Potential anticancer effect of free and nanoformulated Deferasirox for breast cancer treatment: in-vitro and in-vivo evaluation.

BACKGROUND: Breast cancer (BC) stands as the second-leading cause of mortality among women worldwide. Many chemotherapeutic treatments for BC come with significant adverse effects. Additionally, BC is recognized as one of the most resistant forms of malignancy to treatment. Consequently, there exists a critical need for innovative therapeutic agents that are both highly effective and exhibit reduced toxicity and side effects for patients. Deferasirox (DFX), an iron-chelating drug approved by the FDA for oral use, emerges as a promising contender in the fight against BC proliferation. DFX, primarily administered orally, is utilized to address chronic iron excess resulting from blood transfusions, and it is the inaugural treatment for chronic iron overload syndrome. However, DFX encounters limitations due to its poor water solubility. AIM: This study aimed at incorporating DFX into lipid nanocapsules (DFX-LNCs) followed by investigating the anticancer effect of the DFX nanoform as compared to free DFX in-vitro and on an orthotopic BC mouse model in-vivo. METHODS: The DFX-LNCs was prepared and imaged using TEM and also characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI) using DLS. Moreover, drug release, cytotoxicity, and anticancer effect were assessed in-vitro, and in-vivo. RESULTS: The results revealed that DFX-LNCs are more cytotoxic than free DFX with IC50 of 4.417 µg/ml and 16.114 µg/ml, respectively, while the plain LNCs didn't show any cytotoxic effect on the 4T1 cell line (IC50 = 122.797 µg/ml). Besides, the apoptotic effect of DFX-LNCs was more pronounced than that of free DFX, as evidenced by Annexin V/PI staining, increased BAX expression, and decreased expression of BcL-2. Moreover, DFX-LNCs showed a superior antitumor effect in-vivo with potent antioxidant and anti-proliferative effects. CONCLUSION: The newly developed DFX nanoform demonstrated a high potential as a promising therapeutic agent for BC treatment.

A comprehensive review on lipid nanocarrier systems for cancer treatment: fabrication, future prospects and clinical trials.

Over the last few decades, cancer has been considered a clinical challenge, being among the leading causes of mortality all over the world. Although many treatment approaches have been developed for cancer, chemotherapy is still the most utilized in the clinical setting. However, the available chemotherapeutics-based treatments have several caveats including their lack of specificity, adverse effects as well as cancer relapse and metastasis which mainly explains the low survival rate of patients. Lipid nanoparticles (LNPs) have been utilized as promising nanocarrier systems for chemotherapeutics to overcome the challenges of the currently applied therapeutic strategies for cancer treatment. Loading chemotherapeutic agent(s) into LNPs improves drug delivery at different aspects including specific targeting of tumours, and enhancing the bioavailability of drugs at the tumour site through selective release of their payload, thus reducing their undesired side effects on healthy cells. This review article delineates an overview of the clinical challenges in many cancer treatments as well as depicts the role of LNPs in achieving optimal therapeutic outcomes. Moreover, the review contains a comprehensive description of the many LNPs categories used as nanocarriers in cancer treatment to date, as well as the potential of LNPs for future applications in other areas of medicine and research.

Folic/lactobionic acid dual-targeted polymeric nanocapsules for potential treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor that affects many patients diagnosed with hepatic cell inflammation and liver cirrhosis. Targeted polymeric nanocapsules could facilitate the internalization and accumulation of anticancer drugs. Dual-targeted folic acid/lactobionic acid-poly lactic co-glycolic acid nanocapsules (NCs) were prepared and loaded with pterostilbene (PTN) and characterized for their physicochemical properties, as well as in vitro and in vivo anticancer activity. NCs displayed a size of 222 nm, zeta potential of - 16.5 mV, and sustained release for 48 h. The IC50 of PTN NCs (5.87 ± 0.8 µg/mL) was 20 times lower than unencapsulated PTN (121.26 ± 9.42 µg/mL) on HepG2 liver cancer cells owing to the enhanced cellular uptake of the former, as delineated by flow cytometry. In vivo study on HCC-induced animals delineated the superiority of the dual-targeted NCs over the unencapsulated PTN, which significantly reduced the liver markers ALT, AST, and ALP, as well as the tumor-related markers AFP and Bcl2, and elevated the anti-apoptotic marker caspase 3. Furthermore, the NCs significantly reduced the oxidative stress and exhibited almost comparable histological features to the normal group. Therefore, it can be concluded that the dual-ligated folic acid/lactobionic acid nanocapsules can be considered a promising potential treatment option for hepatocellular carcinoma.

