Targeted therapy of breast tumor by PLGA-based nanostructures: The versatile function in doxorubicin delivery.

Breast carcinoma is a molecularly diverse illness, and it is among the most prominent and often reported malignancies in female across the globe. Surgical intervention, chemotherapy, immunotherapy, gene therapy, and endocrine treatment are among the currently viable treatment options for the carcinoma of breast. Chemotherapy is among the most prevalent cancer management strategy. Doxorubicin (DOX) widely employed as a cytostatic medication for the treatment of a variety of malignancies. Despite its widespread acceptance and excellent efficacy against an extensive line up of neoplasia, it has a variety of shortcomings that limit its therapeutic potential in the previously mentioned indications. Employment of nanoparticulate systems has come up as a unique chemo medication delivery strategy and are being considerably explored for the amelioration of breast carcinoma. Polylactic-co-glycolic acid (PLGA)-based nano systems are being utilized in a number of areas within the medical research and medication delivery constitutes one of the primary functions for PLGA given their inherent physiochemical attributes, including their aqueous solubility, biocompatibility, biodegradability, versatility in formulation, and limited toxicity. Herein along with the different application of PLGA-based nano formulations in cancer therapy, the present review intends to describe the various research investigations that have been conducted to enumerate the effectiveness of DOX-encapsulated PLGA nanoparticles (DOX-PLGA NPs) as a feasible treatment option for breast cancer.

Natural product myricetin is a pan-KDM4 inhibitor which with poly lactic-co-glycolic acid formulation effectively targets castration-resistant prostate cancer.

BACKGROUND: Castration-resistant prostate cancer (CRPC) with sustained androgen receptor (AR) signaling remains a critical clinical challenge, despite androgen depletion therapy. The Jumonji C-containing histone lysine demethylase family 4 (KDM4) members, KDM4A‒KDM4C, serve as critical coactivators of AR to promote tumor growth in prostate cancer and are candidate therapeutic targets to overcome AR mutations/alterations-mediated resistance in CRPC. METHODS: In this study, using a structure-based approach, we identified a natural product, myricetin, able to block the demethylation of histone 3 lysine 9 trimethylation by KDM4 members and evaluated its effects on CRPC. A structure-based screening was employed to search for a natural product that inhibited KDM4B. Inhibition kinetics of myricetin was determined. The cytotoxic effect of myricetin on various prostate cancer cells was evaluated. The combined effect of myricetin with enzalutamide, a second-generation AR inhibitor toward C4-2B, a CRPC cell line, was assessed. To improve bioavailability, myricetin encapsulated by poly lactic-co-glycolic acid (PLGA), the US food and drug administration (FDA)-approved material as drug carriers, was synthesized and its antitumor activity alone or with enzalutamide was evaluated using in vivo C4-2B xenografts. RESULTS: Myricetin was identified as a potent α-ketoglutarate-type inhibitor that blocks the demethylation activity by KDM4s and significantly reduced the proliferation of both androgen-dependent (LNCaP) and androgen-independent CRPC (CWR22Rv1 and C4-2B). A synergistic cytotoxic effect toward C4-2B was detected for the combination of myricetin and enzalutamide. PLGA-myricetin, enzalutamide, and the combined treatment showed significantly greater antitumor activity than that of the control group in the C4-2B xenograft model. Tumor growth was significantly lower for the combination treatment than for enzalutamide or myricetin treatment alone. CONCLUSIONS: These results suggest that myricetin is a pan-KDM4 inhibitor and exhibited potent cell cytotoxicity toward CRPC cells. Importantly, the combination of PLGA-encapsulated myricetin with enzalutamide is potentially effective for CRPC.

TB@PLGA Nanoparticles for Photodynamic/Photothermal Combined Cancer Therapy with Single Near-Infrared Irradiation.

