Facilitating gastrointestinal solubilisation and enhanced oral absorption of SN38 using a molecularly complexed silica-lipid hybrid delivery system

Bala, Vaskor; Rao, Shasha; Prestidge, Clive A.

doi:10.1016/j.ejpb.2016.05.021

Cited by 19 publications

(11 citation statements)

References 42 publications

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“…Increasing the lipophilicity through lipophilic conjugate of SN-38 has multiple benefits, including enhancement of drug loading in lipid-based formulations, possible stabilization of the active lactone form, and improvement of the permeability of the drug through cell membranes 26,27. Indeed, many research have focused on the biological activities of the liposomal formulations of lipophilic prodrug of SN38 28. A few studies concern on the effect of lipophilic prodrug on the membrane of liposome formulation 29–32.…”

Section: Introductionmentioning

confidence: 99%

<p>Novel lipophilic SN38 prodrug forming stable liposomes for colorectal carcinoma therapy</p>

Xing¹,

Zhang²,

Wang³

et al. 2019

IJN

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Background: SN38 (7-ethyl-10-hydroxy camptothecin), as a potent metabolite of irinotecan, is highly efficacious in cancer treatment. However, the clinical utility of SN38 has been greatly limited due to its undesirable properties, such as poor solubility and low stability. Materials and methods: In order to overcome these weaknesses, moeixitecan, a lipophilic SN38 prodrug containing a SN-38, a trolox, a succinic acid linker, and a hexadecanol chain, was loaded into liposomal nanoparticles by ethanol injection method. Results: Experiments showed that the moeixitecan-loaded liposomal nanoparticles (MLP) with a diameter of 105.10±1.49 nm have a satisfactory drug loading rate (90.54±0.41%), high solubility and stability, and showed sustained release of SN38. Notably, MLP exhibited better antitumor activity against human colon adenocarcinoma cells than irinotecan, a FDA-approved drug for the treatment of advanced colorectal cancer. Furthermore, xenograft model results showed that MLP outperformed irinotecan in terms of pharmacokinetics, in vivo therapeutic efficacy and safety. Finally, we used molecular dynamic simulations to explore the association between the structure of MLP and the physical and functional properties of MLP, moeixitecan molecules in MLP folded themselves inside the hydrocarbon chain of the lipid bilayer, which led an increased acyl chain order of the lipid bilayer, and therefore enhanced the lactone ring stability protecting it from hydrolysis. Conclusion: Our MLP constructing strategy by liposome engineering technology may serve a promising universal approach for the effective and safe delivery of lipophilic prodrug.

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Section: Introductionmentioning

confidence: 99%

<p>Novel lipophilic SN38 prodrug forming stable liposomes for colorectal carcinoma therapy</p>

Xing¹,

Zhang²,

Wang³

et al. 2019

IJN

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“…The solubility of SN38 has previously been identified as problematic, and hence development of soluble SN38 is now being investigated, and may be useful in this model in the future. 28 Nevertheless, afatinib was soluble, and indeed, caused some lethality at doses above 200 µM; however, it is unclear if the lethality was of gastrointestinal origin.…”

Section: Discussionmentioning

confidence: 99%

Use of zebrafish to model chemotherapy and targeted therapy gastrointestinal toxicity

Van Sebille,

Gibson,

Wardill

et al. 2019

Exp Biol Med (Maywood)

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Gastrointestinal toxicity arising from cancer treatment remains a key reason for treatment discontinuation, significantly compromising remission. There are drawbacks to the currently used in vitro and rodent models, and a lack of translatability from in vitro to in vivo work. A screening-amenable alternative in vivo model such as zebrafish would, therefore, find immediate application. This study utilized a transgenic reporter line of zebrafish, Tg(cyp2k18:egfp), that shows eGFP induction as an indicator of drug-induced pathology. Here, we investigate its utility as an alternative vertebrate model to bridge the gap between simple in vitro cellular studies and complex in vivo models for understanding gastrointestinal toxicity induced by chemotherapy and targeted therapy. Transgenic zebrafish larvae were administered afatinib or SN38, and assessed for viability and eGFP induction. Adult zebrafish were administered afatinib via oral gavage, and SN38 via intraperitoneal injection. Fish were killed after 24 h, and had gastrointestinal tracts removed and assessed for histopathological damage, goblet cell changes, and apoptosis. While treatment with either compound did not induce eGFP in the gastrointestinal tract of larvae, SN38 caused histopathological damage to adult intestines. The lack of eGFP induction may be due to poor solubility of the drugs. Chemotherapy agents with high solubility and permeability would be more amenable to these models. Further progress in this area would be greatly facilitated by the generation of robust and reproducible genetic models of zebrafish intestinal toxicity that mimic the known pathobiological pathways in rodents and humans, and can be readily induced in a short time-frame. Impact statement Gastrointestinal toxicity secondary to cancer treatment remains a major reason for the termination of cancer drug candidates in the development pipeline as well as withdrawal or restrictions of marketed drugs. Current cancer treatment-induced gastrointestinal toxicity models available are limited to in vitro and rodent models that lack translatability and are prohibitively expensive and time consuming. An alternative model to study cancer treatment-induced gastrointestinal toxicity that allows rapid, miniaturized, multi-organ toxicity, screening-amenable testing is therefore warranted. The newly developed Tg( cyp2k18:egfp) zebrafish reporter line was found to induce eGFP in the gastrointestinal tract if toxicity was induced in this area. This paper explored utilizing this reporter line for cancer treatment-induced gastrointestinal toxicity, but found that it was not a useful reporter line in this setting. Further progress in this area would be greatly facilitated by the generation of robust and reproducible genetic models of zebrafish intestinal toxicity that mimic the known pathobiological pathways.

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“…Folic acid‐grafted poly(lactic‐ co ‐glycolic acid) (PLGA) NPs reportedly double the oral bioavailability of their naked counterparts. [ 146 ] Inorganic NPs, including calcium phosphate NPs [ 91 ] and mesoporous silica NPs (MSNs) [ 77,147,148 ] (Figure 3), have also been used for lymphatic drug transport. A chylomicron‐decorated MSN system that exploits the digestion, re‐esterification, and lymphatic transport of dietary lipids has been proposed to improve its targeting of the ILS, increasing the bioavailability of oral drugs.…”

Section: Lymphatic Transport By Enterocytesmentioning

confidence: 99%

Engineering Nano‐ and Microparticles as Oral Delivery Vehicles to Promote Intestinal Lymphatic Drug Transport

et al. 2021

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Facilitating gastrointestinal solubilisation and enhanced oral absorption of SN38 using a molecularly complexed silica-lipid hybrid delivery system

Cited by 19 publications

References 42 publications

<p>Novel lipophilic SN38 prodrug forming stable liposomes for colorectal carcinoma therapy</p>

<p>Novel lipophilic SN38 prodrug forming stable liposomes for colorectal carcinoma therapy</p>

Use of zebrafish to model chemotherapy and targeted therapy gastrointestinal toxicity

Engineering Nano‐ and Microparticles as Oral Delivery Vehicles to Promote Intestinal Lymphatic Drug Transport

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