Dataset Information

Nanoparticles from Gantrez-based conjugates for the oral delivery of camptothecin

ABSTRACT: Camptothecin (CPT) exhibits a number of challenges for its oral administration, including a low aqueous solubility, a lactone ring susceptible to hydrolysis, and an affinity to the intestinal P-gp. The aim of this work was to evaluate nanoparticles from Gantrez-based conjugates as carriers for the oral delivery of CPT. For this purpose two different conjugates (G-mPEG and G-HPCD), obtained by the covalent binding of either HP-β-CD or methoxy-PEG (m-PEG) to the polymer backbone of Gantrez™ AN, were synthetized and characterized. Both excipients (m-PEG and HPCD) were selected due to their reported abilities to stabilize the lactone ring of CPT and disturb the effect of intestinal P-gp. The resulting nanoparticles (G-mPEG-NP and G-HPCD-NP) presented a similar size (about 200 nm) and zeta potential (close to −35 mV); although, G-mPEG-NP presented a higher CPT payload than G-HPCD-NP. On the contrary, in rats, nanoparticles based on Gantrez conjugates appeared to be capable of crossing the protective mucus layer and reach the intestinal epithelium, whereas conventional Gantrez nanoparticles displayed a mucoadhesive profile. Finally, the pharmacokinetic study revealed that both formulations were able to enhance the relative oral bioavailability of CPT; although this value was found to be 2.6-times higher for G-mPEG-NP than for G-HPCD-NP. Graphical abstract Unlabelled Image

SUBMITTER: Huarte J

PROVIDER: S-EPMC8604667 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Clinical applications of camptothecin (CPT) have been heavily hindered due to its non-targeted toxicity, active lactone ring instability, and poor water solubility. Targeted drug delivery systems may offer the possibility to overcome the above issues as reported. In this research, a series of prostate-specific membrane antigen (PSMA)-activated CPT prodrugs were designed and synthesized by coupling water-soluble pentapeptide, a PSMA hydrolyzing substrate, to CPT through an appropriate linker. The cytotoxicity of CPT prodrugs was masked temporarily until they were hydrolyzed by the PSMA present within the tumor sites, which restored cytotoxicity. The in vitro selective cytotoxic activities of the prodrugs were evaluated against PSMA-expressing human prostate cancer cells LNCaP-FGC and non-PSMA-expressing cancer cells HepG2, Hela, MCF-7, DU145, PC-3 and normal cells MDCK, LO2 by standard methylthiazol tetrazolium (MTT) assay. Most of the newly synthesized CPT prodrugs showed excellent selective toxicity to PSMA-producing prostate cancer cells LNCaP-FGC with improved water solubility. From among the library, CPT-HT-J-ZL12 showed the best cytotoxic selectivity between the PSMA-expressing and the non-PSMA-expressing cancer cells. For example, the cytotoxicity of CPT-HT-J-ZL12 (IC50 = 1.00 ± 0.20 µM) against LNCaP-FGC (PSMA⁺) was 40-fold, 40-fold, 21-fold, 5-fold and 40-fold, respectively, higher than that against the non-PSMA-expressing cells HepG2 (IC50 > 40.00 µM), Hela (IC50 > 40.00 µM), MCF-7 (IC50 = 21.68 ± 4.96 µM), DU145 (IC50 = 5.40 ± 1.22 µM), PC-3 (IC50 = 42.96 ± 3.69 µM) cells. Moreover, CPT-HT-J-ZL12 exhibited low cytotoxicity (IC50 > 40 μM) towards MDCK and LO2 cells. The cellular uptake experiment demonstrated the superior PSMA-targeting ability of the CPT-HT-J-ZL12, which was significantly accumulated in LNCaP-FGC (PSMA⁺), while it was minimized in HepG2 (PSMA-) cells. Further cell apoptosis analyses indicated that it showed a dramatically higher apoptosis-inducing activity in LNCaP-FGC (PSMA⁺) cells than in HepG2 (PSMA-) cells. Cell cycle analysis indicated that CPT-HT-J-ZL12 could induce cell cycle arrest at the S phase.

Dataset Information

Nanoparticles from Gantrez-based conjugates for the oral delivery of camptothecin

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets