Name: encapsulation of cancer therapeutic agent dacarbazine using nanostructured lipid carrier
Uploaded: 2016-04-26T14:00:00
Description: Watch this Scientific Journal Video about Encapsulation of Cancer Therapeutic Agent Dacarbazine Using Nanostructured Lipid Carrier at JoVE.com

The authors acknowledge the Saudi Arabia-funded scholarship (I821) for making the research possible. The authors are grateful to Dr Xianwei Liu for expert support in TEM analysis at Cranfield University.

1. Preparation of Oil-in-water Emulsion
<ol>
	<li>Weigh glyceryl palmitostearate (120 mg), isopropyl myristate (60 mg), d-&#945;-tocopheryl polyethylene glycol succinate (30 mg) and soybean lecithin (30 mg), and add them to 12.5 ml of organic solvents (6.25 ml acetone and 6.25 ml ethanol). Quickly dissolve the mixture at the temperature 70&#160;&#176;C (5 &#176;C above the melting point of the solid lipid) in water bath.</li>
	<li>Add either 125, 250 or 375 mg of Poloxamer188 in 12.5 ml of ddH2O to achieve 1...

<ol>
	<li>Loo, T. L., Housholder, G. E., Gerulath, A. H., Saunders, P. H., Farquhar, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mechanism+of+action+and+pharmacology+studies+with+DTIC+(NSC+45388).">Mechanism of action and pharmacology studies with DTIC (NSC 45388).</a> Cancer Treat Rep. 60 (2), 149-152 (1976).</li><li>Behringer, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Omission+of+dacarbazine+or+bleomycin,+or+both,+from+the+ABVD+regimen+in+treatment+of+early-stage+favourable+Hodgkin's+lymphoma+(GHSG+HD13):+An+open-label,+randomised,+non-inferiority+trial.">Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): An open-label, randomised, non-inferiority trial.</a> The Lancet. 385 (9976), 1418-1427 (2014).</li><li>Carvajal, R. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+phase+2+randomised+study+of+ramucirumab+(IMC-1121B)+with+or+without+dacarbazine+in+patients+with+metastatic+melanoma.">A phase 2 randomised study of ramucirumab (IMC-1121B) with or without dacarbazine in patients with metastatic melanoma.</a> Eur J Cancer. 50 (12), 2099-2107 (2014).</li><li>Jiang, G., Li, R., Sun, C., Liu, Y., Zheng, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dacarbazine+combined+targeted+therapy+versus+dacarbazine+alone+in+patients+with+malignant+melanoma:+A+meta-analysis.">Dacarbazine combined targeted therapy versus dacarbazine alone in patients with malignant melanoma: A meta-analysis.</a> PLoS ONE. 9 (12), (2014).</li><li>Lazar, V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Sorafenib+plus+dacarbazine+in+solid+tumors:+A+phase+i+study+with+dynamic+contrast-enhanced+ultrasonography+and+genomic+analysis+of+sequential+tumor+biopsy+samples.">Sorafenib plus dacarbazine in solid tumors: A phase i study with dynamic contrast-enhanced ultrasonography and genomic analysis of sequential tumor biopsy samples.</a> Invest New Drugs. 32 (2), 312-322 (2014).</li><li>Niemeijer, N. 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Lipid-based nanostructured particles have been utilized to provide a highly lipophilic carrier for delivery of hydrophobic drugs. A NLC is the second generation of solid lipid nanostructured carrier, which are solid at room and body temperature. The incorporation of a solid lipid into a liquid lipid in a NLC results in a less perfect crystallization, thus increasing the drug loading efficiency and also reducing the expulsion of encapsulated drugs during storage.
For NLC synthesis, the most com...

