1,720,979 research outputs found
Thermosensitive liposomes in cancer therapy
No full textThermosensitive liposomes have been a popular area of investigation for several years leading to a plentitude of scientific literature and several patents. The majority of formulations are still in the early stage of development and preclinical testing, although one formulation, ThermoDox®, is significantly more advanced. This formulation is now in clinical trials for a few different cancer indications. In this review, key patents and publications through the evolution of thermosensitive lipososomes are presented, including the use of polymers, lipids and other molecules to control the temperature sensitivity. ThermoDox® is discussed with an update on recent experiments and reports from the clinical trials. Finally, a summary of recent formulations designed to improve upon the ThermoDox® benchmark is presented, and the challenges and future directions for thermosensitive liposome technology are discussed.</p
Tryptathionine bridges in peptide synthesis
No full textThe tryptathionine linkage is a crosslink formed between tryptophan and cysteine. This feature is characteristic of the bicyclic peptides: the phallotoxins and the amatoxins. These peptides both bind to protein folds of their respective targets (F-actin and RNA pol II, respectively) with extremely high affinities. Studies on these peptides have shown that the tryptathionine crosslink is essential for this binding affinity. Tryptathionines have been investigated for many years and several syntheses exist for their formation. In this review, we report on the various methodologies employed in tryptathionine synthesis, and discuss some of the advantages and disadvantages associated with each of them.</p
Intraannular savige-fontana reaction: One-step conversion of one class of monocyclic peptides into another class of bicyclic peptides
No full textCyclisation and cross-linking strategies are important for the synthesis of cyclic and bicyclic peptides. These macrolactams are of great interest due to their increased biological activity compared to linear analogues. Herein, we describe the synthesis of a cyclic peptide containing an Hpi toxicophore, reminiscent of phakellistatins and omphalotins. The first intraannular cross-linking of such a peptide is then presented: using neat TFA to catalyse a Savige-Fontana tryptathionylation, the Hpi-containing peptide is converted to a bicyclic amatoxin analogue. As such, this methodology represents an efficient cyclisation method for cross-linking peptides and exposes a heretofore unrealised relationship between two different classes of peptide natural products. This finding increases the degree of potential chemical space for library generation.</p
Diastereoselectivity in the synthesis of syn-cis-3a-hydroxypyrrolo[2,3-b] indoline N<sup>α′</sup>-methyl-dipeptide methyl esters
No full textDescribed herein is a high yielding, diastereoselective synthesis of the syn-cis hydroxypyrroloindoline moiety by oxidation of the Nα-trityl- tryptophan-Nα-methyl-dipeptide methyl esters.</p
Hyperthermia-induced drug targeting
No full textIntroduction: Specific delivery of a drug to a target site is a major goal of drug delivery research. Using temperature-sensitive liposomes (TSLs) is one way to achieve this; the liposome acts as a protective carrier, allowing increased drug to flow through the bloodstream by minimizing clearance and non-specific uptake. On reaching microvessels within a heated tumor, the drug is released and quickly penetrates. A major advance in the field is ThermoDox® (Celsion), demonstrating significant improvements to the drug release rates and drug uptake in heated tumors (∼ 41°C). Most recently, magnetic resonance-guided focused ultrasound (MRgFUS) has been combined with TSL drug delivery to provide localized chemotherapy with simultaneous quantification of drug release within the tumor. Areas covered: In this article the field of hyperthermia-induced drug delivery is discussed, with an emphasis on the development of TSLs and their combination with hyperthermia (both mild and ablative) in cancer therapy. State-of-the-art image-guided heating technologies used with this combination strategy will also be presented, with examples of real-time monitoring of drug delivery and prediction of efficacy. Expert opinion: The specific delivery of drugs by combining hyperthermia with TSLs is showing great promise in the clinic and its potential will be even greater as the use of image-guided focused ultrasound becomes more widespread-a technique capable of penetrating deep within the body to heat a specific area with improved control. In conjunction with this, it is anticipated that multifunctional TSLs will be a major topic of study in this field.</p
Stereoselective Synthesis of Brevianamide E
