Efficient intracellular trafficking and targeted delivery to the site of action are essential to overcome the current drawbacks of cancer therapeutics. Cell Penetrating Peptides (CPPs) offer the ...possibility of efficient intracellular trafficking, and, therefore the development of drug delivery systems using CPPs as cargo carriers is an attractive strategy to address the current drawbacks of cancer therapeutics. Additionally, the possibility of incorporating Tumor Targeting Peptides (TTPs) into the delivery system provides the necessary drug targeting effect. Therefore the conjugation of CPPs and/or TTPs with therapeutics provides a potentially efficient method of improving intracellular drug delivery mechanisms. Peptides used as cargo carriers in DDS have been shown to enhance the cellular uptake of drugs and thereby provide an efficient therapeutic benefit over the drug on its own. After providing a brief overview of various drug targeting approaches, this review focusses on peptides as carriers and targeting moieties in drug-peptide covalent conjugates and summarizes the most recent literature examples where CPPs on their own or CPPs together with TTPs have been conjugated to anticancer drugs such as Doxorubicin, Methotrexate, Paclitaxel, Chlorambucil etc. A short section on CPPs used in multicomponent drug delivery systems is also included.
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The presence of "hypoxic" tissue (with O
levels of <0.1 mmHg) in solid tumours, resulting in quiescent tumour cells distant from blood vessels, but capable of being reactivated by reoxygenation ...following conventional therapy (radiation or drugs), have long been known as a limitation to successful cancer chemotherapy. This has resulted in a sustained effort to develop nitroaromatic "hypoxia-activated prodrugs" designed to undergo enzyme-based nitro group reduction selectively in these hypoxic regions, to generate active drugs. Such nitro-based prodrugs can be classified into two major groups; those activated either by electron redistribution or by fragmentation following nitro group reduction, relying on the extraordinary difference in electron demand between an aromatic nitro group and its reduction products. The vast majority of hypoxia-activated fall into the latter category and are discussed here classed by the nature of their nitroaromatic trigger units.
The p38 MAP kinases are a sub-family of the broad group of mitogen-activated serinethreonine protein kinases. The best-characterised, most widely expressed, and most targeted by drugs is p38α MAP ...kinase. This review briefly summarises the place of p38α MAP kinase in cellular signalling and discusses the structures and activity profiles of representative examples of the major classes of inhibitors and activators (both synthetic compounds and natural products) of this enzyme. Primary screening was direct in vitro inhibition of isolated p38α enzyme.
Acridine derivatives are one of the oldest classes of bioactives, widely used as antibacterial and antiprotozoal agents. Some work in these areas continues, but recent research has focused mainly on ...their use as anticancer drugs, because of the ability of the acridine chromophore to intercalate DNA and inhibit topoisomerase enzymes.
Colony stimulating factor 1 receptor (CSF-1R, also known as c-FMS kinase) is in the class III receptor tyrosine kinase family, along with c-Kit, Flt3 and PDGFRα. CSF-1/CSF-1R signaling promotes the ...differentiation and survival of myeloid progenitors into populations of monocytes, macrophages, dendritic cells and osteoclasts, as well as microglial cells and also recruits host macrophages to develop into tumor-associated macrophages (TAMs), which promote tumor progression and metastasis.
In the last 5 years, and recently stimulated by the approval of pexidartinib (Turalio™, Daiichi Sankyo) in 2019 for the treatment of tenosynovial giant cell tumors, there has been a large increase in activity (both journal articles and patent applications) around small molecule inhibitors of CSF1R. Features of this work have been the surprising diversity of chemical classes shown to be potent and selective inhibitors, and the breadth of disease states (cancer, arthritis, and 'cytokine storm' syndromes) covered by CSF1R inhibitors. All these aspects are covered in the following sections.
The field has developed rapidly from 2014 to the present, with many different chemotypes proving to be potent inhibitors. The range of potential utilities of CSF1R inhibitors has also expanded to include dementia, ulcerative colitis/Crohn's disease, rheumatoid arthritis inflammation, and fibrosis.
The l-type amino acid transporter 1 (LAT1) is a transmembrane protein carrying bulky and neutral amino acids into cells. LAT1 is overexpressed in several types of tumors, and its inhibition can ...result in reduced cancer cell growth. However, known LAT1 inhibitors lack selectivity over other transporters. In the present study, we designed and synthesized a novel selective LAT1 inhibitor (1), which inhibited the uptake of LAT1 substrate, l-leucin as well as cell growth. It also significantly potentiated the efficacy of bestatin and cisplatin even at low concentrations (25 μM). Inhibition was slowly reversible, as the inhibitor was able to be detached from the cell surface and blood-brain barrier. Moreover, the inhibitor was metabolically stable and selective toward LAT1. Since the inhibitor was readily accumulated into the prostate after intraperitoneal injection to the healthy mice, this compound may be a promising agent or adjuvant especially for the treatment of prostate cancer.
The aim of this study was to investigate the effect of wet milling on the solid state of indomethacin (IMC) and simvastatin (SIM). Wet milling was performed using high pressure homogenization (HPH). ...Polyvinylpyrrolidone-K25 (PVP) and poloxamer 407 (P407) were used as suspension stabilizers. Samples were characterized before and after wet milling using particle size analyzer, scanning electron microscopy (SEM), infrared (IR) spectroscopy and modulated temperature differential scanning calorimetry (MTDSC) techniques. After wet milling of IMC, physical appearance and IR spectra indicated surface amorphization; however, the solid state of SIM remained unaffected. MTDSC could not detect surface amorphization in IMC, suggesting that if present, it was only at very low levels. These results are in contradiction to the previous reports where dry milling of IMC and SIM resulted in amorphization of crystalline particles. Moreover, cryogrinding of IMC in the absence of water resulted in an amorphous form while presence of water using the same cryogrinding conditions resulted in a solid state similar to that obtained after wet milling. These results signify the role of water in inhibiting the amorphization during wet milling of crystalline drugs.
This review provides an update on the mutagenicity of intercalating chemicals, as carried out over the last 17 years. The most extensively studied DNA intercalating agents are acridine and its ...derivatives, that bind reversibly but non-covalently to DNA. These are frameshift mutagens, especially in bacteria and bacteriophage, but do not otherwise show a wide range of mutagenic properties. Di-acridines or di-quinolines may be either mono- or bis-intercalators, depending upon the length of the alkyl chain separating the chromophores. Those which monointercalate appear as either weak frameshift mutagens in bacteria, or as non-mutagens. However, some of the bisintercalators act as "petite" mutagens in Saccharomyces cerevisiae, suggesting that they may be more likely to target mitochondrial as compared with nuclear DNA. Some of the new methodologies for detecting intercalation suggest this may be a property of a wider range of chemicals than previously recognised. For example, quite a number of flavonoids appear to intercalate into DNA. However, their mutagenic properties may be dominated by the fact that many of them are also able to inhibit topoisomerase II enzymes, and this property implies that they will be potent recombinogens and clastogens. DNA intercalation may serve to position other, chemically reactive molecules, in specific ways on the DNA, leading to a distinctive (and wider) range of mutagenic properties, and possible carcinogenic potential.
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