Dacarbazine (Dac) is an alkylating agent that exerts anti-tumor activity through nucleic acids methylation or direct DNA damage, leading to cell cycle arrest and cell death 1.
As a first line chemotherapeutic agent, Dac has been used alone or in combination with other chemotherapy drugs for treating various cancers 2-6. It is the most active agent so far used in treating cutaneous and metastatic melanoma, which is the most aggressive form of skin cancer 3,7,8. The response rate, however, is only 20% at best, and the therapeutic effects are often accompanied with severe systemic side effects.
In its natural form, Dac is hydrophilic and is unstable due to its photosensitivity 9. The only available formula for clinical use currently is a sterile powder to be used in suspension for intravenous infusion 7,8. The low response rate and high systemic toxicity rate of the drug is largely attributable to its poor water solubility, therefore low availability at target site, and high distribution at non-target sites, which limits the maximum dose of the drug 10. The rapid degradation and metabolism after intravenous admission together with the development of drug resistance limit the clinical application and therapeutic effect of the drug 11. Therefore, there is an urgent need to develop alternative Dac formulations for treating malignant melanoma.
Colloidal systems containing liposomes, micelles or nanostructured particles have been intensively investigated for their use in drug delivery as reviewed by Marilene et al. 12 Nanostructured particles as potential drug carriers have been attracting increasing attention in the last decade due to their ability to increase drug loading efficiency, control drug release, improve drug pharmacokinetics and biodistribution, and therefore reduce drug systemic toxicity 13. Only a few nanoformulations, however, have been investigated so far for Dac delivery, showing protection of the drug from photo degeneration, increased drug solubility, and improved therapeutic effect 10,14,15. However these formulations suffered from low encapsulating efficiency while some also using synthetic polymer nanoparticles that are not cost effective.
Nanostructured lipid carriers (NLC), made of a mixture of solid and liquid lipids, have been developed for drug delivery 16,17. The drugs to be encapsulated are often soluble in both the liquid lipids and solid lipids phases 18, resulting in a high loading and controlled release 19. This study aims to develop a new Dac formulation based on NLC-encapsulation using glyceryl palmitostearate and isopropyl myristate as lipids. The preparation involved oil-in-water emulsion, evaporation, solidification, and homogenization. The preparations have been characterized for NLC size, shape, ultrastructure, and dispersity, drug encapsulation efficiency and drug loading 20.

<table border="0" cellpadding="0" cellspacing="0" width="968">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Dacarbazine (DAC)</td>
			<td style="width:467px;">Sigma Aldrich (Gillingham Dorset, UK)</td>
			<td style="width:119px;">D2390-100MG</td>
			<td style="width:167px;">drug used for uploading</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">glyceryl palmitostearate&#160;</td>
			<td>Gattefoss&#233; (Saint_Priest_c&#233;dex, France)</td>
			<td style="width:119px;">85251-77-0</td>
			<td>solid lipid&#160;</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">d-&#945;- Tocopherol polyethylene glycol succinate (TPGS)</td>
			<td>Sigma Aldrich (Gillingham Dorset, UK)</td>
			<td style="width:119px;">57668</td>
			<td>lipid phase surfactant</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Poloxamer 188</td>
			<td>Sigma Aldrich (Gillingham Dorset, UK)</td>
			<td style="width:119px;">15759-1KG</td>
			<td>liqiud phase surfactant</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Acetone&#160;</td>
			<td>Sigma Aldrich (Gillingham Dorset, UK)</td>
			<td style="width:119px;">650501-1L</td>
			<td>organic solvent</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Ethanol&#160;</td>
			<td>Sigma Aldrich (Gillingham Dorset, UK)</td>
			<td style="width:119px;">459836-1L</td>
			<td>organic solvent</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Soybean lecithin (SL)</td>
			<td>Cuisine Innovation (Dijon, France)</td>
			<td style="width:119px;">SLL1402</td>
			<td>lipid phase surfactant</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Double-distilled water was collected in our laboratory from</td>
			<td>Millipore-Q Gradient A10 ultra-pure water system (Millipore, France)</td>
			<td style="width:119px;">SAS - 67120&#160;</td>
			<td>aqueous phase&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">T 25 digital ULTRA-TURRAX</td>
			<td style="width:467px;">IKA</td>
			<td style="width:119px;">3725000</td>
			<td>as high shear disperser</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Hotplate Magnetic Stirrer</td>
			<td>Scientific Support, Inc</td>
			<td style="width:119px;">1454&#160;</td>
			<td>emulsion homogenization</td>
		</tr>
	</tbody>
</table>

encapsulation of cancer therapeutic agent dacarbazine using nanostructured lipid carrier