In-vitro and in-vivo assessment of pH-responsive core-shell nanocarrier system for sequential delivery of methotrexate and 5-fluorouracil for the treatment of breast cancer.

Breast cancer (BC) is one of the leading fatal diseases affecting females worldwide. Despite the presence of tremendous chemotherapeutic agents, the resistance emergence directs the recent research towards synergistic drugs' combination along with encapsulation inside biocompatible smart nanocarriers. Methotrexate (MTX) and 5-fluorouracil (Fu) are effective against BC and have sequential synergistic activity. In this study, a core-shell nanocarrier composed of mesoporous silica nanoparticles (MSN) as the core and zeolitic imidazolate framework-8 nano metal organic frameworks (ZIF-8 NMOF) as the shell was developed and loaded with Fu and MTX, respectively. The developed nanostructure; Fu-MSN@MTX-NMOF was validated by several characterization techniques and conferred high drugs' entrapment efficiency (EE%). In-vitro assessment revealed a pH-responsive drug release pattern in the acidic pH where MTX was released followed by Fu. The cytotoxicity evaluation indicated enhanced anticancer effect of the Fu-MSN@MTX-NMOF relative to the free drugs in addition to time-dependent fortified cytotoxic effect due to the sequential drugs' release. The in-vivo anticancer efficiency was examined using Ehrlich ascites carcinoma (EAC) animal model where the anticancer effect of the developed Fu-MSN@MTX-NMOF was compared to the sequentially administrated free drugs. The results revealed enhanced anti-tumor effect while maintaining the normal functions of the vital organs as the heart, kidney and liver.

Core-Shell Nanostructured Drug Delivery Platform Based on Biocompatible Metal-Organic Framework-Ligated Polyethyleneimine for Targeted Hepatocellular Carcinoma Therapy.

Multifunctional nanosized metal-organic frameworks (NMOFs) have advanced rapidly over the past decade to develop drug delivery systems (DDSs). These material systems still lack precise and selective cellular targeting, as well as the fast release of the quantity of drugs that are simply adsorbed within and on the external surface of nanocarriers, which hinders their application in the drug delivery. Herein, we designed a biocompatible Zr-based NMOF with an engineered core and the hepatic tumor-targeting ligand, glycyrrhetinic acid grafted to polyethyleneimine (PEI) as the shell. The improved core-shell serves as a superior nanoplatform for efficient controlled and active delivery of the anticancer drug doxorubicin (DOX) against hepatic cancer cells (HepG2 cells). In addition to their high loading capacity of 23%, the developed nanostructure DOX@NMOF-PEI-GA showed an acidic pH-stimulated response and extended the drug release time to 9 days as well as enhanced the selectivity toward the tumor cells. Interestingly, the DOX-free nanostructures showed a minimal toxic effect on both normal human skin fibroblast (HSF) and hepatic cancer cell line (HepG2), but the DOX-loaded nanostructures exhibited a superior killing effect toward the hepatic tumor, thus opening the way for the active drug delivery and achieving efficient cancer therapy applications.

Investigation of thymine as a potential cancer biomarker employing tryptophan with nanomaterials as a biosensor.

