Advancing Cancer Therapy with Copper/Disulfiram Nanomedicines and Drug Delivery Systems.

Disulfiram (DSF) is a thiocarbamate based drug that has been approved for treating alcoholism for over 60 years. Preclinical studies have shown that DSF has anticancer efficacy, and its supplementation with copper (CuII) significantly potentiates the efficacy of DSF. However, the results of clinical trials have not yielded promising results. The elucidation of the anticancer mechanisms of DSF/Cu (II) will be beneficial in repurposing DSF as a new treatment for certain types of cancer. DSF's anticancer mechanism is primarily due to its generating reactive oxygen species, inhibiting aldehyde dehydrogenase (ALDH) activity inhibition, and decreasing the levels of transcriptional proteins. DSF also shows inhibitory effects in cancer cell proliferation, the self-renewal of cancer stem cells (CSCs), angiogenesis, drug resistance, and suppresses cancer cell metastasis. This review also discusses current drug delivery strategies for DSF alone diethyldithocarbamate (DDC), Cu (II) and DSF/Cu (II), and the efficacious component Diethyldithiocarbamate-copper complex (CuET).

Clinical outcomes of chemotherapy in cancer patients with different ethnicities.

BACKGROUND: Choosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti-cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup. RECENT FINDINGS: Pharmacogenomics, the study of how an individual's genes impact the processing and action of a drug, can optimize drug responsiveness and reduce toxicities by creating a customized medication regimen. However, these differences are rarely considered in the initial determination of standardized chemotherapeutic protocols and treatment algorithms. Because pharmacoethnicity is influenced by both genetic and nongenetic variables, clinical data highlighting disparities in the frequency of polymorphisms between different ethnicities is steadily growing.  Recent data suggests that ethnic variations in the expression of allelic variants may result in different pharmacokinetic properties of the anti-cancer medication. In this article, the clinical outcomes of various chemotherapy classes in patients of different ethnicities were reviewed. CONCLUSION: Genetic and nongenetic variables contribute to the interindividual variability in response to chemotherapeutic drugs. Considering pharmacoethnicity in the initial determination of standard chemotherapeutic protocols and treatment algorithms can lead to better clinical outcomes of patients of different ethnicities.

Liposomal DQ in Combination with Copper Inhibits ARID1A Mutant Ovarian Cancer Growth.

Therapeutic strategies for ARID1A-mutant ovarian cancers are limited. Higher basal reactive oxygen species (ROS) and lower basal glutathione (GSH) empower the aggressive proliferation ability and strong metastatic property of OCCCs, indicated by the increased marker of epithelial-mesenchymal transition (EMT) and serving the immunosuppressive microenvironment. However, the aberrant redox homeostasis also empowers the sensitivity of DQ-Lipo/Cu in a mutant cell line. DQ, a carbamodithioic acid derivative, generates dithiocarbamate (DDC) in response to ROS, and the chelation of Cu and DDC further generates ROS and provides a ROS cascade. Besides, quinone methide (QM) released by DQ targets the vulnerability of GSH; this effect, plus the increase of ROS, destroys the redox homeostasis and causes cancer cell death. Also importantly, the formed Cu(DDC)2 is a potent cytotoxic anti-cancer drug that successfully induces immunogenic cell death (ICD). The synergistic effect of EMT regulation and ICD will contribute to managing cancer metastasis and possible drug resistance. In summary, our DQ-Lipo/Cu shows promising inhibitory effects in cancer proliferation, EMT markers, and "heat" the immune response.

Topical Delivery of Diacetyl Boldine in a Microemulsion Formulation for Chemoprotection against Melanoma.

This study aimed to develop a microemulsion formulation for topical delivery of Diacetyl Boldine (DAB) and to evaluate its cytotoxicity against melanoma cell line (B16BL6) in vitro. Using a pseudo-ternary phase diagram, the optimal microemulsion formulation region was identified, and its particle size, viscosity, pH, and in vitro release characteristics were determined. Permeation studies were performed on excised human skin using Franz diffusion cell assembly. The cytotoxicity of the formulations on B16BL6 melanoma cell lines was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay. Two formulation compositions were selected based on the higher microemulsion area of the pseudo-ternary phase diagrams. The formulations showed a mean globule size of around 50 nm and a polydispersity index of <0.2. The ex vivo skin permeation study demonstrated that the microemulsion formulation exhibited significantly higher skin retention levels than the DAB solution in MCT oil (Control, DAB-MCT). Furthermore, the formulations showed substantially higher cytotoxicity toward B16BL6 cell lines than the control formulation (p < 0.001). The half-maximal inhibitory concentrations (IC50) of F1, F2, and DAB-MCT formulations against B16BL6 cells were calculated to be 1 µg/mL, 10 µg/mL, and 50 µg/mL, respectively. By comparison, the IC50 of F1 was 50-fold lower than that of the DAB-MCT formulation. The results of the present study suggest that microemulsion could be a promising formulation for the topical administration of DAB.

