Self-assembling tyrosine kinase inhibitors for localised targeted delivery

Localised delivery of cancer therapy is an approach used to overcome the serious side effects associated with the systemic treatment of many anticancer drugs which is the main route of administration. Low molecular weight gelators have received great attention in recent years as a drug delivery strategy for localised targeted therapy. These are small molecules, which self-assemble into a 3D network fibre via non-covalent interactions to create macroscopically a gel. Studies on this drug delivery platform provide an alternative to the extensively investigated gel delivery systems based on polymers. One of the approaches of low molecular weight gelators is the development of gelators based on anticancer drugs, i.e. self-assembled anticancer prodrug gelators that form a gel. Indeed, there are only a limited number of studies which investigate the gelation ability of anticancer drugs. Therefore, this project intends to search for an anticancer agent which demonstrates gelation. This has been achieved by preliminary screening of selected members of two categories of cancer treatments which are five benzothiazole-based quinols and four tyrosine kinase inhibitors (sorafenib, linifanib, semaxanib and orantinib). These anticancer drugs have significant anticancer activity but suffer from systemic toxicity. Therefore, the development of LMWGs based on these drugs is a useful approach for localised drug delivery helping improve the toxicity profile. Preliminary screening showed that only linifanib out of the compounds investigated formed gels. Therefore, it was decided to focus on this potent tyrosine kinase inhibitor as the main part in this project. Further characterisation and analysis showed that the urea functional group and the fluorine substitution on the adjacent aromatic ring are key elements in promoting self-assembly. Also, oscillatory rheology showed that linifanib has superior mechanical strength to gels of structurally related analogues. The prodrug approach was then progressed with linifanib to provide more controlled delivery of the drug. The first library of potential linifanib prodrugs were carbamate derivatives. Unfortunately, all of these compounds failed in inducing gel formation in the preliminary screening regardless of the length and nature of side chain. The second linkage used for creating linifanib prodrugs was the amide conjugation with aliphatic carboxylic acids, single amino acid and dipeptides. With regard to the derivatives with aliphatic carboxylic acid side chain, gels were formed for compounds with clog P between 3.98 and 4.72 which means that there is a correlation between hydrophobicity and gel formation. Preliminary screening of dipeptide derivatives of linifanib were negative for all compounds except the proline-proline derivative which formed a gel after 7 days. Stability study in DMSO – water mixtures of these compounds showed that proline-containing dipeptides degraded to linifanib, at a quicker cleavage rate than other compounds, with the highest cleavage rate for the proline-proline analogue. This has led to the conclusion that the gel observed for this analogue was due to the gelation of linifanib. Finally, the single amino acid derivatives gelation screening revealed that the serine analogue of linifanib was the most stable gel. Further characterisation of this compound showed that the formation of gel and its mechanical strength are affected mainly by changes in pH and possibly the buffer composition. The highest mechanical strength was observed with the concentration of 0.5% w/v serine analogue in 5% v/v DMSO/phosphate buffer pH 7.4. Overall, the serine analogue of linifanib can be considered as the best gelator prodrug of linifanib for two main reasons. This derivative exhibited stable gels with good mechanical strength (> 4 kPa) at physiologic pH. In addition, the serine derivative of linifanib demonstrated a cleavage rate half-life of 7 days in phosphate buffer pH 7.4. These findings suggest that it is a promising linifanib prodrug gelator for targeted delivery

Linifanib – a multi-targeted receptor tyrosine kinase inhibitor and a low molecular weight gelator

In this study we demonstrate that linifanib, a multi-targeted receptor tyrosine kinase inhibitor, with a key urea containing pharmacophore, self-assembles into a hydrogel in the presence of low amounts of solvent. We demonstrate the role of the urea functional group and that of fluorine substitution on the adjacent aromatic ring in promoting self-assembly. We have also shown that linifanib has superior mechanical strength to two structurally related analogues and hence increased potential for localisation at an injection site for drug delivery applications

[87] Articulated laparoscopic instruments: A new technology to overcome challenging uro-laparoscopic surgery

Objective: To demonstrate the use of articulated laparoscopic instruments. Technological development in laparoscopic instruments acts as a corner stone in facilitating and overcoming challenges in laparoscopic operations. The laparoscopic ureteric stent guider (LUSG) helps to overcome stenting difficulty. Other challenges like suturing, dealing with tissue areas in acute angles, changing the axis of the instrument from straight to right angle to give the same ability as robotic instruments, are overcome by an articulated instrument called the laparoscopic flexible forceps dissector (LFFD). Methods: From October 2010 to August 2016, 41 laparoscopic ureteric surgeries were performed. In all, 22 patients underwent laparoscopic pyeloplasty (14 females aged 10–55 and eight males aged 12–45 years). Laparoscopic ureterolithotomy was performed in 16 patients aged 10–38 years. Retrocaval ureter repair was performed in two male cases, with a mean age of 18 years. LUSG was used in 17 cases. From August 2016 to August 2017, the LFFD was used in laparoscopic uro-surgery; five cases of simple nephrectomy (three females and two males aged 38–62 years); three cases of radical nephrectomy (two males and one female aged 45–50 years); and laparoscopic pyeloplasty in one female aged 58 years. LFFD is designed to act like a robotic instrument but is hand-held and reusable. Results: The mean (range) operation time without LUSG was 2:42 (2:15–3:30) h and with LUSG was 2:15 (2:00–2:25) h, thus the LUSG decreased the operation time by 20–30 min, decreased ureteric over manipulation, and overcame stenting difficulties. The LFFD allows for easy manipulation of tissue and has the ability to flex and reach difficult tissue areas better than standard laparoscopic instruments with faster suture ligation and has movement ability that mimics the Da Vinci robotic instrument. Conclusion: Articulated laparoscopic instruments are the future of laparoscopic surgery, simple, affordable and more cost-effective than robotic surgery

