CD44 tagged hyaluronic acid - chitosan liposome carrier for the delivery of berberine and doxorubicin into lung cancer cells.

Liposomes are unique biomolecular, capable of loading both hydrophilic and hydrophobic molecules and delivered into the biological system. Liposomes (L) coated with hyaluronic acid (HA) and chitosan (CS) carrier system was fabricated. Berberine (BER) and doxorubicin (DOX) were encapsulated to enhance drug proliferation and therapeutic effect in lung cancer cells. The FTIR, XRD, SEM, and TEM techniques were carried out for functional group identification, crystallinity, and surface morphology analysis, respectively. In-vitro drug release confirms the sustained release of BER and DOX in various physiological environments. HA-CS@BER&DOX-L has good penetration ability and higher cytotoxicity effect in the A549 cells, and the IC50 value of HA-CS@BER&DOX-L is 89.19 µg/300 µL. The pure liposome showed a negligible cytotoxicity effect, and the HA-CS@BER&DOX-L could efficiently induce the apoptosis of A549 cells. The cellular uptake analysis of the HA-CS@BER&DOX-L effectively targeted and entered the A549 cells and clearly observed C. elegans images. Hence, the proposed system will be a potential treatment methodology to enhance the cytotoxicity of the A549 cancer cells and be useful to future drug administration methodology development.

Engineered Hyaluronic Acid-Based Smart Nanoconjugates for Enhanced Intracellular Drug Delivery.

Bacterial polysaccharides can be easily modified to offer dual stimuli-responsive drug delivery systems with double targeting potential. In this research work, bacterial polysaccharides hyaluronic acid (HA) were functionalized with α-tocopherol polyethylene glycol succinate (TPGS) and cholic acid (CA) to form multifunctional polysaccharides nanoconjugates (TPGS-HA-CA). Smart nanoconjugates were synthesized by forming a redox-responsive disulfide bond, and it is composed of double targeting ligands. Doxorubicin (DOX) encapsulated smart nanoconjugates were exhibited an average size of 200 nm with a uniform core-shell structure. It serves the pH-responsive side chain modulation of TPGS-HA-CA, which affords a high degree of swelling at acidic pH. Under the pH 5.0 it shows 57% of release due to the side chain modulation of C-H/N-H. Polysaccharides nanoconjugates exhibited the double stimuli-responsive drug delivery by rapid disassembly of disulfide linkage, which exhibited 72% drug release (pH 5.0+GSH 10 mM). In cytotoxic studies, DOX@TPGS-HA-CA exhibited a higher cytotoxic effect compared to DOX. Hyaluronic acid functionalization with CA, TPGS increases cell internalization, and dual stimuli activity promotes more cell death. Overall, multifunctional polysaccharides hydrogel nanoconjugates is a prospective material that has great potential for targeting breast cancer therapy.

Synergistic effect of polymer functionalized graphene oxide system for breast cancer treatment.

The multifaceted drug carrier system is an emerging trend in delivering chemotherapeutic drugs and photosensitizers for the synergistic effect. In this work, we have designed a functionalized graphene oxide (GO) based carrier system for combined chemo-photodynamic therapeutic effects. Doxorubicin (DOX) and rose bengal (RB) were entrapped on the surface of GO via hydrophobic and π-π stacking interactions. The functional group determination, crystalline properties, surface morphology, and hydrodynamic size were evaluated using FT-IR, XRD, SEM, TEM, AFM, and DLS analysis. At 24 h, the entrapment efficiency was 65 % DOX and 40.92 % RB, and the loading capacities were 16.9 % DOX and 5.68 % RB observed at 30 min. The drug release percentage was higher in pH-2.6 rather than in pH-5.5, 6.8, and 7.4 pH environments. The in-vitro toxicity analysis using the LDH assay reveals that the DOX and RB co-loaded carriers had a significant cytotoxic effect on MCF-7 cells, indicating that the carrier could improve the therapeutic efficacy of DOX. Morphological changes were studied using inverted light microscopy; the cells were irradiated with a laser 525 nm 10 J/cm2 for 2 min 51 sec, and it was observed that the DOX and RB co-loaded carrier with laser-irradiated cells exposed the high-level morphological changes with the occurrence of apoptotic cell death. Compared to free DOX, the DOX/RB co-loaded carrier + laser had an efficient anticancer activity, as confirmed by DAPI staining cell uptake, flow cytometry, and intracellular ROS generation analysis. The DOX and RB co-loaded carrier clearly exhibits the RB-mediated photodynamic action on MCF-7 cells in response to external laser light irradiation. It permits an on-demand dual-payload release to trigger an instantaneous photodynamic and chemo treatment for cancer cell eradication. Finally, the ensuing dual-agent release is probable to successfully fight cancer via a synergistic effect.

