Octreotide-periplocymarin conjugate prodrug for improving targetability and anti-tumor efficiency: synthesis, <i>in vitro</i> and <i>in vivo</i> evaluation

Zhang, Huiyun; Xu, Wenqian; Zheng, Yuanyuan; Omari‐Siaw, Emmanuel; Zhu, Yuan; Cao, Xia; Tong, Shanshan; Yu, Jiangnan; Xu, Ximing

doi:10.18632/oncotarget.13389

Cited by 18 publications

(17 citation statements)

References 35 publications

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“…6). Moreover, the FTIR studies showed no interaction between the CTX, OCT, and alginate, which was consistent with other results that used FTIR to confirm the physical interaction of all components but found no interaction between CTX, OCT and alginate 32,36 .…”

Section: Octreotide (Oct) Cetuximab (Ctx)supporting

confidence: 91%

“…Moreover, CTX was measured spectrophotometrically at a wavelength of 360 nm, while OCT was measured at 291 nm. It was previously reported that the CTX absorbance could be measured using a multiwall scanning spectrophotometer at 440 nm 31 , while OCT could be detected at 220 nm 32 . The variance between the published wavelength and our method could be due to the difference in the type of instruments used.…”

Section: Resultsmentioning

confidence: 99%

“…www.nature.com/scientificreports www.nature.com/scientificreports/ between 400 and 4000 cm −1 . CTX-OCT loaded alginate-bead powder, sodium alginate, OCT powder, and CTX powder were subjected to FTIR (Nicolet ™ iS50 FTIR Spectrometer, Thermo SCIENTIFIC Co., Twin, USA)32,36 .…”

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confidence: 99%

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Cetuximab Conjugated with Octreotide and Entrapped Calcium Alginate-beads for Targeting Somatostatin Receptors

Abdellatif

Ibrahim

Amin

et al. 2020

Sci Rep

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There is a need to formulate oral cetuximab (CTX) for targeting colorectal cancer, which is reported to express somatostatin receptors (SSTRs). Therefore, coating CTX with a somatostatin analogue such as octreotide (OCT) is beneficial. Alginate was used to coat CTX to facilitate delivery to the gastrointestinal tract (GIT). This study aimed to deliver CTX conjugated with OCT in the form of microparticles as a GIT-targeted SSTR therapy. Both CTX and OCT were conjugated using a solvent evaporation method and the conjugated CTX-OCT was then loaded onto Ca-alginate-beads (CTX-OCT-Alg), which were characterized for drug interactions using differential scanning calorimetry (DSC), and Fourier transform infrared spectra (FTIR). Moreover, the morphology of formulated beads was examined using a scanning electron microscope (SEM). The drug content and release profile were studied using UV spectroscopy. Finally, in vitro cytotoxicity of all compounds was evaluated. The results showed homogenous conjugated CTX-OCT with a diameter of 0.4 mm. DSC showed a delay in the OCT peak that appeared after 200 °C due to small polymer interaction that shifted the OCT peak. Moreover, FTIR showed no prominent interaction. SEM showed clear empty cavities in the plain Ca-alginate-beads, while CTX-OCT-Alg showed occupied beads without cavities. CTX-OCT-Alg had a negligible release in 0.1 N HCl, while the CTX-OCT was completely released after 300 min in phosphate buffer pH 7.4. All formulations showed good antiproliferative activity compared with free drugs. The formulated CTX-OCT-Alg are a promising platform for targeting colorectal cancer through Git.Oral dosage forms of medications are generally a convenient dosage form for drug delivery 1,2 . However, one of the main challenges in drug delivery is to overcome gastric barriers and preventing the drug release in the stomach 3 . There was a huge increase in the development of orally delivered anti-cancer agents in the past 10 years, as a quarter of all available anti-cancer drugs are now administered orally 4 . Colorectal cancer is one of the most common forms of malignancy and the fourth most common contributor to cancer mortalities 5 . Moreover, targeting specific cells in cancer therapy provides an advantageous way to treat cancer directly 6-10 . For example, the release of drug in the colon and drug particles can be driven by octreotide (OCT) and bind to somatostatin receptors (SSTRs), which are a component of ligand-mediated targeting 8 . The inhibition effect of somatostatin (SST) analogues on tumor cells is one effective approach to cancer therapy. Moreover, SST and its analogues have open Scientific RepoRtS | (2020) 10:4736 | https://doi.org/10.1038/s41598-020-61605-y www.nature.com/scientificreports www.nature.com/scientificreports/ shown proliferative inhibition of colon cancer cell lines 11 . There are five subtypes of SSTRs expressed in colorectal cancer, and SSTR1 is the most prevalent compared to the others 12 .Cetuximab (CTX) is a recombinant monoclonal antibody drug used in the...