Self-assembling tyrosine kinase inhibitors for localised targeted delivery

Localised delivery of cancer therapy is an approach used to overcome the serious side effects associated with the systemic treatment of many anticancer drugs which is the main route of administration. Low molecular weight gelators have received great attention in recent years as a drug delivery strategy for localised targeted therapy. These are small molecules, which self-assemble into a 3D network fibre via non-covalent interactions to create macroscopically a gel. Studies on this drug delivery platform provide an alternative to the extensively investigated gel delivery systems based on polymers. One of the approaches of low molecular weight gelators is the development of gelators based on anticancer drugs, i.e. self-assembled anticancer prodrug gelators that form a gel. Indeed, there are only a limited number of studies which investigate the gelation ability of anticancer drugs. Therefore, this project intends to search for an anticancer agent which demonstrates gelation. This has been achieved by preliminary screening of selected members of two categories of cancer treatments which are five benzothiazole-based quinols and four tyrosine kinase inhibitors (sorafenib, linifanib, semaxanib and orantinib). These anticancer drugs have significant anticancer activity but suffer from systemic toxicity. Therefore, the development of LMWGs based on these drugs is a useful approach for localised drug delivery helping improve the toxicity profile. Preliminary screening showed that only linifanib out of the compounds investigated formed gels. Therefore, it was decided to focus on this potent tyrosine kinase inhibitor as the main part in this project. Further characterisation and analysis showed that the urea functional group and the fluorine substitution on the adjacent aromatic ring are key elements in promoting self-assembly. Also, oscillatory rheology showed that linifanib has superior mechanical strength to gels of structurally related analogues. The prodrug approach was then progressed with linifanib to provide more controlled delivery of the drug. The first library of potential linifanib prodrugs were carbamate derivatives. Unfortunately, all of these compounds failed in inducing gel formation in the preliminary screening regardless of the length and nature of side chain. The second linkage used for creating linifanib prodrugs was the amide conjugation with aliphatic carboxylic acids, single amino acid and dipeptides. With regard to the derivatives with aliphatic carboxylic acid side chain, gels were formed for compounds with clog P between 3.98 and 4.72 which means that there is a correlation between hydrophobicity and gel formation. Preliminary screening of dipeptide derivatives of linifanib were negative for all compounds except the proline-proline derivative which formed a gel after 7 days. Stability study in DMSO – water mixtures of these compounds showed that proline-containing dipeptides degraded to linifanib, at a quicker cleavage rate than other compounds, with the highest cleavage rate for the proline-proline analogue. This has led to the conclusion that the gel observed for this analogue was due to the gelation of linifanib. Finally, the single amino acid derivatives gelation screening revealed that the serine analogue of linifanib was the most stable gel. Further characterisation of this compound showed that the formation of gel and its mechanical strength are affected mainly by changes in pH and possibly the buffer composition. The highest mechanical strength was observed with the concentration of 0.5% w/v serine analogue in 5% v/v DMSO/phosphate buffer pH 7.4. Overall, the serine analogue of linifanib can be considered as the best gelator prodrug of linifanib for two main reasons. This derivative exhibited stable gels with good mechanical strength (> 4 kPa) at physiologic pH. In addition, the serine derivative of linifanib demonstrated a cleavage rate half-life of 7 days in phosphate buffer pH 7.4. These findings suggest that it is a promising linifanib prodrug gelator for targeted delivery

Immunological study of dental caries and periodontitis among patients with chronic kidney disease in Babylon province

The study is conduct at the College of Dentistry, University of Babylon, in which 90 people participated, including 47 patients suffering from chronic kidney disease and 43 are healthy. Patient samples were collect, namely saliva. The effect of IL 17 was evident in patients with chronic kidney disease (CKD), as it was highly significant (0.001) compared to those without CKD. Inflammatory Patients with chronic kidney disease frequently experience changes in their oral health, such as periodontitis and other signs of poor oral hygiene (CKD). According to numerous studies, uremic patients have greater rates of periapical and mucosal lesions, loss of attachment, and teeth that are decaying, missing, or filled than the general population. Plaque formation by streptococcus mutans via synthesis specific enzyme Glucosyltransferase enzyme (Gtf) because formation glucan by fermentation of sucrose and this will be provide site of deposition on the surface of teeth and lead to dental caries which leads to the loss of teeth and this was observed in this study in patients with CKD compared to those without CKD it was highly significant (0.001)