Retraction of "Cisplatin-Loaded Graphene Oxide/Chitosan/Hydroxyapatite Composite as a Promising Tool for Osteosarcoma-Affected Bone Regeneration".

[This retracts the article DOI: 10.1021/acsomega.8b02090.].

Matrix Metalloproteinases in Chemoresistance: Regulatory Roles, Molecular Interactions, and Potential Inhibitors.

Cancer is one of the major causes of death worldwide. Its treatments usually fail when the tumor has become malignant and metastasized. Metastasis is a key source of cancer recurrence, which often leads to resistance towards chemotherapeutic agents. Hence, most cancer-related deaths are linked to the occurrence of chemoresistance. Although chemoresistance can emerge through a multitude of mechanisms, chemoresistance and metastasis share a similar pathway, which is an epithelial-to-mesenchymal transition (EMT). Matrix metalloproteinases (MMPs), a class of zinc and calcium-chelated enzymes, are found to be key players in driving cancer migration and metastasis through EMT induction. The aim of this review is to discuss the regulatory roles and associated molecular mechanisms of specific MMPs in regulating chemoresistance, particularly EMT initiation and resistance to apoptosis. A brief presentation on their potential diagnostic and prognostic values was also deciphered. It also aimed to describe existing MMP inhibitors and the potential of utilizing other strategies to inhibit MMPs to reduce chemoresistance, such as upstream inhibition of MMP expressions and MMP-responsive nanomaterials to deliver drugs as well as epigenetic regulations. Hence, manipulation of MMP expression can be a powerful tool to aid in treating patients with chemo-resistant cancers. However, much still needs to be done to bring the solution from bench to bedside.

Enhanced Doxorubicin Delivery in Folate-Overexpressed Breast Cancer Cells Using Mesoporous Carbon Nanospheres.

Nanoparticle-based drug delivery reveals the safety and effectiveness and avoids premature drug release from the nanocarrier. These nanoparticles improve the bioavailability and stability of the drug against chemical and enzymatic degradation and facilitate targeted drug delivery. Herein, targeted folic acid-conjugated oxidized mesoporous carbon nanospheres (Ox-MPCNPs) were successfully fabricated and developed as antitumoral doxorubicin delivery for targeted breast cancer therapy. Fourier transform infrared spectroscopy studies confirmed that the doxorubicin was successfully bound on the Ox-MPCNP through hydrogen bonding and π-π interactions. X-ray diffraction studies showed that the synthesized doxorubicin-loaded Ox-MPCNP is semi-crystalline. The surface morphology of the synthesized doxorubicin-loaded Ox-MPCNP (DOX/Ox-MPCNP-Cys-PAsp-FA) was studied by scanning electron microscopy and high-resolution transmission electron microscopy, which demonstrates a sphere-shaped morphology. The cytotoxic effects of DOX/Ox-MPCNP-Cys-PAsp-FA were studied in MCF-7 breast cancer cells using the CytoTox96 assay kit. The study confirmed the cytotoxic effects of the synthesized nanospheres in vitro. Moreover, DOX/Ox-MPCNP-Cys-PAsp-FA-treated cells displayed efficient cell apoptosis and cell death in flow cytometry analysis. The mitochondrial fragmentation and nucleus damages were further confirmed by fluorescence microscopy. Thus, the approach used to construct the DOX/Ox-MPCNP-Cys-PAsp-FA carrier provides excellent opportunities for the targeted treatment of breast cancer.

Natural Drug-Loaded Bimetal-Substituted Hydroxyapatite-Polymeric Composite for Osteosarcoma-Affected Bone Repair.

