxicity test on HaCaT, MDCK, and HeLa cell lines reiterated the cytocompatibility (≥82% cell viability) of the mPEG-P(LA-DSeDEA)-PCL copolymer and DOX@CCMs selectively inhibit the viabilities of 48.85% of HeLa cells as compared to 15.75% of HaCaT and 7.85% of MDCK cells at a maximum dose of 10 µg/mL. Overall, all these appealing attributes make CCMs desirable as nanocarriers for the delivery and controlled release of DOX in tumor cells.

Diselenide linkage containing triblock copolymer nanoparticles based on Bi(methoxyl poly(ethylene glycol))-poly(ε-carprolactone): Selective intracellular drug delivery in cancer cells.

Redox-responsive diselenide bond containing triblock copolymer Bi(mPEG-SeSe)-PCL,Bi(mPEG-SeSe)-PCL was developed for specific drug release in cancer cells. Initially, ditosylated polycaprolactone was prepared via the reaction between polycaprolactone diol (PCL-diol) and tosyl chloride (TsCl). Next, Bi(mPEG-SeSe)-PCL was synthesized via the reaction between ditosylated polycaprolactone and sodium diselenide initiated poly (ethylene glycol) methyl ether tosylate. The synthesized amphiphilic triblock copolymer could self-assemble into uniform nanoparticles in aqueous medium and disassemble upon redox stimuli. The Bi(mPEG-SeSe)-PCL nanoparticles showed a DOX loading content of 5.1 wt% and a loading efficiency of 49%. In vitro drug release studies showed that about 62.4% and 56% of DOX was released from the nanoparticles during 72 h at 37 °C in PBS containing 2 mg/mL (6 mM) GSH and 0.1% H2O2, respectively, whereas only about 30% of DOX was released in PBS under the same conditions. The cell viability (MTT assays) results showed that the synthesized material was biocompatible with above 90% cell viability, and that the DOX-loaded Bi(mPEG-SeSe)-PCL nanoparticles had a high antitumor activity against HeLa cells and low antitumor activity against HaCaT cells, following a 24-h incubation period. Three-dimensional (3D) spheroids of HeLa cells were established for the evaluation of localization of the DOX-loaded nanoparticles into spheroids cells and the successfully inhibition of 3D tumor spheroid growth. The results indicated that the synthesized material Bi(mPEG-SeSe)-PCL was biocompatible and it could be a potential candidate for anticancer drug delivery system.

Redox-responsive Fluorescent Nanoparticles Based on Diselenide-containing AIEgens for Cell Imaging and Selective Cancer Therapy.

A fluorescent, diselenide-containing 9,10-distyrylanthracene (DSA) derivative (SeDSA) with aggregation-induced emission (AIE) characteristic was successfully synthesized and SeDSA nanoparticles (NPs) were prepared through a nanoprecipitation method. SeDSA could coassemble with an antitumor prodrug, diselenide-containing paclitaxel (SePTX), which could be obtained by precipitation, to form SeDSA-SePTX Co-NPs (Co-NPs). Molecular dynamics (MD) simulations reveal that the driving forces for the self-assembly behaviors of SeDSA NPs and SePTX NPs are π-π interactions and hydrophobic interactions, respectively, while the driving forces for Co-NPs include hydrophobic interactions between SeDSA and SePTX, π-π interactions between SeDSA molecules and hydrophobic interactions between SePTX molecules. Meanwhile, Se-Se bonds play a crucial role in balancing the intramolecular forces. These diselenide-containing nanoparticles (SeDSA NPs, SePTX NPs and Co-NPs) exhibit a high stability under physiological conditions and excellent reduction-sensitivity in the presence of the redox agent glutathione (GSH) because of the selenium-sulfur exchange reaction between diselenide and GSH. Both SeDSA NPs and Co-NPs show strong orange fluorescence emissions on the account of the AIE feature of SeDSA and they were easily internalized by HeLa and HepG2 cells. Distinctively, the Co-NPs combine the advantage of SeDSA and SePTX for cell imaging and antineoplastic activity, and exhibit selectivity of cytotoxicities between neoplasia cells and normal cells. This study highlights the development of diselenide-containing AIEgens as a unique approach to prepare uniform and stable fluorescent nanoparticles for the application in cell imaging and tumor treatment.

Fabrication of redox-responsive Bi(mPEG-PLGA)-Se2 micelles for doxorubicin delivery.

Stimuli-responsive polymeric nanostructures have emerged as potential drug carriers for cancer therapy. Herein, we synthesized redox-responsive diselenide bond containing amphiphilic polymer, Bi(mPEG-PLGA)-Se2 from mPEG-PLGA and 3,3'-diselanediyldipropanoic acid (DSeDPA) using DCC/DMAP as coupling agents. Due to its amphiphilic nature, Bi(mPEG-PLGA)-Se2 self-assembled in to stable micelles in aqueous solution with a hydrodynamic size of 123.9 ±â€¯0.85 nm. The Bi(mPEG-PLGA)-Se2 micelles exhibited DOX-loading content (DLC) of 6.61 wt% and encapsulation efficiency (EE) of 54.9%. The DOX-loaded Bi(mPEG-PLGA)-Se2 micelles released 73.94% and 69.54% of their cargo within 72 h upon treatment with 6 mM GSH and 0.1% H2O2, respectively, at pH 7.4 and 37 °C. The MTT assay results demonstrated that Bi(mPEG-PLGA)-Se2 was devoid of any inherent toxicity and the DOX-loaded micelles showed pronounced antitumor activities against HeLa cells, 44.46% of cells were viable at maximum dose of 7.5 µg/mL. The cellular uptake experiment further confirmed the internalization of DOX-loaded Bi(mPEG-PLGA)-Se2 micelles and endowed redox stimuli triggered drug release in cytosol and nuclei of cancer cells. Overall, the results suggested that the smart, biocompatible Bi(mPEG-PLGA)-Se2 copolymer could serve as potential drug delivery biomaterial for the controlled release of hydrophobic drugs in cancer cells.

