Nanotheraputic Platforms to address Chemotherapeutic Challenges in Breast and Ovarian Cancer Treatment

Utilizing nanocarrier based drug delivery for improving the magnitude of efficacy of chemotherapeutic agents in many diseases has acquired more attention in research applications. It has shown promising results in both preclinical and clinical trials. The Food and Drug Administration (FDA) has approved many of these polymeric carriers, and tens of them are in clinical trials. Thousands of compounds in the Compound Screening Libraries have shown efficacy in vitro, but due to their solubility or stability limitations, many of them are unable to demonstrate efficacy in vivo. For example, in oncology, many small molecules have numerous applications in the field but have a weak solubility profile. Several of these drugs fail to achieve favorable outcomes due to toxicity issues or development of resistance to these agents, which leads to a worsening progression of the disease. Herein we utilize nanocarrier based drug delivery strategies to overcome these issues, improving health outcomes and mitigating the toxicity of these agents. In the majority of cases, these chemotherapeutic agents have adverse effects that threaten the lives of patients more than the symptoms of the disease. For example, treatment with Adriamycin causes cardiomyopathy in patients. In the last two decades, researchers have shown that targeting the tumor environment and the tumor blood supply improved treatment in many patients. In many solid tumors, malignant cells occupied a smaller percentage of the tumor mass compared to microenvironment niches, such as collagen and fibroblasts. Since many of these cells can mutate, grow back, and develop resistance to these chemotherapeutic agents, a better treatment methodology has to be developed. The first strategy we performed in this work is utilizing combinatorial treatment to target malignancies. mammalian target of rapamycin (mTOR) inhibitors and taxanes were loaded in copolymer micelles, and screening was completed to determine the optimal dosage regimen to normalize blood vessels and help the immune populations to clear up malignant cells. Copolymer micelles were made of methoxy poly(ethylene glycol)-b-poly(D,L- lactide), an FDA approved, biocompatible, and amphiphilic block copolymer. This nanocarrier was developed to deliver docetaxel and everolimus with tailored dosage regimens at and below their maximum tolerated dose. Treatments allow for tumor growth control and normalization of angiogenesis in the tumor niche. The immune-modulatory effect in the tumor bed was investigated to determine if these agents have a direct effect on the immune populations or an indirect effect where the immune system is induced through immunogenic cell death. A second nanostructure was prepared with Pluronic micelles using poloxamer 407 copolymers (ethylene oxide and propylene oxide blocks). The goal is to encapsulate polyphenols for chemosensitization and mitigation of Adriamycin induced cardiotoxicity at selected ratios. We aim for a better quality of life for the patients who are fighting chronic diseases such as cancer. Using polymeric micelles is a successful approach that helps with increasing the solubility of poorly water-soluble agents in an aqueous medium, resulting in minimization of side effects related to solvents used in solubilizing hydrophobic chemotherapeutic agents. In cancer therapy, combinatorial treatment has a superior effect compared to using a singular agent. Controlling the pharmacokinetic profile of any chemotherapeutic drug that allows for more freedom in tailored dosing is one of the advantages of optimizing these cargos. In this work, we successfully utilized two different drug-loaded copolymer micelles to treat ovarian and triple-negative breast cancer. These strategies allow for the development of optimal treatment regimens using docetaxel and everolimus in triple-negative breast cancer and Adriamycin in combination with polyphenols in ovarian cancer

Combinatorial polymeric conjugated micelles with dual cytotoxic and antiangiogenic effects for the treatment of ovarian cancer

Emerging treatment paradigms like targeting the tumor microenvironment and/or dosing as part of a metronomic regimen are anticipated to produce better outcomes in ovarian cancer, but current drug delivery systems are lacking. We have designed and evaluated paclitaxel (PTX) and rapamycin (RAP) micellar systems that can be tailored for various dosing regimens and target tumor microenvironment. Individual and mixed PTX/RAP (MIX-M) micelles are prepared by conjugating drugs to a poly­(ethylene glycol)-<i>block</i>-poly­(β-benzyl l-aspartate) using a pH-sensitive linker. The micelles release the drug(s) at pH 5.5 indicating preferential release in the acidic endosomal/lysosomal environment. Micelles exhibit antiproliferative effects in ovarian cell cancer lines (SKOV-3 (human caucasian ovarian adenocarcinoma) and ES2 (human ovarian clear cell carcinoma)) and an endothelial cell line (HUVEC; human umbilical vein endothelial cells) with the MIX-M being synergistic. The micelles also inhibited endothelial migration and tube formation. In healthy mice, micelles at 60 mg/kg/drug demonstrated no acute toxicity over 21 days. ES2 xenograft model efficacy studies at 20 mg/kg/drug dosed every 4 days and evaluated at 21 days indicate that the individual micelles exhibit antiangiogenic effects, while the MIX-M exhibited both antiangiogenic and apoptotic induction that results in significant tumor volume reduction. On the basis of our results, MIX-M micelles can be utilized to achieve synergistic apoptotic and antiangiogenic effects when treated at frequent low doses

