Nanotechnology-based Strategies To Enhance Chemo-and Radiation Therapy In Breast Cancer

A major cause of cancer treatment failure is multidrug resistance (MDR) and radioresistance to standard therapies. Overexpression of ATP-binding cassette (ABC) transport proteins by cancer cells, which actively transport anti-cancer agents (e.g. doxorubicin, Dox) out of the cells against concentration gradients, is a major barrier to effective chemotherapy. Low levels of oxygen in tumors are responsible for radioresistance contributing to the failure of radiation therapy (RT) of solid tumors. This thesis concerns the development and evaluation of three nanoparticle delivery systems for overcoming tumor resistance to chemo- and radiotherapy. System 1: polymer lipid hybrid nanoparticles (PLN), co-loaded with a synergistic combination of anticancer agents Dox and mitomycin C (MMC) (DMsPLN), were found to overcome multiple membrane efflux pumps mediated MDR in vitro. Systemic administration of DMsPLN significantly enhanced therapeutic efficacy in orthotopic tumor models of Dox-sensitive and resistant human breast cancer cells, with low systemic toxicity compared to a clinically used liposomal formulation of Dox. System 2: cyclic Arg-Gly-Asp (RGD), a ligand that binds with αvβ3 intergin receptors preferentially expressed in angiogenic tumor blood vessels and certain cancer cells, was conjugated to DMsPLN. The Integrin-targeted RGD-DMsPLN resulted in a significant reduction in lung metastases of human breast cancer cells without producing drug-associated systemic toxicity as observed in mice treated with free Dox-MMC solutions. System 3: Manganese dioxide nanoparticles (MnO2 NPs) were developed and the reactivity of MnO2 towards peroxides was utilized to regulate the tumor microenvironment in a murine breast tumor. Intratumoral administration of MnO2 NPs simultaneously increased tumor oxygenation by 45%, and tumor pH from pH 6.7 to pH 7.2 by reacting with endogenous H2O2 produced within the tumor. Combination treatment of the tumors with NPs and ionizing radiation significantly inhibited breast tumor growth, increased DNA double strand breaks and cancer cell death as compared to RT alone. The design and application of these three novel nanotechnology platforms, in pharmaceutically acceptable NP formulations, provide promising therapeutic strategies for enhanced chemo- and radiation therapy of breast cancer.Ph.D.2016-11-30 00:00:0

Hybrid quantum dot 12fatty ester stealth nanoparticles: toward clinically relevant in vivo optical imaging of deep tissue

Despite broad applications of quantum dots (QDs) in vitro, severe toxicity and dominant liver uptake have limited their clinical application. QDs that excite and emit in the ultraviolet and visible regions have limited in vivo applicability due to significant optical interference exerted by biological fluids and tissues. Hence we devised a new biocompatible hybrid fluorophore composed of near-infrared-emitting PbSe quantum dots encapsulated in solid fatty ester nanoparticles (QD-FEN) for in vivo imaging. The quantum yield and tissue penetration depth of the QD-FEN were characterized, and their biological fate was examined in a breast tumor-bearing animal model. It was found for the first time that chemical modification of the headgroup of QD-encapsulating organic fatty acids was a must as these groups quenched the photoluminescence of PbSe nanocrystals. The use of fatty esters enhanced aqueous quantum yields of PbSe QDs up to 45%, which was 50% higher than that of water-soluble PbSe nanocrystals in an aqueous medium. As a result, a greater than previously reported tissue penetration depth of fluorescence was recorded at 710 nm/840 nm excitation/emission wavelengths. The QD-FEN had much lower short-term cytotoxicity compared to nonencapsulated water-soluble QDs. More importantly, reduced liver uptake, increased tumor retention, lack of toxic response, and nearly complete clearance of QD-FEN from the tested animals was demonstrated. With a combination of near-infrared spectral properties, enhanced optical properties,and significantly improved biosafety profile, this novel hybrid nanoparticulate fluorophore system demonstrably provides real-time, deep-tissue fluorescent imaging of live animals, laying a foundation for further development toward clinical application.Peer reviewed: YesNRC publication: Ye

A cross‐sectional study of the prevalence and clinical management of atherosclerotic cardiovascular diseases in patients with type 2 diabetes across the Middle East and Africa ( PACT‐MEA ): Study design and rationale

© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-Non Commercial-No Derivs License. https://creativecommons.org/licenses/by-nc-nd/4.0/Aim: To investigate the epidemiology and clinical management of patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (eASCVD) or high/very high ASCVD risk, defined by the 2021 European Society of Cardiology Guidelines, in seven countries in the Middle East and Africa (PACT‐MEA; NCT05317845), and to assess physicians' attitudes and the basis for their decision‐making in the management of these patients. Materials and Methods: PACT‐MEA is a cross‐sectional, observational study undertaken in Bahrain, Egypt, Jordan, Kuwait, Qatar, South Africa and the United Arab Emirates based on a medical chart review of approximately 3700 patients with T2D in primary and secondary care settings, and a survey of approximately 400 physicians treating patients with T2D. Results: The primary and secondary objectives are to determine the prevalence of eASCVD and high/very high ASCVD risk in patients with T2D. Current treatment with cardioprotective antidiabetic medication, the proportion of patients meeting the treatment criteria for reimbursement in the study countries where there is an applicable reimbursement guideline, and physician‐reported factors in clinical decision‐making in T2D management, will also be assessed. Conclusions: This large cross‐sectional study will establish the estimated prevalence and management of eASCVD and high/very high ASCVD risk in patients with type 2 diabetes across the Middle East and Africa.Peer reviewe

Multifunctional Albumin–MnO₂ Nanoparticles Modulate Solid Tumor Microenvironment by Attenuating Hypoxia, Acidosis, Vascular Endothelial Growth Factor and Enhance Radiation Response

Insufficient oxygenation (hypoxia), acidic pH (acidosis), and elevated levels of reactive oxygen species (ROS), such as H₂O_2, are characteristic abnormalities of the tumor microenvironment (TME). These abnormalities promote tumor aggressiveness, metastasis, and resistance to therapies. To date, there is no treatment available for comprehensive modulation of the TME. Approaches so far have been limited to regulating hypoxia, acidosis, or ROS individually, without accounting for their interdependent effects on tumor progression and response to treatments. Hence we have engineered multifunctional and colloidally stable bioinorganic nanoparticles composed of polyelectrolyte–albumin complex and MnO₂ nanoparticles (A-MnO₂ NPs) and utilized the reactivity of MnO₂ toward peroxides for regulation of the TME with simultaneous oxygen generation and pH increase. <i>In vitro</i> studies showed that these NPs can generate oxygen by reacting with H₂O₂ produced by cancer cells under hypoxic conditions. A-MnO₂ NPs simultaneously increased tumor oxygenation by 45% while increasing tumor pH from pH 6.7 to pH 7.2 by reacting with endogenous H₂O₂ produced within the tumor in a murine breast tumor model. Intratumoral treatment with NPs also led to the downregulation of two major regulators in tumor progression and aggressiveness, that is, hypoxia-inducible factor-1 alpha and vascular endothelial growth factor in the tumor. Combination treatment of the tumors with NPs and ionizing radiation significantly inhibited breast tumor growth, increased DNA double strand breaks and cancer cell death as compared to radiation therapy alone. These results suggest great potential of A-MnO₂ NPs for modulation of the TME and enhancement of radiation response in the treatment of cancer

A Multifunctional Polymeric Nanotheranostic System Delivers Doxorubicin and Imaging Agents across the Blood–Brain Barrier Targeting Brain Metastases of Breast Cancer

Metastatic brain cancers, in particular cancers with multiple lesions, are one of the most difficult malignancies to treat owing to their location and aggressiveness. Chemotherapy for brain metastases offers some hope. However, its efficacy is severely limited as most chemotherapeutic agents are incapable of crossing the blood–brain barrier (BBB) efficiently. Thus, a multifunctional nanotheranostic system based on poly(methacrylic acid)–polysorbate 80-grafted-starch was designed herein for the delivery of BBB-impermeable imaging and therapeutic agents to brain metastases of breast cancer. <i>In vivo</i> magnetic resonance imaging and confocal fluorescence microscopy were used to confirm extravasation of gadolinium and dye-loaded nanoparticles from intact brain microvessels in healthy mice. The targetability of doxorubicin (Dox)-loaded nanoparticles to intracranially established brain metastases of breast cancer was evaluated using whole body and <i>ex vivo</i> fluorescence imaging of the brain. Coexistence of nanoparticles and Dox in brain metastatic lesions was further confirmed by histological and microscopic examination of dissected brain tissue. Immuno-histochemical staining for caspase-3 and terminal-deoxynucleotidyl transferase dUTP nick end labeling for DNA fragmentation in tumor-bearing brain sections revealed that Dox-loaded nanoparticles selectively induced cancer cell apoptosis 24 h post-injection, while sparing normal brain cells from harm. Such effects were not observed in the mice treated with free Dox. Treatment with Dox-loaded nanoparticles significantly inhibited brain tumor growth compared to free Dox at the same dose as assessed by <i>in vivo</i> bioluminescence imaging of the brain metastases. These findings suggest that the multifunctional nanoparticles are promising for the treatment of brain metastases