Mesoscopic simulations of drug-loaded diselenide crosslinked micelles: Stability, drug loading and release properties.

Intelligent reversible crosslinked micelles that have a good balance of structure stability in normal tissue and controlled drug release responded to the tumor microenvironment are highly promising novel drug delivery systems. However, to date, there have been very few reports about mesoscale simulations of drug-loaded polymeric reversible crosslinked micelles. Here, dissipative particle dynamics (DPD) simulation, the nearest-neighbor bonding principle, and the nearest media-bead bond breaking principle were used to investigate the influence of physiological environment along with low tumor pH and reduction microenvironment on the stability and doxorubicin (DOX) distribution of the star polymer [PCL-b-P(HEMA-Se-Se˜)-b-PPEGMA]6 diselenide crosslinked micelles with different diselenide crosslinking levels (CLs). The self-assembly process results obtained by DPD simulations reveal the formation of three-layer spherical micelles with the loaded DOX mainly distributed at the interfacial regions of the inner PCL core and middle HEMA layer. The structural stability and DOX loading capacity of the micelles can be improved by appropriately increasing the CL based on the nearest-neighbor bonding principle due to the effect of the pressure exerted by the crosslink that squeezes the loaded drugs from the intermediate and interfacial layers into the micelle core. Furthermore, the effect of breaking of the diselenide bond on the drug release properties was investigated through the use of the nearest media-bead bond breaking principle. A low CL gives rise to intense drug release, increasing the toxic side effects on the system. With the increase in the CL, the micelles show the transformation from local crosslinking to compact crosslinking, leading to slower drug release. Therefore, this work can provide some guidance on the mesoscale for the structural design and controlled construction of reversible crosslinked micelles for smart drug delivery systems.

Enhanced bioreduction-responsive diselenide-based dimeric prodrug nanoparticles for triple negative breast cancer therapy.

Efficient drug accumulation in tumor is essential for chemotherapy. We developed redox-responsive diselenide-based high-loading prodrug nanoparticles (NPs) for targeted triple negative breast cancer (TNBC) treatment. Method: Redox-responsive diselenide bond (Se-Se) containing dimeric prodrug (PTXD-Se) was synthesized and co-precipitated with TNBC-targeting amphiphilic copolymers to form ultra-stable NPs (uPA-PTXD NPs). The drug loading capacity and redox-responsive drug release behavior were studied. TNBC targeting effect and anti-tumor effect were also evaluated in vitro and in vivo.Results: On-demand designed paclitaxel dimeric prodrug could co-precipitate with amphiphilic copolymers to form ultra-stable uPA-PTXD NPs with high drug loading capacity. Diselenide bond (Se-Se) in uPA-PTXD NPs could be selectively cleaved by abnormally high reduced potential in tumor microenvironment, releasing prototype drug, thus contributing to improved anti-cancer efficacy. Endowed with TNBC-targeting ligand uPA peptide, uPA-PTXD NPs exhibited reduced systemic toxicity and enhanced drug accumulation in TNBC lesions, thus showed significant anti-tumor efficacy both in vitro and in vivo. Conclusion: The comprehensive advantage of high drug loading, redox-controlled drug release and targeted tumor accumulation suggests uPA-PTXD NPs as a highly promising strategy for effective TNBC treatment.

A tumor targeted near-infrared light-controlled nanocomposite to combat with multidrug resistance of cancer.

Stimuli-responsive nanomaterials have emerged as promising drug delivery systems for tumor therapy, as they can specifically respond to tumor-associated stimuli and release the loaded drugs in a controllable manner. However, most currently available stimuli-responsive nanomedicines rely on surrounding extreme stimulus to trigger the activity, which can be inefficient under dynamic and complex living conditions. Herein, we report a near-infrared (NIR) light-responsive nanocomposite, which can generate reactive oxygen species to efficiently trigger the decomposition upon NIR laser irradiation. This nanocomposite is fabricated by conjugating polyamidoamine-pluronic F68 and graphene oxide via diselenide bond, and encapsulating the NIR photosensitizer indocyanine green and chemotherapeutic drug doxorubicin (DOX) as payloads. Under NIR light, the nanocomposite shows lysosomal escape, controlled drug release, and nuclear trafficking of DOX inside multidrug resistant (MDR) MCF-7/ADR cells. Interestingly, this nanocomposite effectively down-regulates ABCB1 gene and P-glycoprotein of MCF-7/ADR cells, exhibiting significant cytotoxicity. In vivo anti-tumor study demonstrates an effective accumulation and superior therapeutic efficacy of this multifunctional nanocomposite in MCF-7/ADR tumors, representing a great potential for clinical treatment of MDR cancer.