Tryptophan and tryptophan-based nanomaterials sensors in a solution have been developed to directly evaluate thymine. The determination of thymine has been done via quenching of the fluorescence of tryptophan and tryptophan-based nanomaterials such as graphene (Gr), graphene oxide (GO), gold nanoparticles (AuNPs), gold-silver nanocomposite (Au-Ag NC) in a physiological buffer. As the concentration of thymine rises, the fluorescence of tryptophan and tryptophan/nanomaterials becomes less intense. Trp, Trp/Gr, and tryptophan/(Au-Ag) NC systems' quenching mechanisms were dynamic, but tryptophan /GO and tryptophan/AuNPs' quenching mechanisms were static. The linear dynamic range for the determination of thy by tryptophan and tryptophan /nanomaterials is 10 to 200 µM. The detection limits for tryptophan, tryptophan /Gr, tryptophan /GO, tryptophan /AuNPs, and tryptophan/Au-Ag NC were 3.21, 14.20, 6.35, 4.67and 7.79 Μm, respectively. Thermodynamic parameters for the interaction of the Probes with Thy include the enthalpy (H°) and entropy (S°) change values, were assessed, as well as the binding constant (Ka) of Thy with Trp and Trp-based nanomaterials. A recovery study was conducted utilizing a human serum sample after the addition of the required quantity of the investigational thymine.

An in-vitro quantitative investigation on the synergistic effect of capsaicin and 5-fluorouracil encapsulated into lipid nanocapsules to treat breast cancer.

BACKGROUND: Breast cancer conventional therapeutics are effective; however, they encounter some limitations including multidrug resistance, the presence of pharmacological barriers, and non-selectivity which hinder their optimal therapeutic efficacy. AIM: Overcoming such drawbacks necessitates the development of efficient drug vehicles including lipid-based nanoparticles. This study aimed to quantitatively investigate in-vitro the synergistic therapeutic effect of the novel combination of capsaicin and 5-fluorouracil (5-FU) encapsulated in lipid nanocapsules (LNCs). METHOD: To this end, thorough physicochemical and in-vitro assessments on the breast cancer cell line (MCF-7) were done. The drug-loaded LNCs were characterized using DLS, TEM imaging, stability study, and in-vitro release study. Furthermore, the biological activity of the prepared LNCs was assessed by implementing comparative cytotoxicity studies as well as apoptosis, and cell cycle flow cytometric analyses. RESULTS: The developed nanoformulations were monodisperse with average particle size (PS) of 31, 43.8, and 127.3 nm for empty LNCs, Cap-LNCs, and 5-FU-LNCs, respectively, and with a surface charge of -35.4, -21.7 and -31.4 mV, respectively, reflecting good physical stability. The TEM micrographs revealed the spherical morphology of the drugs-loaded LNCs with comparable PS to that obtained by DLS. on the other hand, all the biological assessments confirmed the superior antiproliferative effect of the combined drug-loaded LNCs over their free drug counterparts. CONCLUSION: Intriguingly, the study findings highlighted the potential synergistic activity of the drugs (capsaicin and 5-FU) and the extensive enhancement of their biological activity through incorporation into LNCs. Such promising results will pave the way to further novel combined nanoformulation in preclinical and clinical studies on breast cancer patients.

Correction: Mansour et al. Dual-Enhanced Pluronic Nanoformulated Methotrexate-Based Treatment Approach for Breast Cancer: Development and Evaluation of In Vitro and In Vivo Efficiency. Pharmaceutics 2022, 14, 2668.

In the original publication [...].

Fortified anti-proliferative activity of niclosamide for breast cancer treatment: In-vitro and in-vivo assessment.