No full textThe hydroxypyrroloindolenine (Hpi) motif forms the fundamental core of the pentacyclic natural product, brevianamide E, the concise stereoselective synthesis of which, via oxidative cyclization, is described.</p
Immune responses of therapeutic lipid nanoparticles
No full textNanoparticle-based drug delivery is an emerging technology for targeting therapeutics to the diseased site for enhanced therapy and reduced toxicity. A number of pharmaceutical products that involve nanotechnology have been approved for clinical use, and because of altered pharmacokinetics and biodistribution, their profiles of interaction with host cells and resulting toxicity are different from parent agents. This review focuses on the immune responses induced by therapeutic lipid nanoparticles. These immune responses can provoke toxicity, affect pharmacokinetics of the nanoparticles or induce therapeutic effect. This article begins with a general introduction on immune responses and innate and acquired immunity. Specific examples of therapeutic lipid nanoparticles inducing immune responses in each category are presented with detailed discussions on the mechanisms. Current guidelines for evaluating immune response of nanomedicines are summarized. Finally, perspectives and future directions are provided emphasizing mechanistic studies of immune reactions triggered by nanoparticles.</p
Recent progress in the development of polysaccharide conjugates of docetaxel and paclitaxel
No full textTaxanes are one of the most potent and broadest spectrum chemotherapeutics used clinically, but also induce significant side effects. Different strategies have been developed to produce a safer taxane formulation. Development of polysaccharide drug conjugates has increased in the recent years because of the demonstrated biocompatibility, biodegradability, safety, and low cost of the biopolymers. This review focuses on polysaccharide-taxane conjugates and provides an overview on various conjugation strategies and their effect on the efficacy. Detailed analyses on the designing factors of an effective polysaccharide-drug conjugate are provided with a discussion on the future direction of this field.</p
Synthesis, characterisation, and in vitro evaluation of pro <sup>2</sup>-Ile<sup>3</sup>-S-deoxo-amaninamide and pro<sup>2</sup>-D-allo- Ile<sup>3</sup>-5-deoxo-amaninamide: Implications for structure-activity relationships in amanitin conformation and toxicity
No full textThe amatoxins are a family of toxic bicyclic peptides that inhibit RNA polymerase II. Herein we discuss an improved synthesis of these compounds from easily obtainable amino acids by means of a solid-phase methodology. Interestingly, we obtained two products of the same mass following our final macrocyclisation, relating to a similar distribution of products described in some previous reports. One of these products was the desired amatoxin ; Pro 2-Ile3-S-deoxo-amaninamide 1b. The other compound, after thorough investigation, was confirmed to be the epimer Pro2-D-allo- Ile3-S-deoxoamaninamide 1a, not an atropisomer structure as previously suggested in syntheses of related amanitin analogues. Crystallographic data of 1a confirms the presence of a βII-turn, rather than a βI-turn common to the natural toxin and 1b. This difference explains the large variation in CD spectra, although it seems to have relatively little effect on the bioactivity in vitro. These data provide new insights into the bicyclic amatoxin structure.</p
A thermosensitive liposome prepared with a Cu <sup>2+</sup> gradient demonstrates improved pharmacokinetics, drug delivery and antitumor efficacy
No full textHere we report the development of an enhanced thermosensitive formulation composed of DPPC and Brij78, loaded with doxorubicin (DOX) using a Cu 2+ gradient and post-inserted with an additional amount of Brij78. This optimal formulation (HaT-II: Hyperthermia-activated cytoToxic) displayed significantly improved stability in serum at 37°C, and enhanced drug release rates at 41-42°C, compared to LTSL (lyso-lipid temperature sensitive liposomes, DPPC/MSPC/DSPE-PEG 2000 = 86/10/4, pH gradient drug loading). HaT-II released 100% DOX within 15-40 s at 40-42°C, with only 5% drug leakage at 37°C after 30 min in serum, while LTSL lost 30% of its drug content at 37°C and exhibited ∼ 2-fold decreased release rate constants at 41-42°C under the same conditions. The pharmacokinetics of DOX was significantly improved in non-heated HaT-II treated healthy mice with 2.5-fold increased area under the curve and 2-fold prolonged circulation half life compared to LTSL. This led to 2-fold improved drug delivery to the heated tumor by HaT-II (∼ 20% injected dose/g tissue), relative to LTSL and significantly enhanced antitumor efficacy with complete inhibition of tumor growth after a single dose of HaT-II. Finally, HaT-II exhibited little toxicity in mice, inducing no body weight loss and no abnormality in the blood chemistry (10 mg DOX/kg).</p
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