Hispolon Cyclodextrin Complexes and Their Inclusion in Liposomes for Enhanced Delivery in Melanoma Cell Lines.

Hispolon, a phenolic pigment isolated from the mushroom species Phellinus linteus, has been investigated for anti-inflammatory, antioxidant, and anticancer properties; however, low solubility and poor bioavailability have limited its potential clinical translation. In this study, the inclusion complex of hispolon with Sulfobutylether-ß-cyclodextrin (SBEßCD) was characterized, and the Hispolon-SBEßCD Complex (HSC) was included within the sterically stabilized liposomes (SL) to further investigate its anticancer activity against melanoma cell lines. The HSC-trapped-Liposome (HSC-SL) formulation was investigated for its sustained drug delivery and enhanced cytotoxicity. The inclusion complex in the solid=state was confirmed by a Job's plot analysis, molecular modeling, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), Proton nuclear magnetic resonance (NMR) spectroscopy, and scanning electron microscopy (SEM). The HSC-SL showed no appreciable deviation in size (<150 nm) and polydispersity index (<0.2) and improved drug encapsulation efficiency (>90%) as compared to control hispolon liposomes. Individually incorporated hispolon and SBEßCD in the liposomes (H-CD-SL) was not significant in loading the drug in the liposomes, compared to HSC-SL, as a substantial amount of free drug was separated during dialysis. The HSC-SL formulation showed a sustained release compared to hispolon liposomes (H-SLs) and Hispolon-SBEßCD liposomes (H-CD-SLs). The anticancer activity on melanoma cell lines (B16BL6) of HSC and HSC-SL was higher than in H-CD-SL and hispolon solution. These findings suggest that HSC inclusion in the HSC-SL liposomes stands out as a potential formulation approach for enhancing drug loading, encapsulation, and chemotherapeutic efficiency of hispolon and similar water insoluble drug molecules.

Cardiolipin for Enhanced Cellular Uptake and Cytotoxicity of Thermosensitive Liposome-Encapsulated Daunorubicin toward Breast Cancer Cell Lines.

Daunorubicin (DNR) and cardiolipin (CL) were co-delivered using thermosensitive liposomes (TSLs). 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine (MSPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] or DSPE-mPEG (2000) and CL were used in the formulation of liposomes at a molar ratio of 57:40:30:3:20, respectively. CL forms raft-like microdomains that may relocate and change lipid organization of the outer and inner mitochondrial membranes. Such transbilayer lipid movement eventually leads to membrane permeabilization. TSLs were prepared by thin-film hydration (drug:lipid ratio 1:5) where DNR was encapsulated within the aqueous core of the liposomes and CL acted as a component of the lipid bilayer. The liposomes exhibited high drug encapsulation efficiency (>90%), small size (~115 nm), narrow size distribution (polydispersity index ~0.12), and a rapid release profile under the influence of mild hyperthermia. The liposomes also exhibited ~4-fold higher cytotoxicity against MDA-MB-231 cells compared to DNR or liposomes similar to DaunoXome® (p < 0.001). This study provides a basis for developing a co-delivery system of DNR and CL encapsulated in liposomes for treatment of breast cancer.

Development and evaluation of a novel topically applied sildenafil citrate hydrogel and its influence on wound healing in dogs.