Repairing segmental bone deformities after resection of dangerous bone tumors is a long-standing clinical issue. The study's main objective is to synthesize a natural bioactive compound-loaded bimetal-substituted hydroxyapatite (BM-HA)-based composite for bone regeneration. The bimetal (copper and cadmium)-substituted HAs were prepared by the sol-gel method and reinforced with biocompatible polyacrylamide (BM-HA/PAA). Umbelliferone (UMB) drug was added to the BM-HA/PAA composite to enhance anticancer activity further. The composite's formation was confirmed by various physicochemical investigations, such as FT-IR, XRD, SEM, EDAX, and HR-TEM techniques. The bioactivity was assessed by immersing the sample in simulated body fluid for 1, 3, and 7 days. The zeta potential values of BM-HA/PAA and BM-HA/PAA/UMB are -36.4 mV and -49.4 mV, respectively. The in vitro viability of the prepared composites was examined in mesenchymal stem cells (MSCs). It shows the ability of the composite to produce osteogenic bone regeneration without any adverse effects. From the gene expression and PCR results, the final UMB-loaded composite induced osteogenic markers, such as Runx, OCN, and VEFG. The prepared bimetal substituted polyacrylamide reinforced HA composite loaded with UMB drug has the ability for bone repair/regenerations.

Fabrication of substituted hydroxyapatite-starch-clay bio-composite coated titanium implant for new bone formation.

The clay/polymeric matrices have much attention from researchers in bio-medical applications due to their numerous uses. This study introduces new orthopedic titanium (Ti) implant with increasing bio-activity by treating the surface of the Ti implant with bio-compatible composite coating. Wollastonite (WST) clay combined minerals (Mg2+and Gd3+) substituted hydroxyapatite (HAP)/Starch composite was prepared using in-situ co-precipitation method. It was successfully coated on the orthopedic grade Ti plate by the Electrophoretic Deposition (EPD) method. The functionality, phase, morphology, and bio-activity analysis of the composite were evaluated by FT-IR, XRD, HR-TEM, and SEM analysis, respectively. The mechanical property, i.e., Vickers microhardness value of the MHAP/Starch/WST composite coated Ti plate, showed 242 ± 1.92 Hv. The in-vitro MG-63 osteoblast cells viability, differentiation, and Ca mineralization of MHAP/Starch/WST composite suggests that this new implant will be used for bone regeneration application after careful evaluation of in-vivo and clinical studies.

Correction to Cisplatin-Loaded Graphene Oxide/Chitosan/Hydroxyapatite Composite as a Promising Tool for Osteosarcoma-Affected Bone Regeneration.

[This corrects the article DOI: 10.1021/acsomega.8b02090.].

A promising drug delivery candidate (CS-g-PMDA-CYS-fused gold nanoparticles) for inhibition of multidrug-resistant uropathogenic Serratia marcescens.

Antibiotic resistance amongst microbial pathogens is a mounting serious issue in researchers and physicians. Various alternatives to overcome the multidrug-resistant bacterial infections are under search, and biofilm growth inhibition is one of them. In this investigation, a polymeric drug delivery system loaded with multi-serratial drugs to improve the delivery of drugs against urinary tract infection causative Serratia marcescens. The chitosan grafted pyromellitic dianhydride - cysteine (CS-g-PMDA-CYS) was conjugated with AuNPs by using the -SH group of CYS and RF (rifampicin) and INH (isoniazid) were loaded in AuNPs-fused CS-g-PMDA-CYS system. Several physicochemical techniques characterized this fabricated AuNPs/RF/INH/CS-g-PMDA-CYS system. The successful encapsulation of RF and INH in AuNPs-fused CS-g-PMDA-CYS polymer had confirmed, and it observed the loading capacity for RF and INH was 9.02% and 13.12%, respectively. The in vitro drug discharge pattern was perceived high in pH 5.5 compared with pH 7.4. The AuNPs/RF/INH/CS-g-PMDA-CYS escalates 74% of Caenorhabditis elegans survival during Serratia marcescens infection by aiming biofilm development and virulence in S. marcescens. Author postulate that the fabricated system is a promising drug carrier and delivery system for inhibition of multidrug-resistant bacterias like S. marcescens.

Combined photodynamic-chemotherapy investigation of cancer cells using carbon quantum dot-based drug carrier system.