The only formula of dacarbazine (Dac) in clinical use is intravenous infusion, presenting a poor therapeutic profile due to the low dispersity of the drug in aqueous solution. To overcome this, a nanostructured lipid carrier (NLC) consisting of glyceryl palmitostearate and isopropyl myristate was developed to encapsulate Dac. NLCs with controlled size were achieved using high shear dispersion (HSD) following solidification of oil-in-water emulsion. The synthesis parameters, including surfactant concentration, the speed and time of HSD were optimized to achieve the smallest NLC with size, polydispersion index and zeta potential of 155 &#177; 10 nm, 0.2 &#177; 0.01, and -43.4 &#177; 2 mV, respectively. The optimal parameters were also employed for Dac-loaded NLC preparation. The resultant NLC loaded with Dac possessed size, polydispersion index and zeta potential of 190 &#177; 10 nm, 0.2 &#177; 0.01, and -43.5 &#177; 1.2 mV, respectively. The drug encapsulation efficiency and drug loading reached 98% and 14%, respectively. This is the first report on encapsulation of Dac using NLC, implying that NLC could be a new potential candidate as drug carrier to improve the therapeutic profile of Dac.

The preparations of the NLC and NLC-Dac using glyceryl palmitostearate and isopropyl myristate with different parameters were characterized for PS, PDI, morphology and ultrastructure 20. The PS and PDI of the NLCs were surfactant concentration, HSD speed and duration dependent. As judged by PS and PDI of the NLCs, the best results were achieved with 1% of surfactant and a sheer dispersion speed of 15,000 rpm for 30 min (Figure 1A, B and <strong...

Watch this Scientific Journal Video about Encapsulation of Cancer Therapeutic Agent Dacarbazine Using Nanostructured Lipid Carrier at JoVE.com

Encapsulation of Cancer Therapeutic Agent Dacarbazine Using Nanostructured Lipid Carrier

The most commonly used method for nanostructured lipid carrier (NLC) synthesis involves oil-in-water emulsion, homogenization and solidification. This was modified here by applying high shear dispersion after solidification to achieve a NLC with desirable size, improved drug encapsulation and drug loading efficiency as a potential carrier for dacarbazine delivery.

The only formula of dacarbazine (Dac) in clinical use is intravenous infusion, presenting a poor therapeutic profile due to the low dispersity of the drug ...

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Quantitative Proteomics Using Reductive Dimethylation for Stable Isotope Labeling

Stable isotope labeling of peptides by reductive dimethylation (ReDi labeling) is a method to accurately quantify protein expression differences between ...

A Colorimetric Assay that Specifically Measures Granzyme B Proteolytic Activity: Hydrolysis of Boc-Ala-Ala-Asp-S-Bzl

The serine protease Granzyme B (GzmB) mediates target cell apoptosis when released by cytotoxic T lymphocytes (CTL) or natural killer (NK) cells. GzmB is ...

Facile Preparation of Internally Self-assembled Lipid Particles Stabilized by Carbon Nanotubes

We present a facile method to prepare nanostructured lipid particles stabilized by carbon nanotubes (CNTs). Single-walled (pristine) and multi-walled ...

NMR Spectroscopy as a Robust Tool for the Rapid Evaluation of the Lipid Profile of Fish Oil Supplements

The western diet is poor in n-3 fatty acids, therefore the consumption of fish oil supplements is recommended to increase the intake of these essential ...

From Molecules to Materials: Engineering New Ionic Liquid Crystals Through Halogen Bonding

Herein, we demonstrate that a bottom-up approach, based on halogen bonding (XB), can be successfully applied for the design of a new type of ionic liquid ...

Analysis of Minerals Produced by hFOB 1.19 and Saos-2 Cells Using Transmission Electron Microscopy with Energy Dispersive X-ray Microanalysis

This video presents the use of transmission electron microscopy with energy dispersive X-ray microanalysis (TEM-EDX) to compare the state of minerals in ...

Organic Structure-directing Agent-free Synthesis for *BEA-type Zeolite Membrane

Membrane separation has drawn attention as a novel-energy saving separation process. Zeolite membranes have great potential for hydrocarbon separation in ...