OBJECTIVE: To develop a topical sildenafil hydrogel and evaluate its effect on wound healing in dogs. ANIMALS: 6 purpose-bred, sexually intact, adult Beagles. PROCEDURES: Hydrogels containing sildenafil citrate, N-methyl-2-pyrrolidone, propylene glycol, and poloxamer 407 were developed. Four excision wounds were created along the dorsum of the dogs. Each wound was treated for 21 days with a nonadherent bandage (C) or with a hydrogel containing 0% (G), 5% (5S), or 10% (10S) sildenafil. Daily bandage changes with wound imaging were performed. Biopsy specimens were collected 5 times. RESULTS: Hydrogels were homogenous at room temperature and released > 90% of the sildenafil within 8 hours in vitro. Time to first granulation tissue was significantly shorter for the sildenafil groups (mean ± SD, 2.8 ± 0.8 days [5S and 10S]), compared with the control groups (5.2 ± 0.4 days [C] and 6.3 ± 1.4 days [G]). The G wounds had a 10% to 14% lower contraction rate, compared with the C, 5S, and 10S wounds. 5S wounds had a total wound area 0.7 ± 0.3 cm2 larger than 10S wounds. No significant differences were present when C wounds were compared with 5S and 10S wounds for total wound area, contraction, or epithelialization. Histologic acute inflammatory scores were higher for 5S and 10S wounds in the early and late stages of wound healing, with higher reparative scores on day 7. Neovascularization was higher for 10S wounds on day 7 and 14. CLINICAL RELEVANCE: The topical sildenafil hydrogel promoted early granulation tissue, which may be beneficial for secondary wound closure in clinical settings.

pH-Sensitive Liposomes for Enhanced Cellular Uptake and Cytotoxicity of Daunorubicin in Melanoma (B16-BL6) Cell Lines.

Daunorubicin (DNR) was delivered using a pH-sensitive liposomal system in B16-BL6 melanoma cell lines for enhanced cytotoxic effects. DNR was encapsulated within liposomes and CL as a component of the lipid bilayer. PEGylated pH-sensitive liposomes, containing CL, were prepared in the molar ratio of 40:30:5:17:8 for DOPE/cholesterol/DSPE-mPEG (2000)/CL/SA using the lipid film hydration method and loaded with DNR (drug: lipid ratio of 1:5). The CL liposomes exhibited high drug encapsulation efficiency (>90%), a small size (~94 nm), narrow size distribution (polydispersity index ~0.16), and a rapid release profile at acidic pH (within 1 h). Furthermore, the CL liposomes exhibited 12.5- and 2.5-fold higher cytotoxicity compared to DNR or liposomes similar to DaunoXome®. This study provides a basis for developing DNR pH-sensitive liposomes for melanoma treatment.

Recent Advancements of Stimuli-Responsive Targeted Liposomal Formulations for Cancer Drug Delivery.

Liposomes have gained attention as a well-accepted nanocarrier for several chemotherapeutic drugs and are considered a drug delivery system of choice for a wide range of products. These amphipathic spherical vesicles primarily consist of one or more phospholipid bilayers, showing promise for drug delivery of both hydrophilic and hydrophobic components in addition to unique properties, such as biocompatibility, biodegradability, low toxicity, and nonimmunogenicity. Recent advances in liposomes are mainly centered on chemical and structural modification with the multifunctional approach to target the cancer cells activating the offensive mechanisms within the proximity of the tumors. Stimuli-responsive liposomes are a precisive approach to deliver and release chemotherapeutic drugs in the tumor site in a controlled fashion, thus reducing damage to normal tissues and preventing the side effects of the conventional chemotherapy regimen. The unique characteristics of the tumor microenvironment facilitate applying an endogenous stimulus (pH, redox potential, or enzymatic activity) to trigger the release of the drug or the application of an external stimulus (heat or light) to tailor the drug release from liposomes. This review focuses on newer developments in stimuli-sensitive liposomal drug delivery systems designed to implement either exogenous (temperature, light, and magnetic field) or endogenous (pH changes, enzymatic triggers, or redox potential) approaches.

Niosomal formulation of hydroxytyrosol, a polyphenolic antioxidant, for enhancing transdermal delivery across human cadaver skin.

Hydroxytyrosol (HT), a naturally occurring polyphenol from the olive plant, is a potent antioxidant, cardioprotective, neuroprotective, and anti-inflammatory agent. Upon oral administration, HT undergoes rapid elimination within minutes and thus limiting its therapeutic utility. Due to its hydrophilic nature, percutaneous absorption and transdermal delivery of HT are very low. The aim of this research was to enhance the skin permeation of hydroxytyrosol using a niosome gel formulation. The formulations prepared with Span 60 as surfactant showed uniform particle size and high encapsulation efficiency (>90%). The niosome formulations showed a pseudoplastic behavior for topical application within the lipid/surfactant composition of 45-50%. The formulations showed a controlled release of HT compared to the HT solution. The flux of HT across human skin was increased by 28 and 4.4 fold compared to aqueous and ethanolic HT solutions, respectively (p < 0.001). The presence of lecithin lowered the flux and increased the retention of the formulations compared to HT solutions (p < 0.001). The formulations containing lecithin showed two-fold higher skin retention of hydroxytyrosol (p < 0.05). In conclusion, this study demonstrates niosome gel as a promising alternative to oral delivery of HT, providing sustained delivery and greater efficacy.