Breast cancer represents one of the top lethal cancer types among the females worldwide. Several factors manipulate the clinical outcome of the treatment as the stage of the cancer upon detection, genetic and hormonal factors, drug resistance and metastasis. Accordingly, drug's repositioning, enhancing the bioavailability and encapsulation into nanoparticles (NPs) are among the predilected pathways for enhanced therapeutic outcome. Niclosamide (NIC) is an anthelmintic drug and has been repositioned as anticancer agent after revealing its anti-neoplastic activity. Piperine (PIP) was used as food spice until its anticancer activity was discovered. However, their hydrophobicity constrains their therapeutic efficiency. The cytotoxicity of both drugs in the free form was tested on MCF-7 cells, and the results indicated a NIC cytotoxicity enhancement by PIP. Then, NIC and PIP were encapsulated successfully into F127-NPs with entrapment efficiency of 97 % and 82 %, respectively. Particle size, zeta potential, TEM and FTIR confirmed the micellization process and drug encapsulation. The developed NIC-NPs and PIP-NPs exerted potent anticancer effect as compared to the free forms. Accordingly, the mixture; NIC-NPs/PIP-NPs was tested and its cytotoxicity exceeded the individually encapsulated drugs. Flowcytometry assessment was performed and demonstrated an induced cell death through the apoptotic stage. Additionally, in-vivo therapeutic efficiency of NIC-NPs/PIP-NPs was assessed through Ehrlich ascites tumor and the nanocombination therapy exerted superior additive anticancer effect when compared to NIC-NPs which is attributed to the PIP-NPs induced bioavailability. The study can be considered the first one investigating the PIP role in bioenhancing the anti-proliferative activity of NIC to combat breast cancer.

Layer-by-layer development of chitosan/alginate-based platelet-mimicking nanocapsules for augmenting doxorubicin cytotoxicity against breast cancer.

Breast carcinoma is considered one of the most invasive and life-threatening malignancies in females. Mastectomy, radiation therapy, hormone therapy and chemotherapy are the most common treatment choices for breast cancer. Doxorubicin (DOX) is one of the most regularly utilized medications in breast cancer protocols. However, DOX has showed numerous side effects including lethal cardiotoxicity. This study aims to fortify DOX cytotoxicity and lowering its side effects via its combining with the antidiabetic metformin (MET) as an adjuvant therapy, along with its effective delivery using natural platelet-rich plasma (PRP), and newly-developed PRP-mimicking nanocapsules (NCs). The PRP-mimicking NCs were fabricated via layer-by-layer (LBL) deposition of oppositely charged biodegradable and biocompatible chitosan (CS) and alginate (ALG) on a core of synthesized polystyrene nanoparticles (PS NPs) followed by removal of the PS core. Both natural PRP and PRP-mimicking NCs were loaded with DOX and MET adjuvant therapy, followed by their physicochemical characterizations including DLS, FTIR, DSC, and morphological evaluation using TEM. In-vitro drug release studies, cytotoxicity, apoptosis/necrosis, and cell cycle analysis were conducted using MCF-7 breast cancer cells. Also, an in-vivo assessment was carried out using EAC-bearing balb/c mice animal model to evaluate the effect of DOX/MET-loaded natural PRP and PRP-mimicked NCs on tumor weight, volume and growth biomarkers in addition to analyzing the immunohistopathology of the treated tissues. Results confirmed the development of CS/ALG-based PRP-mimicking NCs with a higher loading capacity of both drugs (DOX and MET) and smaller size (259.7 ± 19.3 nm) than natural PRP (489 ± 20.827 nm). Both in-vitro and in-vivo studies were in agreement and confirmed that MET synergized the anticancer activity of DOX against breast cancer. Besides, the developed LBL NCs successfully mimicked the PRP in improving the loaded drugs biological efficiency more than free drugs.

Dual-Enhanced Pluronic Nanoformulated Methotrexate-Based Treatment Approach for Breast Cancer: Development and Evaluation of In Vitro and In Vivo Efficiency.