Recent Advances of Ocular Drug Delivery Systems: Prominence of Ocular Implants for Chronic Eye Diseases

Chronic ocular diseases can seriously impact the eyes and could potentially result in blindness or serious vision loss. According to the most recent data from the WHO, there are more than 2 billion visually impaired people in the world. Therefore, it is pivotal to develop more sophisticated, long-acting drug delivery systems/devices to treat chronic eye conditions. This review covers several drug delivery nanocarriers that can control chronic eye disorders non-invasively. However, most of the developed nanocarriers are still in preclinical or clinical stages. Long-acting drug delivery systems, such as inserts and implants, constitute the majority of the clinically used methods for the treatment of chronic eye diseases due to their steady state release, persistent therapeutic activity, and ability to bypass most ocular barriers. However, implants are considered invasive drug delivery technologies, especially those that are nonbiodegradable. Furthermore, in vitro characterization approaches, although useful, are limited in mimicking or truly representing the in vivo environment. This review focuses on long-acting drug delivery systems (LADDS), particularly implantable drug delivery systems (IDDS), their formulation, methods of characterization, and clinical application for the treatment of eye diseases

Chitosan/Solid-Lipid Nanoparticles Hybrid Gels for Vaginal Delivery of Estradiol for Management of Vaginal Menopausal Symptoms

Hormonal replacement therapy is the mainstay treatment to improve quality of life and reduce mortality. With the increasing number of young women with early menopause, women now live longer (increased life expectancy). However, poor patient compliance with oral estrogen therapy has emerged. Intravaginal estrogen therapy can provide significant benefits with minimal risk for postmenopausal women with symptoms of the lower urinary tract and vaginal area but who do not want to take oral estrogen. In this study, estradiol-loaded solid lipid nanoparticles (SLPs) were prepared from compritol ATO 888 and precirol ATO 5, and two different stabilizers (Pluronic F127 and Tween 80) were studied. Selected SLPs (F3 and F6) were coated with different concentrations of the mucoadhesive and sustained-release polymer chitosan. Furthermore, gelation time, viscosity, mucoadhesion, ex vivo permeation, and in vitro irritation for vaginal irritation were studied. Particle sizes ranged between 450–850 nm, and EE% recorded 50–83% for the six SLPs depending on the type and amount of lipids used. Cumulative % drug release was significantly enhanced and was recorded at 51% to 83%, compared to that (less than 20%) for the control suspension of estradiol. Furthermore, extensive thermal gelation and mucoadhesion were recorded for chitosan-coated SLPs. Up to 2.2-fold increases in the permeation parameters for SLPs gels compared to the control suspension gel were recorded, revealing a slight to moderate irritation on Hela cell lines. These findings demonstrated chitosan-coated estradiol SLPs as novel and promising vaginal mucoadhesive hybrid nanogels

Preparation and characterization of a curcumin nanoemulsion gel for the effective treatment of mycoses

Abstract Fungal infections of skin including mycoses are one of the most common infections in skin or skins. Mycosis is caused by dermatophytes, non-dermatophyte moulds and yeasts. Various studies show different drugs to treat mycoses, yet there is need to treat it with applied drugs delivery. This study was designed to prepare a bio curcumin (CMN) nanoemulsion (CMN-NEs) for transdermal administration to treat mycoses. The self-nanoemulsification approach was used to prepare a nanoemulsion (NE), utilizing an oil phase consisting of Cremophor EL 100 (Cre EL), glyceryl monooleate (GMO), and polyethylene glycol 5000 (PEG 5000). Particle size (PS), polydispersity index (PDI), zeta potential (ZP), Fourier transform infrared (FTIR) spectrophotometric analysis, and morphological analyses were performed to evaluate the nanoemulsion (NE). The in vitro permeation of CMN was investigated using a modified vertical diffusion cell with an activated dialysis membrane bag. Among all the formulations, a stable, spontaneously produced nanoemulsion was determined with 250 mg of CMN loaded with 10 g of the oil phase. The average droplet size, ZP, and PDI of CMN-NEs were 90.0 ± 2.1 nm, − 7.4 ± 0.4, and 0.171 ± 0.03 mV, respectively. The release kinetics of CMN differed from zero order with a Higuchi release profile as a result of nanoemulsification, which also significantly increased the flux of CMN permeating from the hydrophilic matrix gel. Overall, the prepared nanoemulsion system not only increased the permeability of CMN but also protected it against chemical deterioration. Both CMN-ME (24.0 ± 0.31 mm) and CMN-NE gel (29.6 ± 0.25 mm) had zones of inhibition against Candida albicans that were significantly larger than those of marketed Itrostred gel (21.5 ± 0.34 mm). The prepared CMN-NE improved the bioavailability, better skin penetration, and the CMN-NE gel enhanced the release of CMN from the gel matrix on mycotic patients

