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.

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.

Non-Anticoagulant Heparin Prodrug Loaded Biodegradable and Injectable Thermoresponsive Hydrogels for Enhanced Anti-Metastasis Therapy.

Metastasis is a pathogenic spread of cancer cells from the primary site to surrounding tissues and distant organs, making it one of the primary challenges for effective cancer treatment and the major cause of cancer mortality. Heparin-based biomaterials exhibit significant inhibition of cancer cell metastasis. In this study, a non-anticoagulate heparin prodrug is developed for metastasis treatment with a localized treatment system using temperature sensitive, injectable, and biodegradable (poly-(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide) polymeric hydrogel. The drug molecule (heparin) is conjugated with the polymer via esterification, and its sustained release is ensured by hydrolysis and polymeric biodegradation. An aqueous solution of the polymer could be used as an injectable solution at below 25 °C and it achieves gel formation at 37 °C. The anti-metastasis effect of the hydrogels is investigated both in vitro and in vivo. The results demonstrated that local administration of injectable heparin-loaded hydrogels effectively promote an inhibitory effect on cancer metastasis.

Mixed Lanthanide Oxide Nanoparticles Coated with Alginate-Polydopamine as Multifunctional Nanovehicles for Dual Modality: Targeted Imaging and Chemotherapy.

Integrating anticancer drugs and diagnostic agents in a polymer nanosystem is an emerging and promising strategy for improving cancer treatment. However, the development of multifunctional nanoparticles (NPs) for an "all-in-one" platform characterized by specific targeting, therapeutic efficiency, and imaging feedback remains an unmet clinical need. In this study, pH-responsive mixed-lanthanide-based multifunctional NPs were fabricated based on simple metal-ligand interactions for simultaneous cancer cell imaging and drug delivery. We investigated two new systems of alginate-polydopamine complexed with either terbium/europium or dysprosium/erbium oxide NPs (Tb/Eu@AlgPDA or Dy/Er@AlgPDA NPs). Tb/Eu@AlgPDA NPs were then functionalized with the tumor-targeting ligand folic acid (FA) and loaded with the anticancer drug doxorubicin (DOX) to form FA-Tb/Eu@AlgPDA-DOX NPs. Using such systems, the mussel-inspired property of PDA was introduced to improve tumor targetability and penetration, in addition to active targeting (via FA-folate receptor interactions). Determining the photoluminescence efficiency showed that the Tb/Eu@AlgPDA system was superior to the Dy/Er@AlgPDA system, presenting intense and sharp emission peaks on the fluorescence spectra. In addition, compared to Dy/Er@AlgPDA NPs (82.4%), Tb/Eu@AlgPDA NPs exhibited negligible cytotoxicity with >93.3% HeLa cell viability found in MTT assays at NP concentrations of up to 0.50 mg/mL and high biocompatibility when incubated with zebrafish (Danio rerio) embryos and larvae. The FA-Tb/Eu@AlgPDA-DOX system exhibited a pH-responsive and sustained drug-release pattern. In a spheroid model of HeLa cells, the FA-Tb/Eu@AlgPDA-DOX system showed a better penetration efficiency and spheroid growth-inhibitory effect than free DOX. After incubation with zebrafish embryos, the FA-Tb/Eu@AlgPDA-DOX system also showed improved antitumor efficacies versus the other experimental groups in HeLa tumor cell xenografted zebrafish. Therefore, our results suggested that FA-Tb/Eu@AlgPDA-DOX NPs are promising multifunctional nanocarriers with therapeutic capacity for tumor targeting and penetration.

Potential fluorescence and magnetic resonance imaging modality using mixed lanthanide oxide nanoparticles.

Imaging is a very important technique in the diagnosis and treatment of cancer diseases. This study developed a dual modality (fluorescence/MR) imaging technique for cancer cell lines (HeLa) and T2-weighted phantom imaging by using a mixed lanthanide (Dy/Er/Tb) oxide nanoparticles. To further enhance the solubility, stability and biocompatibility of mixed lanthanide oxide, the nanoparticles were coated with folic acid as well as G4.5 PAMAM dendrimer. The coated nanoparticles were then compared, the later with results demonstrating pronounced effects in both T2 weighted phantom MR and fluorescence imaging of the cancer cell lines. Imaging enhancement was attributed to a synergistic effect of the fluorescent properties and higher water solubility of the PAMAM dendrimer when compared to the folic acid. Besides, mixed lanthanides of Dy and Tb were used for T2 weighted MR imaging, while mixed lanthanides of Er and Tb were used for fluorescence imaging in the near infrared and visible regions, and were synthesized in the facile composition control. Hence, the mixed lanthanide oxides are packed together, and stable, which is used to facilitate biomedical imaging in vitro. To conclude, the G4.5 PAMAM dendrimer coated mixed lanthanide oxide nanoparticles will be used for dual-modality (fluorescence/MR imaging) cancer cell line detection in both in vitro and in vivo study.

Bioinspired, Manganese-Chelated Alginate-Polydopamine Nanomaterials for Efficient in Vivo T1-Weighted Magnetic Resonance Imaging.

Manganese-based nanomaterials are an emerging new class of magnetic resonance imaging (MRI) contrast agents (CAs) that provide impressive contrast abilities. MRI CAs that can respond to pathophysiological parameters such as pH or redox potential are also highly in demand for MRI-guided tumor diagnosis. Until now, synthesizing nanomaterials with good biocompatibility, physiochemical stability, and good contrast effects remains a challenge. This study investigated two new systems of calcium/manganese cations complexed with either alginate-polydopamine or alginate-dopamine nanogels [AlgPDA(Ca/Mn) NG or AlgDA(Ca/Mn) NG]. Under such systems, Ca cations form ionic interactions via carboxylic acids of the Alg backbone to enhance the stability of the synthetic nanogels (NGs). Likewise, complexation of Mn cations also increased the colloidal stability of the synthetic NGs. The magnetic property of the prepared CAs was confirmed with superconducting quantum interference device measurements, proving the potential paramagnetic property. Hence, the T1 relaxivity measurement showed that PDA-complexed synthetic NGs reveal a strong positive contrast enhancement with r1 = 12.54 mM-1·s-1 in 7.0 T MRI images, whereas DA-complexed synthetic NGs showed a relatively lower T1 relaxivity effect with r1 = 10.13 mM-1·s-1. In addition, both the synthetic NGs exhibit negligible cytotoxicity with >92% cell viability up to 0.25 mM concentration, when incubated with the mouse macrophage (RAW 264.7) and HeLa cells, and high biocompatibility under in vivo analysis. The in vivo MRI test indicates that the synthetic NG exhibits a high signal-to-noise ratio for longer hours, which provides a longer image acquisition time for tumor and anatomical imaging. Furthermore, T1-weighted MRI results revealed that PEGylated AlgPDA(Ca/Mn) NGs significantly enhanced the signals from liver and tumor tissues. Therefore, owing to the enhanced permeability and retention effect, significantly enhanced in vitro and in vivo imagings, low cost, and one-pot synthesis method, the Mn-based biomimetic approach used in this study provides a promising and competitive alternative for noninvasive tumor detection and comprehensive anatomical diagnosis.