The combined chemotherapy and photodynamic therapy have significant advantages for cancer treatments, which have higher therapeutic effects compared with other medicines. Herein, we focused on the synthesis of carbon quantum dot (CQD) based nanocarrier system. CQD and 5-aminolevulinic acid (5-ALA) were conjugated with mono-(5-BOC-protected-glutamine-6-deoxy) ß-cyclodextrin (CQD-Glu-ß-CD) moiety, and finally, the anticancer chemotherapy doxorubicin (DOX) drug was loaded in the 5-ALA-CQD-Glu-ß-CD system. The stepwise physicochemical changes for the preparation of the DOX loaded 5-ALA-CQD-Glu-ß-CD system were investigated by Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), transmission electron microscopy (TEM), atomic force microscopy (AFM), and Raman fluorescence spectroscopy. The encapsulation efficiency of DOX in 5-ALA-CQD-Glu-ß-CD was observed at ∼83.0%, and the loading capacity of DOX is ∼20.37%. The in vitro releasing of DOX and 5-ALA was observed through the UV-vis spectroscopy by the λmax value of 487 nm and 253 nm, respectively. By the investigation against the breast MCF-7 cancer cells, the high cytotoxicity and morphological changes of cancer cells were observed by the treating of DOX/5-ALA-CQD-Glu-ß-CD. The generation of reactive oxygen species (ROS) upon 635 nm (25 mW cm-2) for 15 min laser irradiation-induced improved the therapeutic effects. In vitro cellular uptake studies recommend the synthesized DOX/5-ALA-CQD-Glu-ß-CD nanocarrier could significantly enhance the cell apoptosis and assist in the MCF-7 cell damages. The result suggests a multifunctional therapeutic system for chemo/photodynamic synergistic effects on cancer therapy.

Natural deep eutectic solvent supported targeted solid-liquid polymer carrier for breast cancer therapy.

Solid-liquid nanocarriers (SLNs) are at the front of the rapidly emerging field of medicinal applications with a potential role in the delivery of bioactive agents. Here, we report a new SLN of natural deep eutectic solvent (NADES) and biotin-conjugated lysine-polyethylene glycol copolymer. The SLN system was analyzed for its functional groups, thermal stability, crystalline nature, particle size, and surface morphology through the instrumental analysis of FT-IR, TGA, XRD, DLS, SEM, and TEM. Encapsulation of PTX (paclitaxel) and 7-HC (7-hydroxycoumarin) with the SLN was carried out by dialysis, and UV-visible spectra evidenced the drug loading capacity and higher encapsulation efficiency obtained. The enhanced anticancer potential of PTX- and 7-HC-loaded SLN was assessed in vitro, and the system reduces the cell viability of MDA-MB-231 cells. The PTX- and 7-HC-loaded SLN system was investigated in a breast cancer-induced rat model via in vivo studies. It shows decreased lysosomal enzymes and increased levels of caspase to cure breast tumors. It very well may be reasoned that the designed PTX- and 7-HC-loaded SLN system has strong anticancer properties and exhibits potential for delivery of drug molecules in cancer treatment.

In Vivo Assessment of a Hydroxyapatite/κ-Carrageenan-Maleic Anhydride-Casein/Doxorubicin Composite-Coated Titanium Bone Implant.

Here, we focus on the fabrications of an osteosarcoma implant for bone repair via the development of a hydroxyapatite/κ-carrageenan-maleic anhydride/casein with doxorubicin (HAP/κ-CA-MA-CAS/DOX) composite-deposited titanium (Ti) plate. The HAP/κ-CA-MA-CAS/DOX material was coated on the Ti plate through the EPD method (electrophoretic deposition), applying direct current (DC) signals to deposit the composite on the surface of the Ti plate. The physicochemical and morphological possessions and biocompatibility in vitro of the prepared nanocomposite were examined to assess its prospective effectiveness for purposes of bone regeneration. Excellent biocompatibility and elevated osteoconductivity were confirmed using MG63 osteoblast-like cells. In vivo studies were performed at tibia sites in Wistar rats, and rapid bone regeneration was detected at four weeks in defective bone. Overall, the studies demonstrate that the HAP/κ-CA-MA-CAS/DOX composite enhances the biocompatible and cell-stimulating biointerface of Ti metallic implants. As such, HAP/κ-CA-MA-CAS/DOX implants are viable prospects for osteosarcoma-affected bone regeneration.