BACKGROUND: Phototherapy has significant potential as an effective treatment for cancer. However, the application of a multifunctional nanoplatform for photodynamic therapy (PDT) and photothermal therapy (PTT) at a single excitation wavelength remains a challenge. MATERIALS AND METHODS: The double emulsion solvent evaporation method was used to prepare toluidine blue@poly lactic-co-glycolic acid (TB@PLGA) nanoparticles (NPs). The biocompatibility of TB@PLGA NPs was evaluated, and a 660 nm luminescence was used as the light source. The photothermal effect, photothermal stability, and singlet oxygen yield of NPs in an aqueous solution verified the feasibility of NPs as a PTT/PDT synergistic therapy drug. RESULTS: TB@PLGA NPs were successfully prepared and characterized. In vitro experiments demonstrated that TB@PLGA NPs can cause massive necrosis of tumor cells and induce apoptosis through a photodynamic mechanism under 660 nm laser irradiation. The TB@PLGA NPs also achieved optimal tumor inhibition effect in vivo. CONCLUSION: The TB@PLGA NPs prepared in this study were applied as a dual-mode phototherapeutic agent under single laser irradiation. Both in vitro and in vivo experiments demonstrated the good potential of PTT/PDT for tumor inhibitors.

Dual Functions of Riboflavin-functionalized Poly(lactic-co-glycolic acid) Nanoparticles for Enhanced Drug Delivery Efficiency and Photodynamic Therapy in Triple-negative Breast Cancer Cells.

Combating triple-negative breast cancer (TNBC) is one of the greatest challenges in cancer therapy. This is primarily due to the difficulties in developing drug delivery systems that can effectively target cancer sites. In this study, we demonstrated a proof-of-principle concept using modified surfaces of poly(lactic-co-glycolic acid) nanoparticles linked with a riboflavin analogue (PLGA-CSRf) to obtain a dual-functional material. PLGA-CSRf nanoparticles were able to function as a drug delivery ligand and a photodynamic therapy agent for TNBC cells (MDA-MB-231). Biocompatibility of novel PLGA-CSRf nanoparticles was evaluated with both breast cancer and normal breast (MCF-10A) cells. In vitro studies revealed a six-fold increase in the cellular uptake of PLGA-CSRf nanoparticles in cancer cells compared with normal cells. The results demonstrate the ability of riboflavin (Rf) to enhance the delivery of PLGA nanoparticles to TNBC cells. The viability of TNBC cells was decreased following treatment with doxorubicin-encapsulated PLGA-CSRf nanoparticles in combination with UV irradiation, due to the photosensitizing property of Rf on the surface of the nanoparticles. This work demonstrated the ability of PLGA-CSRf to function both as an effective drug delivery carrier and as a therapeutic entity, with the potential to enhance photodynamic effects in the highly aggressive TNBC model.

Angiopep-2 Modified Cationic Lipid-Poly-Lactic-Co-Glycolic Acid Delivery Temozolomide and DNA Repair Inhibitor Dbait to Achieve Synergetic Chemo-Radiotherapy Against Glioma.

The therapeutic treatment of glioblastoma multiforme (GBM) remains a major challenge. Synergistic chemotherapy and radiotherapy (RT) have been considered the standard clinical therapy for malignant glioma, but there are some outstanding problems. First, gliomas are deemed exceedingly radio-resistant tumors, owing to efficient DNA double-strand break repair. In addition, the first-line chemotherapeutic agent (temozolomide, TMZ) for glioma shows extensive side effects and low accumulation in brain tumors. Therefore, we designed and constructed an Angiopep-2 modified cationic lipid-Poly-lactic-co-glycolic acid (PLGA), Angiopep-2 (A2)/DSPE-PEG2000/DOTAP/PLGA (APDP), to transport TMZ and a DNA repair inhibitor (Dbait) into glioblastoma cells, achieving concomitant chemo-radiotherapy treatment of glioma. At the cellular level, the APDP+TMZ/Dbait can be well endocytosed and enhance accumulation of the agent in brain tumors. Furthermore, the nanoparticle combined with Dbait improves the efficiency of radiotherapy in GBM. Our experimental data demonstrate that APDP+TMZ/Dbait has great potential as a multipurpose nanomedicine for the synergistic chemo-radiotherapy and radio-sensitization of malignant glioma in precise medical applications.

Fomepizole for the treatment of pediatric ethylene and diethylene glycol, butoxyethanol, and methanol poisonings.