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Section: Octreotide (Oct) Cetuximab (Ctx)supporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

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Cetuximab Conjugated with Octreotide and Entrapped Calcium Alginate-beads for Targeting Somatostatin Receptors

Abdellatif

Ibrahim

Amin

et al. 2020

Sci Rep

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“…In this study, we employed periplocymarin, a monomer component extracted from Periplocae Cortex. Currently, there are few studies on periplocymarin, most of which focus on its antitumor effects, while its role in cardiovascular disease remains largely unknown (Shiferaw et al, 2003;Zhang et al, 2016). The present study showed that acute administration of periplocymarin facilitated the cardiac function, resulting in an increase of MAP in mice.…”

Section: Discussionsupporting

confidence: 47%

Periplocymarin Plays an Efficacious Cardiotonic Role via Promoting Calcium Influx

et al. 2020

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Periplocymarin, which belongs to cardiac glycosides, is an effective component extracted from Periplocae Cortex. However, its cardiovascular effects remain unidentified. In the present study, injection of periplocymarin (5 mg/kg) through external jugular vein immediately increased the mean arterial pressure (MAP) in anesthetized C57BL/6 mice. Ex vivo experiments using mouse mesenteric artery rings were conducted to validate the role of periplocymarin on blood vessels. However, periplocymarin failed to induce vasoconstriction directly, and had no effects on vasoconstriction induced by phenylephrine (Phe) and angiotensin II (Ang II). In addition, vasodilatation induced by acetylcholine (Ach) was insusceptible to periplocymarin. Echocardiography was used to evaluate the effects of periplocymarin on cardiac function. The results showed that the injection of periplocymarin significantly increase the ejection fraction (EF) in mice without changing the heart rate. In vitro studies using isolated neonatal rat ventricular myocytes (NRVMs) revealed that periplocymarin transiently increased the intracellular Ca 2+ concentration observed by confocal microscope. But in Ca 2+-free buffer, this phenomenon vanished. Besides, inhibition of sodium potassium-activated adenosine triphosphatase (Na +-K +-ATPase) by digoxin significantly suppressed the increase of MAP and EF in mice, and the influx of Ca 2+ in cardiomyocytes, mediated by periplocymarin. Collectively, these findings demonstrated that periplocymarin increased the contractility of myocardium by promoting the Ca 2+ influx of cardiomyocytes via targeting on Na +-K +-ATPase, which indirectly led to the instantaneous rise of blood pressure.

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“…In radiation oncology, this conjugate was more cytotoxic to MCF-7 and HepG2 tumor cells, but less cytotoxic to L-02 non-tumor cells. Tissue distribution of the conjugate using the H22 tumor model in mice resulted in a greater accumulation in tumors and a lower distribution in heart and liver compared to periplocymarin ( 15 ) alone [ 89 ]. Another study that sought to improve the delivery of CGs to reduce cardiotoxicity was performed with acetylthevetin B ( 16 ), isolated from the seeds of Thevetia peruviana (Pers), which showed potent in vitro cytotoxic activity.…”

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

Anticancer and Immunogenic Properties of Cardiac Glycosides

et al. 2017

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Cardiac glycosides (CGs) are natural compounds widely used in the treatment of several cardiac conditions and more recently have been recognized as potential antitumor compounds. They are known to be ligands for Na/K-ATPase, which is a promising drug target in cancer. More recently, in addition to their antitumor effects, it has been suggested that CGs activate tumor-specific immune responses. This review summarizes the anticancer aspects of CGs as new strategies for immunotherapy and drug repositioning (new horizons for old players), and the possible new targets for CGs in cancer cells.

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Octreotide-periplocymarin conjugate prodrug for improving targetability and anti-tumor efficiency: synthesis, in vitro and in vivo evaluation

Cited by 18 publications

References 35 publications

Cetuximab Conjugated with Octreotide and Entrapped Calcium Alginate-beads for Targeting Somatostatin Receptors

Cetuximab Conjugated with Octreotide and Entrapped Calcium Alginate-beads for Targeting Somatostatin Receptors

Periplocymarin Plays an Efficacious Cardiotonic Role via Promoting Calcium Influx

Anticancer and Immunogenic Properties of Cardiac Glycosides

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