Fabrication of bioactive rifampicin loaded κ-Car-MA-INH/Nano hydroxyapatite composite for tuberculosis osteomyelitis infected tissue regeneration.

Biocompatible polymers and ceramic materials have been identified as vital components to fabricate drug delivery and tissue engineering applications because of their high drug loading capability, sustained release and higher mechanical strength with remarkable in-vivo bioavailability. In the present work, initially we designed κ-carrageenan grafted with maleic anhydride and then reacted it with isoniazid drug (κ-Car-MA-INH). The polymeric system was cross linked with nanohydroxyapatite (NHAP) via electrostatic interaction followed by the addition of rifampicin (RF) and loaded to fabricate κ -Car-MA-INH/NHAP/RF nanocomposites. The chemical modification and interaction of drug with the polymeric-ceramic system were characterised by Fourier Transform Infrared spectroscopy (FT-IR). The zeta potential of the κ -Car-MA-INH/NHAP/RF nanocomposite was observed to be -20.04 mV using Zetasizer. The in vitro drug release studies demonstrated that the nanocomposite releases 76% of RF and 82% of INH in 12 days at pH 5.5. Scanning Electron Microscope analysis revealed the structural deformation of Staphylococcus aureus and Klebsiella pneumoniae upon treatment with this nanocomposite. By using ex-vivo studies combined with physio-chemical characterization methods on the erythrocytes, L929 and MG-63 cell lines, this composite was found to be biocompatible, non-cytotoxic and inducing cell proliferation with less significant hemolysis. Thus, our modified drug delivery nanocomposites afforded higher drug bioavailability with large potential for fabrication as long-acting drug delivery nanocomposites, especially with hydrophobic drugs inducing the growth of osteoblastic bone cells.

Development of biotin molecule targeted cancer cell drug delivery of doxorubicin loaded κ-carrageenan grafted graphene oxide nanocarrier.

Cervical cancer is one of the most occurring cancers and the fourth leading occurrence of cancer in women, worldwide. In this study, we planned to synthesis κ-Carrageenan grafted graphene oxide nanocarrier conjugated with biotin (GO-κ-Car-biotin) for targeted cervical cancer. Doxorubicin (DOX) is a well-known anticancer drug for any type of cancer and it is used to entrap over on the graphene oxide surface via π-π stacking interaction. The chemical function and crystalline nature of the synthesized nanocarrier was characterized by Fourier Transformed Infrared Spectroscopy (FT-IR) and X-ray diffraction Analysis (XRD). The surface morphological study was carried out through Scanning Electron Microscopy (SEM), Transmission electron microscopy (TEM) and Atomic force microscopy (AFM). The in-vitro drug release profile of DOX was carried out by UV-Vis spectrometer at the λmax value of 480 nm. The entrapment of DOX on GO-κ-car-biotin has been observed at 94%. The hydrophilic DOX drug has excellent pH-sensitive drug released in an in-vitro study. The anticancer efficiency of the synthesized GO-based nanocarrier was examined using HeLa cell line in-vitro. Cell viability, proliferation, cytotoxicity, and nuclear chromatin condensation was studied by trypan blue assay, triphosphate assay (ATP), lactate dehydrogenase assay (LDH) and Hoechst staining respectively. Finally, biotin leading GO-κ-Car carrier demonstrated is a promising drug delivery system for cervical cancer treatment.

Folate receptor targeted delivery of paclitaxel to breast cancer cells via folic acid conjugated graphene oxide grafted methyl acrylate nanocarrier.