INTRODUCTION: The use and clinical efficacy of the alcohol dehydrogenase inhibitor fomepizole is well established for the treatment of ethylene glycol and methanol poisonings in adults. METHODS: A computerized search of the U.S. National Academy of medicine and EMBase databases was undertaken to identify published cases of patients treated with fomepizole. This search strategy identified 14 published cases related to the topic of this review: 10 due to ethylene glycol poisoning, 1 due to diethylene glycol poisoning, 1 due to butoxyethanol ingestion, and 2 due to methanol poisoning. The median age of these cases was 5.5 years old. FOMEPIZOLE IN GLYCOL AND GLYCOL ETHER POISONING: For the 10 ethylene glycol poisoned patients, the median recorded values of their arterial pH was 7.27 (range 7.03-7.38), serum bicarbonate concentration was 13 mEq/L (range 2-25), and ethylene glycol concentration was 2,140 mg/L (range 130-3,840). Eight of these patients were not hemodialyzed. The eight patients who were not hemodialyzed had ethylene glycol concentrations as high as 3,500 mg/L and serum bicarbonate concentrations as low as 4 mEq/L. All 10 patients had resolution of their metabolic acidosis and recovered without sequelae. The half-times of ethylene glycol elimination ranged from 9 to 15 h during fomepizole therapy, which is faster than the 19.7 h reported in adults. The two patients who ingested diethylene glycol or butoxyethanol all recovered without sequelae. The patient who ingested the butoxyethanol had a serum bicarbonate concentration of 13 mEq/L and was not hemodialyzed. FOMEPIZOLE IN METHANOL POISONING: One of the two children who ingested methanol was hemodialyzed. Both cases had a similar degree of severity. DOES FOMEPIZOLE OBVIATE THE NEED FOR HEMODIALYSIS?: Based on the experience reviewed herein it appears that, as in adults, hemodialysis may not be necessary in most cases of pediatric ethylene glycol poisoning if treated with fomepizole. FOMEPIZOLE PHARMACOKINETICS: Plasma fomepizole concentrations were measured in three cases and were found to be therapeutic with apparent Michaelis-Menton kinetics, having a zero-order elimination rate of 0.6-1 mg/L/h at higher concentrations and a first-order elimination with an apparent elimination half-time of 3.9 h at lower concentrations. FOMEPIZOLE REGIMEN: Most cases used the current U.S.-approved regimen. ADVERSE EFFECTS OF FOMEPIZOLE: The one adverse effect reported during fomepizole therapy was transient nystagmus in a 6-year-old with a serum ethylene glycol concentration of 130 mg/L and a serum bicarbonate concentration of 2 mEq/L; it is likely that ethylene glycol itself was the cause. COMPARISON OF FOMEPIZOLE WITH ETHANOL THERAPY: Two cases were originally treated with ethanol but switched to fomepizole because of adverse effects. In both cases, the adverse reactions to ethanol resolved once fomepizole treatment was initiated. CONCLUSIONS: The limited data available suggest that fomepizole, using the same dosage regimen as that used for adults, is efficacious and well tolerated in pediatric patients. In many cases of pediatric ethylene glycol poisoning treated with fomepizole, hemodialysis may not be necessary despite high concentrations and the presence of metabolic acidosis.

Ear drops for the removal of ear wax.

BACKGROUND: Problems attributed to the accumulation of wax (cerumen) are one of the most common reasons for people to present to their general practitioners with ear trouble (Sharp 1990). Treatment for this condition often involves use of a wax softening agent (cerumenolytic) in order to disperse the cerumen and reduce the need for syringing, or to facilitate syringing should it prove necessary, but there is no consensus on the effectiveness of the wide variety of cerumenolytics in use. OBJECTIVES: To assess the effectiveness of ear drops (cerumenolytics) for the removal of symptomatic ear wax. SEARCH STRATEGY: We searched the Cochrane ENT Group Register, the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2003), and MEDLINE and EMBASE up to March 2003. Reference lists of all trials were also manually searched. SELECTION CRITERIA: We identified all randomised controlled trials (with or without blinding) in which a cerumenolytic was evaluated in comparison with either no treatment, a placebo, or other cerumenolytics in participants with hard or impacted ear wax, and in which the proportion of participants with sufficient clearance of the external canal to make further mechanical clearance unnecessary (primary outcome measure) was stated or calculable. The full text articles of all the retrieved trials of possible relevance were reviewed by the two reviewers and the inclusion criteria applied independently. Any differences in opinion about which studies to include in the review were resolved by discussion. DATA COLLECTION AND ANALYSIS: Trials were graded for methodological quality using the Cochrane approach. Data extraction was performed in a standardised manner by one reviewer and rechecked by the other reviewer, and where necessary investigators were contacted to obtain missing information. Meta-analysis was neither possible nor considered appropriate because of the heterogeneity of the treatments, treatment amounts and durations, trial procedures, and scoring systems. A narrative overview of the results is therefore presented. MAIN RESULTS: Eight trials satisfied the inclusion criteria, the majority of which were of poor quality. In all, 587 participants received one of nine different cerumenolytics. One trial compared active treatments with no treatment, two trials compared active treatments with water or a saline 'placebo', and all eight trials placed two or more active treatments in head-to-head comparisons. Seven trials included syringing as a secondary treatment where necessary.Overall, results were inconclusive. One trial found a significant difference between one of three active agents (Cerumol) in comparison to no treatment, but no statistically significant difference was found between these three agents (sodium bicarbonate ear drops; Cerumol; sterile water). In two trials no statistical difference was found between the effectiveness of either sodium bicarbonate ear drops, Cerumol, Cerumenex or Colace versus a sterile water or saline 'placebo'. Three trials (from the same source) found statistically significant differences in favour of the same active agent (Exterol) in comparison to glycerol and Cerumol. Three trials found no statistically significant difference between two or more cerumenolytics (Otocerol versus Cerumol; Audax versus Earex; sodium bicarbonate ear drops versus Cerumol). Two trials comparing the same two cerumenolytics (Cerumenex versus Colace) also failed to show any significant benefit of one over the other. No serious adverse effects were reported from any of the interventions. REVIEWER'S CONCLUSIONS: Trials to date have been heterogeneous and of poor quality, making it difficult to offer any definitive recommendations on the effectiveness of cerumenolytics for the removal of symptomatic ear wax. Future trials should be of high methodological quality, have large sample sizes, and compare both oil-based and water-based solvents with placebo and/or no treatment.