Breast cancer is a prevalent tumor and causes deadly metastatic complications. Myriad cancer types, including breast cancer, are effectively treated by methotrexate (MTX). However, MTX hydrophobicity, adverse effects and the development of resistance have inspired a search for new effective strategies to overcome these challenges. These may include the addition of a bioenhancer and/or encapsulation into appropriate nano-based carriers. In the present study, the anticancer effect of MTX was fortified through dual approaches. First, the concomitant use of piperine (PIP) as a bioenhancer with MTX, which was investigated in the MCF-7 cell line. The results depicted significantly lower IC50 values for the combination (PIP/MTX) than for MTX. Second, PIP and MTX were individually nanoformulated into F-127 pluronic nanomicelles (PIP-NMs) and F-127/P-105 mixed pluronic nanomicelles (MTX-MNMs), respectively, validated by several characterization techniques, and the re-investigated cytotoxicity of PIP-NMs and MTX-MNMs was fortified. Besides, the PIP-NMs/MTX-MNMs demonstrated further cytotoxicity enhancement. The PIP-NMs/MTX-MNMs combination was analyzed by flow cytometry to understand the cell death mechanism. Moreover, the in vivo assessment of PIP-NMs/MTX-MNMs was adopted through the Ehrlich ascites model, which revealed a significant reduction of the tumor weight. However, some results of the tumor markers showed that the addition of PIP-NMs to MTX-MNMs did not significantly enhance the antitumor effect.

How an ACE2 mimicking epitope-MIP nanofilm recognizes template-related peptides and the receptor binding domain of SARS-CoV-2.

Here we aim to gain a mechanistic understanding of the formation of epitope-imprinted polymer nanofilms using a non-terminal peptide sequence, i.e. the peptide GFNCYFP (G485 to P491) of the SARS-CoV-2 receptor binding domain (RBD). This epitope is chemisorbed on the gold surface through the central cysteine 488 followed by the electrosynthesis of a ∼5 nm thick polyscopoletin film around the surface confined templates. The interaction of peptides and the parent RBD and spike protein with the imprinted polyscopoletin nanofilm was followed by electrochemical redox marker gating, surface enhanced infrared absorption spectroscopy and conductive AFM. Because the use of non-terminal epitopes is especially intricate, here we characterize the binding pockets through their interaction with 5 peptides rationally derived from the template sequence, i.e. implementing central single amino acid mismatch as well as elongations and truncations at its C- and N- termini. Already a single amino acid mismatch, i.e. the central Cys488 substituted by a serine, results in ca. 15-fold lower affinity. Further truncation of the peptides to tetrapeptide (EGFN) and hexapeptide (YFPLQS) results also in a significantly lower affinity. We concluded that the affinity towards the different peptides is mainly determined by the four amino acid motif CYFP present in the sequence of the template peptide. A higher affinity than that for the peptides is found for the parent proteins RBD and spike protein, which seems to be due to out of cavity effects caused by their larger footprint on the nanofilm surface.

Baicalin lipid nanocapsules for treatment of glioma: characterization, mechanistic cytotoxicity, and pharmacokinetic evaluation.

OBJECTIVES: Baicalin is a promising anticancer nutraceutical compound, but its application is hindered by its low water solubility and bioavailability, which can be remedied by its encapsulation in nanoparticles. METHODS: Lipid nanocapsules (LNCs) were developed to enhance baicalin delivery via intravenous and intranasal routes, and potentiate its therapeutic activity in treatment of glioma. RESULTS: LNCs displayed a particle size of 17.76 nm and sustained release of 74.36% after 24 h. The IC50 of baicalin LNCs (13 ± 5 µg/ml) was 60 times lower than free baicalin (780 ± 107 µg/ml) on human glioblastoma multiform cell line U87, with adequate cellular uptake as delineated by confocal laser microscopy. Both baicalin and LNCs induced cell cycle arrest at S and G2/M phases, with significant up-regulation in P21 gene, and decline in Nrf-2, HO-1 and VEGF gene expression. LNCs increased baicalin's bioavailability, either after intravenous (AUC0-24 h 10.94 ± 0.28 vs 3.53 ± 0.09 µg/ml*h), or intranasal administration (AUC0-24 h 6.26 ± 0.11 vs 3.17 ± 0.04 µg/ml*h). They also bypassed the blood brain barrier and achieved significantly higher brain delivery compared to free baicalin (drug targeting efficiency 160.73% vs 52.9%). CONCLUSION: Baicalin LNCs is a promising treatment modality for glioma, when administered through intravenous or intranasal routes.

