Synthetic Polymers as Drug-Delivery Vehicles in Medicine

Cancerous diseases present a formidable health problem worldwide. While the chemotherapy of cancer, in conjunction with other treatment modalities, has reached a significant level of maturity, efficacious use of such agents is still restricted by numerous pharmacological deficiencies, such as poor water solubility, short serum circulation lifetimes, and low bioavailability resulting from lack of affinity to cancer tissue and inadequate mechanisms of cell entry. More critically still, most drugs suffer from toxic side effects and a risk of drug resistance. The class of platinum anticancer drugs, although outstandingly potent, is particularly notorious in that respect. Among the countless methods developed in recent years in an effort to overcome these deficiencies, the technology of polymer-drug conjugation stands out as a particularly advanced treatment modality. The strategy involves the bioreversible binding, conjugating, of a medicinal agent to a water-soluble macromolecular carrier. Following pharmacokinetic pathways distinctly different from those of the common, nonpolymeric drugs, the conjugate so obtained will act as a prodrug providing safe transport of the bioactive agent to and into the affected, that is, cancerous cell for its ultimate cell-killing activity. The present treatise will acquaint us with the pharmacological fundamentals of this drug delivery approach, applied here specifically to the metalorganic platinum-type drug systems and the organometallic ferrocene drug model. We will see just how this technology leads to conjugates distinctly superior in antiproliferative activity to cisplatin, a clinically used antitumor agent used here as a standard. Polymer-drug conjugation involving metal-based and other medicinal agents has unquestionably matured to a practical tool to the pharmaceutical scientist, and all indications point to an illustrious career for this nascent drug delivery approach in the fight against cancer and other human maladies

Unintended outcomes of Ethiopia’s state-led development

Ethiopia’s centralized programmes of economic growth and social development are bringing the nation towards achievement of its goal of becoming “a middle-income country by the year 2025” (MoE, 2015: 11). Significant advances in social programmes have resulted in longer life spans, increased incomes, and a much better educated population. Yet, unexpected outcomes are inadvertently threatening the state. The emergence of a thriving middle class, especially among those employed in service industries in the metropolis of Addis Ababa, has resulted in a demand for better and more comfortable housing. However, residential and other construction has only been possible through the expropriation of land along the periphery of the city and this is displacing hundreds of thousands of smallholders. At the same time, the federal government has considerably increased educational opportunities. Although this has been widely beneficial, it has also resulted in secondary school leavers and university graduates who substantially outnumber current employment opportunities. While issues of developmentally induced ousting and youth unemployment pertain to other areas of Ethiopia, they are occurring particularly rapidly along the periphery of Addis Ababa. Ousted smallholders must quickly adopt new non-farm livelihoods while a better-educated youth cohort must find suitable and proper employment. A sense of groupism has moderated the reactions of smallholders to their ousting even as the frustration of unemployment among youth groups is manifesting in anti-government disturbances. These issues existentially threaten Ethiopia’s political and social order. This thesis explores the reactions of smallholders and students to Ethiopia’s successful social and economic development through a conceptual examination of the role of in situ and ex situ displacement narratives. It finds that different groups have exhibited significantly divergent reactions to their circumstances. It concludes that while Ethiopia’s form of centralized development has undeniably benefitted the nation, those benefits are, themselves, inadvertently resulting in secondary issues which impinge upon stability and individual prosperity

Carrier-bound Methotrexate. III.‡ Antiproliferative Activity of Macromolecular MTX Conjugates Against the Human HeLa and Colo Carcinoma Cell Lines

In continuation of studies in these laboratories aiming at the bioevaluation of macromolecular anticancer drug models, in vitro cytotoxicity screens are performed on several series of water-soluble polymer-methotrexate  conjugates. The methotrexate drug in these conjugates is bound through amide or ester linkages to water- soluble polyamide- or polyamidoamine-type carriers by previously developed anchoring techniques.Tests were  conducted against the HeLahumancervical carcinoma cell line generally considered to be drug-sensitive, and  against two variants of the rather refractory Colo 320 DM, a human colon adenocarcinoma line.KEYWORDS: Drug conjugation, Colo cell line, HeLa cell line, methotrexate, polyaspartamide,  polyamidoamine

Synthesis and Anchoring of Antineoplastic Ferrocene and Phthalocyanine Derivatives on Water-Soluble Polymeric Drug Carriers Derived from Lysine and Aspartic Acid

The general synthetic strategy towards water-soluble biodegradable drug carriers and the properties that they must have are discussed. The syntheses of water-soluble biodegradable copolymers of lysine and aspartic acid as potential drug-delivering devices, having amine-functionalised side chains are then described. Covalent anchoring of carboxylic acid derivatives of the antineoplastic ferrocene and photodynamically active phthalocyanine moieties to the amine-containing drug carrier copolymers under mild coupling conditions has been achieved utilising the coupling reagent O-benzotriazolyl-N,N,N′,N′-tetramethyluronium hexafluorophosphate to promote formation of the biodegradable amide bond. Even though the parent antineoplastic ferrocene and phthalocyanine derivatives are themselves insoluble in water at pH < 7, the new carrier-drug conjugates that were obtained are well water-soluble

Dichloridobis[(ferrocenyl­methyl­idene)(furan-2-ylmeth­yl)amine-κN]palladium(II)

The title compound, [Fe2Pd(C5H5)2(C11H10NO)2Cl2], exhibits a square-planar geometry at the PdII atom, which is determined by inversion-related chlorine and ferrocenyl­imine mol­ecules across a center of symmetry. The ferrocenyl­imine moieties are trans to each other

Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes

Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with significant heterogeneity in disease progression. Existing clinical models of progression risk do not fully capture this heterogeneity. Here we integrate 42 genetic alterations from 214 SMM patients using unsupervised binary matrix factorization (BMF) clustering and identify six distinct genetic subtypes. These subtypes are differentially associated with established MM-related RNA signatures, oncogenic and immune transcriptional profiles, and evolving clinical biomarkers. Three genetic subtypes are associated with increased risk of progression to active MM in both the primary and validation cohorts, indicating they can be used to better predict high and low-risk patients within the currently used clinical risk stratification models

Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression

PURPOSE: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway (KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models

Aryl Germanes as Ligands for transition Polymetallic Complexes: Synthesis, Structure, and Properties

A series of new carbonyl dichromium complexes bearing aryl germanes as ligands were prepared using improved approaches. The thermal reaction of Cr(CO)6 (1) with Me3GeGePh3 (3) led to the formation of Me3GeGePh[(η6‐C6H5)Cr(CO)3]2 (3a). The lithiation of [(η6‐C6H6)Cr(CO)3] (2) with nBuLi followed by the addition of Me2GeCl2 (4) or ClGeMe2GeMe2Cl (5) gave Me2Ge[(η6‐C6H5)Cr(CO)3]2 (4a) and [(OC)3Cr(η6‐C6H5)]GeMe2GeMe2[(η6‐C6H5)Cr(CO)3] (5a), respectively. The molecular structures of 3a and 4a, in their crystal forms, were studied by X‐ray diffraction analysis. The crystals of oligogermane 3a have shown to undergo a fully reversible phase transition at 160 K without any sign of decomposition. The complexes synthesized were also studied by multinuclear NMR, IR and UV/Vis spectroscopy, DFT calculations and electrochemistry. The presence of a Cr(CO)3 group in a range of oligogermanes has shown to impact on the physical and chemical properties of the compounds