Therapeutic delivery to the peritoneal lymphatics: Current understanding, potential treatment benefits and future prospects

Sarfarazi, Ali; Lee, Given; Mirjalili, S. Ali; Phillips, Anthony R.J.; Windsor, John A.; Trevaskis, Natalie L.

doi:10.1016/j.ijpharm.2019.118456

Cited by 21 publications

(30 citation statements)

References 103 publications

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“…Once taken up by the lymphatic capillaries and passed through regional lymph nodes, they reach the general circulation. On the contrary, BER would be absorbed into the mesenteric vessels which drain into portal vein and pass through the liver, thus, undergoing hepatic metabolism before reaching systemic circulation [ 50 , 51 ]. The result is that LP-BER greatly decrease the Cl of the free drug.…”

Section: Discussionmentioning

confidence: 99%

Berberine-Loaded Liposomes for the Treatment of Leishmania infantum-Infected BALB/c Mice

et al. 2020

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Berberine (BER)—an anti-inflammatory quaternary isoquinoline alkaloid extracted from plants—has been reported to have a variety of biologic properties, including antileishmanial activity. This work addresses the preparation of BER-loaded liposomes with the aim to prevent its rapid liver metabolism and improve the drug selective delivery to the infected organs in visceral leishmaniasis (VL). BER liposomes (LP-BER) displayed a mean size of 120 nm, negative Z-potential of −38 mV and loaded 6 nmol/μmol lipid. In vitro, the loading of BER in liposomes enhanced its selectivity index more than 7-fold by decreasing its cytotoxicity to macrophages. In mice, LP-BER enhanced drug accumulation in the liver and the spleen. Consequently, the liposomal delivery of the drug reduced parasite burden in the liver and spleen by three and one logarithms (99.2 and 93.5%), whereas the free drug only decreased the infection in the liver by 1-log. The organ drug concentrations—far from IC50 values— indicate that BER immunomodulatory activity or drug metabolites also contribute to the efficacy. Although LP-BER decreased 10-fold—an extremely rapid clearance of the free drug in mice—the value remains very high. Moreover, LP-BER reduced plasma triglycerides levels.

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Section: Discussionmentioning

confidence: 99%

Berberine-Loaded Liposomes for the Treatment of Leishmania infantum-Infected BALB/c Mice

et al. 2020

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“…Considering that ovarian cancer metastasis very frequently targets the peritoneum/omentum, knowledge of the biology of this serous membrane is crucial to designing optimal siRNA delivery systems. The surface of the peritoneum contains a single layer of mesothelial cells (Figure 2) with a cuboidal shape and adipocytes (reviewed as reported by Sarfarazi et al [39]). Tight junctions and plasmalemma interdigitations connect mesothelial cells.…”

Section: Small Interfering Rnasmentioning

confidence: 95%

“…The diameter of lacuna aperture is 1.8–6 μm in most animal species, and 3.2–3.6 μm in humans. Blood vessels are abundantly scattered in the connective tissue layer [39].…”

Section: Small Interfering Rnasmentioning

confidence: 99%

Strategies for Delivery of siRNAs to Ovarian Cancer Cells

et al. 2019

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The unmet need for novel therapeutic options for ovarian cancer (OC) deserves further investigation. Among the different novel drugs, small interfering RNAs (siRNAs) are particularly attractive because of their specificity of action and efficacy, as documented in many experimental setups. However, the fragility of these molecules in the biological environment necessitates the use of delivery materials able to protect them and possibly target them to the cancer cells. Among the different delivery materials, those based on polymers and lipids are considered very interesting because of their biocompatibility and ability to carry/deliver siRNAs. Despite these features, polymers and lipids need to be engineered to optimize their delivery properties for OC. In this review, we concentrated on the description of the therapeutic potential of siRNAs and polymer-/lipid-based delivery systems for OC. After a brief description of OC and siRNA features, we summarized the strategies employed to minimize siRNA delivery problems, the targeting strategies to OC, and the preclinical models available. Finally, we discussed the most interesting works published in the last three years about polymer-/lipid-based materials for siRNA delivery.

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“…2 This is particularly true when drugs are administered intraperitoneally in complex delivery systems such as liposomes or nanoparticles. 2,9,11 Liposomes are the commercially available formulation for several chemotherapeutics (e.g., doxorubicin) administered via the IP route to treat localized cancers. 12 Liposomes and nanoparticles are also commonly employed in preclinical studies.…”

Section: ■ Introductionmentioning

confidence: 99%

“…14,15 Following IP administration, liposomes and nanoparticles are also expected to be absorbed via the lymphatic system. 2,16,17 This is because although the peritoneum contains a rich supply of blood vessels, the blood vessels are located within a connective tissue layer beneath the mesothelial cells that line the peritoneum. 1,2 Small-molecule drugs can readily diffuse across the mesothelial cell layer and be absorbed into the blood vessels below, whereas liposomes and nanoparticles are too large to readily cross either the mesothelial cells or the blood vessel endothelium.…”

Section: ■ Introductionmentioning

confidence: 99%

Lymphatic Uptake of Liposomes after Intraperitoneal Administration Primarily Occurs via the Diaphragmatic Lymphatics and is Dependent on Liposome Surface Properties

et al. 2019

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Drugs are commonly administered via the intraperitoneal (IP) route to treat localized infections and cancers in patients and to test drug efficacy and toxicity in preclinical studies. Despite this, there remain large gaps in our understanding of drug absorption routes (lymph vs blood) and pharmacokinetics following IP administration. This is particularly true when drugs are administered in complex delivery systems such as liposomes which are the main marketed formulation for several drugs that are administered intraperitoneally. This study investigated the impact of liposome surface properties (charge and PEGylation) on absorption into lymph and blood, and lymphatic disposition patterns, following IP administration. To achieve this, stable 3H-dipalmitoyl-phosphatidylcholine (DPPC) and 14C-sucrose-radiolabeled liposomes of 100–150 nm diameter with negative, neutral, or positive surface charge, or a PEGylated surface, were prepared and administered intraperitoneally to rats. Radiolabel concentrations were measured in lymph, blood, and lymph nodes (LNs). Lymph was collected from the thoracic lymph duct at either the abdomen (ABD) or the jugular–subclavian junction (JSJ). The lymphatic recovery of the radiolabels was substantially lower after administration in positively charged compared to the neutral, negative, or PEGylated liposomes. Radiolabel recovery was substantially greater (up to 18-fold) in the thoracic lymph collected at the JSJ when compared to that at the ABD, suggesting that liposomes entered the lymphatics at the diaphragm. Consistent with this, the concentration of the liposome labels was substantially higher (up to seven-fold) in mediastinal than in mesenteric LNs. Overall, this study shows how the peritoneal absorption and lymphatic disposition of drugs administered intraperitoneally can be manipulated through a careful selection of the drug delivery system and may thus be optimized to treat localized conditions such as cancers, infections, inflammatory diseases, and acute and critical illness.

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Therapeutic delivery to the peritoneal lymphatics: Current understanding, potential treatment benefits and future prospects

Cited by 21 publications

References 103 publications

Berberine-Loaded Liposomes for the Treatment of Leishmania infantum-Infected BALB/c Mice

Berberine-Loaded Liposomes for the Treatment of Leishmania infantum-Infected BALB/c Mice

Strategies for Delivery of siRNAs to Ovarian Cancer Cells

Lymphatic Uptake of Liposomes after Intraperitoneal Administration Primarily Occurs via the Diaphragmatic Lymphatics and is Dependent on Liposome Surface Properties

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