Advances in Cancer Diagnosis: Bio-Electrochemical and Biophysical Characterizations of Cancer Cells.

Cancer is a worldwide leading cause of death, and it is projected that newly diagnosed cases globally will reach 27.5 million each year by 2040. Cancers (malignant tumors), unlike benign tumors are characterized by structural and functional dedifferentiation (anaplasia), breaching of the basement membrane, spreading to adjacent tissues (invasiveness), and the capability to spread to distant sites (metastasis). In the cancer biology research field, understanding and characterizing cancer metastasis as well as features of cell death (apoptosis) is considered a technically challenging subject of study and clinically is very critical and necessary. Therefore, in addition to the cytochemical methods traditionally used, novel biophysical and bioelectrochemical techniques (e.g., cyclic voltammetry and electrochemical impedance spectroscopy), atomic force microscopy, and electron microscopic methods are increasingly being deployed to better understand these processes. Implementing those methods at the preclinical level enables the rapid screening of new anticancer drugs with understanding of their central mechanism for cancer therapy. In this review, principles and basic concepts of new techniques suggested for metastasis, and apoptosis examinations for research purposes are introduced, along with examples of each technique. From our recommendations, the privilege of combining the bio-electrochemical and biosensing techniques with the conventional cytochemical methods either for research or for biomedical diagnosis should be emphasized.

Mitochondria-targeted alginate/triphenylphosphonium-grafted-chitosan for treatment of hepatocellular carcinoma.

Mitochondrial targeting of anticancer drugs can effectively eradicate chemotherapy-refractory cells through different mechanisms. This work presents the rational designing of mitochondria-targeted core-shell polymeric nanoparticles (NPs) for efficient delivery of doxorubicin (DOX) to the hepatic carcinoma mitochondria. DOX was electrostatically nano-complexed with sodium alginate (SAL) then coated with mitotropic triphenylphosphonium-grafted chitosan (TPP+-g-CS) nanoshell. Polyvinyl alcohol (PVA) was co-solubilized into the TPP+-g-CS solution to enhance the stability of the developed NPs. The optimum NPs formula is composed of TPP+-g-CS (0.05% w/v) coating a DOX-SAL core complex (0.05% w/v), with 0.2% PVA relative to CS (w/w). The optimum NPs attained an entrapment efficiency of 63.33 ± 10.18%; exhibited a spherical shape with particle size of 70-110 nm and a positive surface charge which enhances mitochondrial uptake. FTIR and DSC studies results were indicative of an efficacious poly-complexation. In vitro biological experiments proved that the developed mitotropic NPs exhibited a significantly lower IC50, effectively induced apoptotic cell death and cell cycle arrest. Moreover, the in vivo studies demonstrated an enhanced antitumor bioactivity for the mitotropic NPs along with a reduced biological toxicity profile. In conclusion, this study proposes a promising nanocarrier system for the efficient targeting of DOX to the mitochondria of hepatic tumors.

Nanomicelles-in-coaxial nanofibers with exit channels as a transdermal delivery platform for smoking cessation.