A Novel Curcumin Arginine Salt: A Solution for Poor Solubility and Potential Anticancer Activities

Curcumin is a natural polyphenolic compound with well-known anticancer properties. Poor solubility and permeability hamper its use as an anticancer pharmaceutical product. In this study, L-arginine, a basic amino acid and a small hydrophilic molecule, was utilized to form a salt with the weak acid curcumin to enhance its solubility and potentiate the anticancer activities of curcumin. Two methods were adopted for the preparation of curcumin: L-arginine salt, namely, physical mixing and coprecipitation. The ion pair or salt was characterized for docking, solubility, DSC, FTIR, XRD, in vitro dissolution, and anticancer activities using MCF7 cell lines. The molecular docking suggested a salt/ion-pair complex between curcumin and L-arginine. Curcumin solubility was increased 335- and 440-fold by curcumin in L-arginine, physical, and co-precipitated mixtures, respectively. Thermal and spectral analyses supported the molecular docking and formation of a salt/ion pair between curcumin and L-arginine. The cytotoxicity of curcumin L-arginine salt significantly improved (p &lt; 0.05) by 1.4-fold, as evidenced by the calculated IC50%, which was comparable to Taxol (the standard anticancer drug but with common side effects)

Fabrication and Characterization of Acute Myocardial Infarction Myoglobin Biomarker Based on Chromium-Doped Zinc Oxide Nanoparticles

In this article, we describe the fabrication and characterization of a sensor for acute myocardial infarction that detects myoglobin biomarkers using chromium (Cr)-doped zinc oxide (ZnO) nanoparticles (NPs). Pure and Cr-doped ZnO NPs (13 &times; 1017, 20 &times; 1017, and 32 &times; 1017 atoms/cm3 in the solid phase) were synthesized by a facile low-temperature sol-gel method. Synthesized NPs were examined for structure and morphological analysis using various techniques to confirm the successful formation of ZnO NPs. Zeta potential was measured in LB media at a negative value and increased with doping. XPS spectra confirmed the presence of oxygen deficiency in the synthesized material. To fabricate the sensor, synthesized NPs were screen-printed over a pre-fabricated gold-coated working electrode for electrochemical detection of myoglobin (Mb). Cr-doped ZnO NPs doped with 13 &times; 1017 Cr atomic/cm3 revealed the highest sensitivity of ~37.97 &mu;A.cm&minus;2nM&minus;1 and limit of detection (LOD) of 0.15 nM for Mb with a response time of &le;10 ms. The interference study was carried out with cytochrome c (Cyt-c) due to its resemblance with Mb and human serum albumin (HSA) abundance in the blood and displayed distinct oxidation potential and current values for Mb. Cr-doped ZnO NP-based Mb biosensors showed 3 times higher sensitivity as compared to pure ZnO NP-based sensors

Design, Preparation and Evaluation of Supramolecular Complexes with Curcumin for Enhanced Cytotoxicity in Breast Cancer Cell Lines

Curcumin is one of the most researched phytochemicals by pharmacologists and formulation scientists to unleash its potential therapeutic benefits and tackle inherent biopharmaceutic problems. In this study, the native β-cyclodextrin (CD) and three derivatives, namely, Captisol (sulfobutyl ether β-CD), hydroxypropyl β-cyclodextrin, and hydroxyethyl β-cyclodextrin were investigated for inclusion complexes with curcumin using two preparation methods (physical mixing and solvent evaporation). The prepared complexes were studied for docking, solubility, FTIR, DSC, XRD, and dissolution rates. The best-fitting curcumin: cyclodextrins (the latter of the two CDs) were evaluated for cytotoxicity using human breast cell lines (MCF-7). Dose-dependent cytotoxicity was recorded as IC50% for curcumin, curcumin: hydroxyethyl β-cyclodextrin, and curcumin: hydroxypropyl β-cyclodextrin were 7.33, 7.28, and 19.05 µg/mL, respectively. These research findings indicate a protective role for the curcumin: hydroxypropyl β-cyclodextrin complex on the direct cell lines of MCF-7