The efficiency of humectants as skin moisturizers in the presence of oil.

BACKGROUND/AIMS: The research on the treatment of "dry skin syndrome" is hampered by the lack of a suitable animal model. Formerly, we developed a validated guinea pig in vivo model in which the dry skin syndrome persists at least for 1 week. We can, therefore, compare the pharmacological effectiveness of known and potential moisturizers for the treatment of dry skin syndrome. Our aim is to study whether the moisturizing efficiency of humectants depends on the solvents in which they are dissolved. METHODS: "Dry skin syndrome" was induced on the shaved skin on one side of guinea pigs by daily application of 2% sodium lauryl sulphate in deionized water (SLS) for 3 days. The other shaved side was used as control. After ascertaining skin dryness, that side was treated for 6 days with glycerol or 1,2-hexanediol in different solvents: water, or medium chain triglycerides (MCT) or mixtures of MCT with isopropyl alcohol in different proportions. Measurement of the in vivo moisturizing effect was carried out by a Comeometer CM 825; erythema was measured by a Mexameter MX 16. RESULTS: Treatments with glycerol (1M) in water reversed the skin dryness shown by both instruments. When dissolving glycerol in MCT, no moisturizing effect was found, probably because glycerol does not dissolve in the oil. No moisturizing effect was found with different combinations of glycerol in the mixtures of MCT and isopropyl alcohol. No moisturizing effect was found using another polyol moisturizer: 1,2 hexanediol (1M) dissolved in MCT oil. Glycerol or 1,2-hexanediol abolished the erythema only when they were dissolved in water alone. CONCLUSION: Polyol moisturizers such as glycerol or 1,2-hexanediol do not act in the presence of oils against the sodium lauryl sulphate-induced dry skin in our guinea pig model. Since in an oil-in-water (O/W) emulsion, the water evaporates within several minutes, one has to question the ability of moisturizing emulsions to treat dry skin. In such instances, one cannot draw conclusions about the moisturizing efficiency of the preparation merely from the presence of the humectant. One has to study the effect of the finished preparation.

Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease.

Amyloid is a term for extracellular protein fibril deposits that have characteristic tinctorial and structural properties. Heparan sulphate, or the heparan sulphate proteoglycan perlecan, has been identified in all amyloids and implicated in the earliest stages of inflammation-associated (AA) amyloid induction. Heparan sulphate interacts with the AA amyloid precursor and the beta-peptide of Alzheimer's amyloid, imparting characteristic secondary and tertiary amyloid structural features. These observations suggest that molecules that interfere with this interaction may prevent or arrest amyloidogenesis. We synthesized low-molecular-weight (135-1,000) anionic sulphonate or sulphate compounds. When administered orally, these compounds substantially reduced murine splenic AA amyloid progression. They also interfered with heparan sulphate-stimulated beta-peptide fibril aggregation in vitro.