Smoking is a life-threatening habit; that is why many nicotine-replacement therapies (NRTs), which include chewing gums, nicotine patches, lozenges, mouth sprays, inhalers and nasal sprays that are usually administered for 8-12 weeks, have been reported for smoking cessation. We report the fabrication of patches comprising nanomicelles-in-coaxial nanofibers (NFs) for the transdermal delivery of varenicline (VAR) tartrate, a partial agonist of the α4ß2 receptor subtype, for smoking cessation. The cores of the fabricated coaxial NF structures are composed of polyethylene oxide, VAR-loaded Pluronic F127 nanomicelles (NPs) and free VAR, while the shell consists of a blend of cellulose acetate (CA) and polycaprolactone (PCL) in a ratio of 1 : 9 (w/w) that incorporates 50% (wt%) free VAR. The morphology and the coaxial structure of the NFs were investigated using TEM, SEM and fluorescent microscopy. The physicochemical and mechanical properties of the scaffolds were analyzed using FTIR, DSC, DLS, TGA and a universal testing machine. SEM micrographs depict NFs with a size ranging from 793.7 ± 518.9 to 324.5 ± 144.1 nm. In vitro release of VAR reaches almost 100% after 3, 9 and 28 days for free VAR, VAR-loaded NPs and the NPs-in-NFs patches, respectively, while the ex vivo release tested using albino rat skin, over a period of 60 days, showed up to 94% sustained release of VAR. Besides, skin permeation, in vivo release and plasma concentrations of VAR from the NF transdermal patches were monitored via cyclic voltammetric measurements during the course of treatment. DFT calculations as well as mathematical release kinetic models were performed in order to study the release mechanism. The cell viability of human skin fibroblast (HSF) cells in the case of plain and VAR-loaded NFs was 75.09 and 32.11%, respectively. The in vivo results showed that VAR was being continuously released from the transdermal patch over a period of 14 days. Besides, the treatment with VAR-loaded patches did not cause any severe conditions in the studied animal model. The new fabricated NPs-in-NFs transdermal patch for VAR tartrate delivery is considered as an effective, economic, safe and long-acting NRT for smoking cessation.

Switching indication of PEGylated lipid nanocapsules-loaded with rolapitant and deferasirox against breast cancer: Enhanced in-vitro and in-vivo cytotoxicity.

Breast cancer (BC) is considered the leading cause of mortality and morbidity among adult women worldwide, and it is associated with many genetic or hormonal factors. Despite the advanced therapeutic and theranostic strategies for BC treatment, cancer metastasis and relapse are often observed among patients which lead to therapeutic failure. Accordingly, among the repositioned medication against BC proliferation is neurokinin receptor antagonists and iron chelating agents especially rolapitant HCl (RP) and deferasirox (DFO), respectively. However, RP and DFO are classified as class II with low aqueous solubility. Both drugs were nanoformulated into PEGylated lipid nanocapsules (LNCs) for enhancing their aqueous solubility and augmenting their efficacy. RP-LNCs, DFO-LNCs and their combinations were evaluated according to particle size (PS), zeta potential, polydispersity index (PDI) and surface morphology. Importantly, the antitumor effect of these novel molecules and their nanoforms was evaluated against the suppression of Ehrlich Ascites tumor model using female mice. Results revealed that RP-LNCs, DFO-LNCs and RP/DFO-LNCs exerted PS from 45.23 ± 3.54 to 60.1 ± 3.32 nm with PDI around 0.20 which indicates homogenous particles distribution. Also, RP-LNCs, DFO-LNCs and RP/DFO-LNCs displayed surface charges of +16.6 ± 6.9, -13.3 ± 5.82 and - 20.2 ± 5.40 mV, respectively. The obtained LNCs conferred a high potent cytotoxic effect against MCF7 cancer cells as compared to parent drugs, with IC50 of 10.86 ± 0.89, 3.34 ± 0.99 and 2.24 ± 0.97 µg/mL for RP-LNCs, DFO-LNCs and RP/DFO-LNCs, respectively. The in-vivo pharmacodynamics effect of the developed nano-formulations showed superior antitumor effect for the individual drugs rather than their combinations as compared to the control group. The current study confirmed the potential of RP and DFO nanoforms as promising therapeutic agents for BC treatment.

Development and Evaluation of Core-Shell Nanocarrier System for Enhancing the Cytotoxicity of Doxorubicin/Metformin Combination Against Breast Cancer Cell Line.