The adaptability, joint with a large surface area, electronic flexibility, high intrinsic mobility, high mechanical strength and supreme thermal conductivity have condensed graphene family materials attractive as technological tools of the drug delivery system. In this present study, investigate a modified graphene oxide-methyl acrylate (GO-g-MA) nanocarrier for targeted anti-cancer drug delivery in breast cancer cells and the GO-g-MA fascinated with folic acidas a targeting ligand to target the cancer cells. Paclitaxel (PTX) was assembled through π-π stacking, hydrophophic interaction on the surface of the GO-g-MA/FA carrier. Structural modification of GO-g-MA, functionalization of targeting ligands GO-g-MA/FA and drug loaded GO-g-MA/FA-PTX was characterized and confirmed through FTIR, XRD, SEM,TEM and AFM analysis. The in-vitro drug release pattern of PTX from the GO-g-MA/FA was examined in different pH ranges. An MTT assay was performed to evaluate the cytotoxicity behaviour of the carrier and PTX loaded nanocarrier in the human breast cancer cell line (MDA-MB-231). GO-g-MA/FA-PTX carrier showed that 39% of cytotoxic effect. Furthermore, the in-vivo (DMBA induced breast cancer rats) studies were carried out and treatment with PTX- loaded GO-g-MA/FA nanocarrier attenuates the levels of mitochondrial citric acids enzymes to near normal.

Cisplatin-Loaded Graphene Oxide/Chitosan/Hydroxyapatite Composite as a Promising Tool for Osteosarcoma-Affected Bone Regeneration.

Presently, tissue engineering approaches have been focused toward finding new potential scaffolds with osteoconductivity on bone-disease-affected cells. This work focused on the cisplatin (CDDP)-loaded graphene oxide (GO)/hydroxyapatite (HAP)/chitosan (CS) composite for enhancing the growth of osteoblast cells and prevent the development of osteosarcoma cells. The prepared composites were characterized for the confirmation of composite formation using Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, and X-ray diffraction techniques. A flowerlike morphology was observed for the GO/HAP/CS-3/CDDP composite. UV-vis spectroscopy was used to observe the controlled release of CDDP from the GO/HAP/CS-3/CDDP composite, and 67.34% of CDDP was released from the composite over a time period of 10 days. The GO/HAP/CS-3/CDDP nanocomposites showed higher viability in comparison with GO/HAP/CS-3 on MG63 osteoblast-like cells and higher cytotoxicity against cancer cells (A549). The synthesized composite was found to show enhanced proliferative, adhesive, and osteoinductive effects on the alkaline phosphatase activity of osteoblast-like cells. Our results suggested that the CDDP-loaded GO/HAP/CS-3 nanocomposite has an immense prospective as a bone tissue replacement in the bone-cancer-affected tissues.

Modulatory and regenerative potential of transplanted bone marrow-derived mesenchymal stem cells on rifampicin-induced kidney toxicity.

INTRODUCTION: Anti-tuberculosis agent rifampicin is extensively used for its effectiveness. Possible complications of tuberculosis and prolonged rifampicin treatment include kidney damage; these conditions can lead to reduced efficiency of the affected kidney and consequently to other diseases. Bone marrow-derived mesenchymal stem cells (BMMSCs) can be used in conjunction with rifampicin to avert kidney damage; because of its regenerative and differentiating potentials into kidney cells. This research was designed to assess the modulatory and regenerative potentials of MSCs in averting kidney damage due to rifampicin-induced kidney toxicity in Wistar rats and their progenies. BMMSCs used in this research were characterized according to the guidelines of International Society for Cellular Therapy. METHODS: The rats (male and female) were divided into three experimental groups, as follows: Group 1: control rats (4 males & 4 females); Group 2: rats treated with rifampicin only (4 males & 4 females); and Group 3: rats treated with rifampicin plus MSCs (4 males & 4 females). Therapeutic doses of rifampicin (9 mg/kg/day for 3-months) and MSCs infusions (twice/month for 3-months) were administered orally and intravenously respectively. At the end of the three months, the animals were bred together to determine if the effects would carry over to the next generation. Following breeding, the rats were sacrificed to harvest serum for biochemical analysis and the kidneys were also harvested for histological analysis and quantification of the glomeruli size, for the adult rats and their progenies. RESULTS: The results showed some level of alterations in the biochemical indicators and histopathological damage in the rats that received rifampicin treatment alone, while the control and stem cells treated group showed apparently normal to nearly normal levels of both bio-indicators and normal histological architecture. CONCLUSIONS: Intravenous administration of MSCs yielded sensible development, as seen from biochemical indicators, histology and the quantitative cell analysis, hence implying the modulatory and regenerative properties of MSCs.