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.

Actively Targeting Redox-Responsive Multifunctional Micelles for Synergistic Chemotherapy of Cancer.

Stimuli-responsive polymeric micelles decorated with cancer biomarkers represent an optimal choice for drug delivery applications due to their ability to enhance therapeutic efficacy while mitigating adverse side effects. Accordingly, we synthesized a digoxin-modified novel multifunctional redox-responsive disulfide-linked poly(ethylene glycol-b-poly(lactic-co-glycolic acid) copolymer (Bi(Dig-PEG-PLGA)-S2) for the targeted and controlled release of doxorubicin (DOX) in cancer cells. Within the micellar aggregate, the disulfide bond confers redox responsiveness, while the presence of the digoxin moiety acts as a targeting agent and chemosensitizer for DOX. Upon self-assembly in aqueous solution, Bi(Dig-PEG-PLGA)-S2 formed uniformly distributed spherical micelles with a hydrodynamic diameter (D h ) of 58.36 ± 0.78 nm and a zeta potential of -24.71 ± 1.01 mV. The micelles exhibited desirable serum and colloidal stability with a substantial drug loading capacity (DLC) of 6.26% and an encapsulation efficiency (EE) of 83.23%. In addition, the release of DOX demonstrated the redox-responsive behavior of the micelles, with approximately 89.41 ± 6.09 and 79.64 ± 6.68% of DOX diffusing from DOX@Bi(Dig-PEG-PLGA)-S2 in the presence of 10 mM GSH and 0.1 mM H2O2, respectively, over 96 h. Therefore, in HeLa cell lines, DOX@Bi(Dig-PEG-PLGA)-S2 showed enhanced intracellular accumulation and subsequent apoptotic effects, attributed to the targeting ability and chemosensitization potential of digoxin. Hence, these findings underscore the promising characteristics of Bi(Dig-PEG-PLGA)-S2 as a multifunctional drug delivery vehicle for cancer treatment.

Multifunctional thermosensitive hydrogel based on alginate and P(NIPAM-co-HEMIN) composites for accelerated diabetic wound healing.

Non-healing wounds in patients with diabetes are a concerning issue associated with amputation and a high mortality rate. These wounds are exacerbated by oxidative stress and microbial infections resulting from hyperglycemia. Therefore, advanced materials for repairing wound beds must be identified urgently. This paper introduces a topically applicable composite hydrogel with thermosensitive properties and presents the antibacterial and antioxidant activities in mice with diabetes-induced wounds. This composite is developed by combining poly N-isopropyl acrylamide (NIPAM)-copolymerized HEMIN (NIPAM-co-HEMIN) and amine-modified alginate (ALG-EDA) biomaterials, with Ag nanoparticles (AgNPs) incorporated into the system as an antibacterial agent. Results of antibacterial tests show that the p(NIPAM-co-HEMIN)/ALG-EDA/AgNP composite system is effective against E. coli and S. aureus. Additionally, the AgNP composite exhibits low cellular toxicity in NIH3T3 and CT-2A cell lines. The wounds in diabetic mice treated with the composite system healed in <12 days, and the composite system accelerated the healing process by increasing collagen synthesis. In conclusion, the biocomposite reported herein is highly promising for repairing diabetic skin wounds and treating infections caused by bacterial microbes.

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.

Combination of ovalbumin-coated iron oxide nanoparticles and poly(amidoamine) dendrimer-cisplatin nanocomplex for enhanced anticancer efficacy.

Enhancement of drug efficacy is essential in cancer treatment. The immune stimulator ovalbumin (Ova)-coated citric acid (AC-)-stabilized iron oxide nanoparticles (AC-IO-Ova NPs) and enhanced permeability and retention (EPR)-based tumor targeted 4.5 generation poly(amidoamine) dendrimer(4.5GDP)-cisplatin (Cis-pt) nanocomplex (NC) (4.5GDP-Cis-pt NC) were used for enhanced anticancer efficiency. The formations of 4.5GDP-Cis-pt NC, AC-IO, and AC-IO-Ova NPs were examined via FTIR spectroscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy. The conjugation of Cis-pt with 4.5GDP was confirmed using carbon NMR spectroscopy. The tumor-specific 4.5GDP-Cis-pt NC provided 45%and 28% cumulative cisplatin release in 72 h at pH 6.5 and 7.4, respectively. A significant immune response with high TNF-α and IL-6 cytokine secretion was confirmed for the co-incubation of AC-IO-Ova with RAW 264.7 or HaCaT cells. AC-IO-Ova NPs were biocompatible with different cell lines, even at a high concentration (200 µg mL-1). However, AC-IO-Ova NPs mixed with 4.5GDP-Cis-pt NC (Cis-pt at 15 µg mL-1) significantly increased the cytotoxicity against the cancer cells in a dose-dependent manner with the increasing AC-IO-Ova NPs concentrations. The increased anticancer effects may be attributed to the generation of reactive oxygen species (ROS). Moreover, AC-IO-Ova NPs might assist the efficiency of anticancer cells, inducing an innate immune response via M1 macrophage polarization. We provide a novel synergistic chemoimmunotherapeutic strategy to enhance the anticancer efficacy of cisplatin via a chemotherapeutic agent 4.5GDP-Cis-pt NC and induce proinflammatory cytokines stimulating innate immunity through AC-IO-Ova NPs against tumors.