Breast cancer is the most invasive and life-threatening cancer in women. The treatment options are usually a combination of mastectomy, radiation therapy, hormonal therapy and chemotherapy. As a standard practice, doxorubicin (DOX) is one of the commonly used drugs for breast cancer treatment. However, DOX is known to have many harmful adverse effects including its cardiotoxicity. Hence, recent reports used metformin (MET), an anti-diabetic drug, as an adjuvant therapy to decrease the severity of DOX's adverse effects and to improve its ultimate therapeutic outcome. The current study is aimed at co-loading and enhancing the encapsulation efficiency of the hydrophilic DOX and MET in poly(lactic-co-glycolic acid) (PLGA) nanocapsules (NCs) with oil core for breast cancer treatment. The NCs were developed by single emulsification-solvent diffusion technique, and were optimized through using two types of oils, pluronics and PLGA (50:50) of different molecular weights followed by various physicochemical characterizations. The obtained DOX/MET-loaded NCs showed the size and polydispersity index (PDI) of 203.0 ± 3.4 nm and 0.081 ± 0.03, respectively with a surface charge of -2.15 ± 0.2 mV. The entrapment efficiency of DOX and MET were about 93.7% ± 2.9 and 70% ± 1.6, respectively. The developed PLGA core-shell NCs successfully sustained the DOX/MET release for more than 30 days. The in-vitro results showed a significant enhancement in DOX cytotoxic effect as well as a duplication in its apoptotic effect upon addition of MET for both free DOX/MET combination and DOX/MET-loaded PLGA NCs against MCF-7. Besides, flow cytometry demonstrated that the DOX/MET-loaded NCs possess their antitumor effect by preventing DNA replication and cell division. This study provides a promising facile, rapid and reproducible single emulsification-solvent diffusion technique for improving the encapsulation and release of hydrophilic drugs in nanocapsules for biomedical applications.

Ticagrelor.

Ticagrelor is one of the most recent antiplatelet agents used to inhibit platelet aggregation via blocking the ADP receptors of the subtype P2Y12. It belongs to the non-thienopyridine class. The drug was first discovered by Astra Zeneca and approved for use in 2011 by the FDA. Ticagrelor is usually used for the prevention and treatment of thromboembolism in adult patients with acute coronary syndrome. This chapter include an overview on the physical properties, chemical properties, mode of action, pharmacokinetics and common uses of ticagrelor. In addition, the reported methods of ticagrelor assay will be discussed briefly in order to help analysts to find the most convenient method for its estimation in routine analysis. The methods of synthesis used for the preparation of ticagrelor will also be covered in this chapter. Moreover, the analytical and characterization techniques used to characterize ticagrelor row material are summarized herein.

New repurposed rolapitant in nanovesicular systems for lung cancer treatment: Development, in-vitro assessment and in-vivo biodistribution study.

Lung cancer is characterized by poor prognosis, and is considered a serious disease that causes a significant mortality. The available conventional chemotherapeutic agents suffer from several limitations; hence, new drug molecules are constantly being sought. In the current study, lipid nanovesicles (LNVs) were selected as a colloidal vehicle for encapsulation of the FDA-approved drug; rolapitant (RP), which is used particularly for the treatment of nausea and vomiting, but is repurposed for the treatment of lung cancer in the current work. RP was loaded into various LNVs (liposomes, ethosomes and transethosomes) using the thin film hydration method, and the LNVs were evaluated for particle size, zeta potential, entrapment efficiency (EE%), storage stability and surface morphology. Besides, the in-vitro drug release, in-vitro cytotoxicity on A549 lung cancer cells, nebulization performance using next generation impactor (NGI), and the in-vivo biodistribution behavior were evaluated. The selected ethosomal and transethosomal vesicles displayed a particle size less than 400 nm, a positive charge, and EE% exceeding 90% for RP, with a sustained release pattern over 15 days. The in-vivo biodistribution results proved the high lung deposition potential of RP-LNVs with a considerable safety. Besides, the developed RP-LNVs were able to reach the metastatic organs of lung cancer, hence they were proven promising as a possible treatment modality for lung cancer.