Resveratrol-loaded nanomedicines for cancer applications.

BACKGROUND: Resveratrol (3, 5, 4' -trihydroxystilbene), a natural polyphenol and phytoalexin, has drawn considerable attention in the past decade due to its wide variety of therapeutic activities such as anticancer, anti-inflammatory, and antioxidant properties. However, its poor water solubility, low chemical stability, and short biological half-life limit its clinical utility. RECENT FINDINGS: Nanoparticles overcome the limitations associated with conventional chemotherapeutic drugs, such as limited availability of drugs to the tumor tissues, high systemic exposures, and consequent toxicity to healthy tissues. This review focuses on the physicochemical properties of resveratrol, the therapeutic potential of resveratrol nano-formulations, and the anticancer activity of resveratrol encapsulated nanoparticles on various malignancies such as skin, breast, prostate, colon, liver, ovarian, and lung cancers (focusing on both in vitro and in vivo studies). CONCLUSIONS: Nanotechnology approaches have been extensively utilized to achieve higher solubility, improved oral bioavailability, enhanced stability, and controlled release of resveratrol. The resveratrol nanoparticles have markedly enhanced its anticancer activity both in vitro and in vivo, thus considering it as a potential strategy to fight various cancers.

Co-Delivery of Hispolon and Doxorubicin Liposomes Improves Efficacy Against Melanoma Cells.

Hispolon is a small molecular weight polyphenol that has antioxidant, anti-inflammatory, and anti-proliferative activities. Our recent study has demonstrated hispolon as a potent apoptosis inducer in melanoma cell lines. Doxorubicin is a broad spectrum first-line treatment for various kinds of cancers. In this study, co-delivery of doxorubicin and hispolon using a liposomal system in B16BL6 melanoma cell lines for synergistic cytotoxic effects was investigated. Liposomes were prepared using a lipid film hydration method and loaded with doxorubicin or hispolon. The formulations were characterized for particle size distribution, release profile, and encapsulation efficiency (EE). In addition, in vitro cytotoxicity, in vitro cell apoptosis, and cellular uptake were evaluated. Liposomes exhibited small particle size (mean diameter ~ 100 nm) and narrow size distribution (polydispersity index (< 0.2) and high drug EE% (> 90%). The release from liposomes showed slower release compared to free drug solution as an additional time required for the release of drug from the liposome lipid bilayer. Liposome loaded with doxorubicin or hispolon exhibited significantly higher cytotoxicity against B16BL6 melanoma cells as compared to doxorubicin solution or hispolon solution. Likewise, co-delivery of hispolon and doxorubicin liposomes showed two-fold and three-fold higher cytotoxicity, as compared to hispolon liposomes or doxorubicin liposomes, respectively. In addition, co-delivery of doxorubicin and hispolon in liposomes enhanced apoptosis more than the individual drugs in the liposome formulation. In conclusion, the co-delivery of hispolon and doxorubicin could be a promising therapeutic approach to improve clinical outcomes against melanoma.

Application of Extrusion-Based 3D Printed Dosage Forms in the Treatment of Chronic Diseases.

Chronic disease management has been a significant burden in many countries. As most treatment options involve long-term pharmacotherapy, patient compliance has been a challenge, as patients have to remember taking medications on time at the prescribed dose for each disease state. Patients are often required to split the dosage unit, which may lead to under- or over-dose and dose-related adverse effects. However, 3D printing technologies have been used for fabricating personalized medications and multiple drugs in a single dose unit (polypills), which might greatly reduce treatment monitoring, dosing errors, and follow-ups with the health care providers. Extrusion-based 3D printing is the most used technology to fabricate polypills and to customize the dose, dosage form, and release kinetics, which might potentially reduce the risk of patient non-compliance. Although extrusion-based 3D printing has existed for some time, interest in its potential to fabricate dosage forms for treating chronic diseases is still in its infancy. This review focuses on the various extrusion-based 3D printing technologies such as fused deposition modeling, pressure-assisted microsyringe, and direct powder extrusion 3D printing in the preparation of customizable, multi-drug dosage forms for treating chronic diseases.