Oral pemetrexed facilitates low-dose metronomic therapy and enhances antitumor efficacy in lung cancer

Mahmud, Foyez; Jeon, Ok-Cheol; Alam, Fakhrul; Maharjan, Ruby; Choi, Jeong Uk; Park, Jooho; Lee, So Jung; Park, Jin Woo; Lee, Dong Hoon; Byun, Youngro

doi:10.1016/j.jconrel.2018.06.018

Cited by 14 publications

(6 citation statements)

References 35 publications

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“…More importantly, compared with 2D cultures, 3D spheroids have become a useful model for investigation the penetration of drugs into in vivo tissue because they possess the necessary 3D architecture. 36) Thus, the effect of deoxycholic acid on uptake of G2 and CPT were further investigate in a 3D Caco-2 spheroid cell model. As revealed in Fig.…”

Section: Characterization Of G2mentioning

confidence: 99%

Transporter-Targeted Bile Acid-Camptothecin Conjugate for Improved Oral Absorption

et al. 2019

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Camptothecin (CPT), a natural alkaloid, possesses potent anticancer activity. However, its application was terminated due to its low bioavailability and high toxicity. This work evaluated the potential of deoxycholic acid-CPT conjugate (G2) to improve the oral absorption of CPT. Deoxycholic acid significantly reduced cytotoxicity and inhibited the uptake of G2, in vitro. And G2 showed sodium-dependent uptake. In addition, in vivo study in rats indicated that the oral bioavailability of G2 was 2.06-fold higher than that of CPT. The present study suggested that using bile acid as the conjugated moiety is a hopeful strategy to improve the oral bioavailability of CPT.

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Section: Characterization Of G2mentioning

confidence: 99%

Transporter-Targeted Bile Acid-Camptothecin Conjugate for Improved Oral Absorption

et al. 2019

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“…However, limited absorption and transport of PMs by the intestinal epithelium is still the main great challenge, and the enhanced oral absorption of PMs is also necessary and urgent. [7][8][9][10] Recently, membrane transporter-targeted nanocarriers have been put forward and have attracted more attention, which could selectively identify and target certain transporters, such as bile acid transporter, 11,12 and thereby result in more transcellular delivery of nanocarriers. 13 Peptide transporter 1 (PepT1) is an oligopeptide transporter and abundantly expressed in the apical (AP) membrane of the intestinal epithelium.…”

Section: Introductionmentioning

confidence: 99%

Apically targeted oral micelles exhibit highly efficient intestinal uptake and oral absorption

Wang¹,

Wang²,

Liu³

et al. 2018

IJN

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IntroductionPolymeric micelles (PMs) hold promise for improving solubility and oral absorption of poorly soluble drugs. Unfortunately, the oral absorption of PMs is also limited by intestinal epithelium. To improve the oral delivery efficiency of micelles, transporter-mediated micelles could enhance the transport efficiency across the epithelial barrier, and they have attracted more attention.MethodsPeptide transporter 1 (PepT1)-mediated micelles (Val-PMs/Phe-PMs) were designed by grafting valine (or phenylalanine) onto the surface of curcumin (Cur)-loaded-D-α-tocopheryl polyethylene glycol 1000 succinate micelles (TP-PMs). The oral absorption mechanism and oral bioavailability were further investigated in vitro and in vivo.ResultsThe cellular study showed that Val-PMs/Phe-PMs had a high PepT1 affinity, resulting in a higher drug uptake and transcellular transport than TP-PMs. In rats, Val-PMs/Phe-PMs exhibited higher intestinal accumulation in the apical side of the intestinal epithelium than TP-PMs, promoting drug diffusion across epithelial barrier. The oral bioavailability of Cur was significantly improved by Val-PMs/Phe-PMs, which was about 10.50- and 3.40-fold greater than that of Cur-Sol and TP-PMs, respectively.ConclusionPepT-1-mediated micelles, using PepT1 as a target on intestinal epithelium, have unique functions with intestine and prove promising for oral delivery of poorly water-soluble drugs.

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“…Maintenance therapy using antifolates was shown to be effective, as observed with PEM for NSCLC, although such maintenance phase treatment still relies on IV infusions every 21-days due to poor oral absorption of the drug (41,46,47). Recent preclinical studies reported PEM bioavailability using PEM-bile acid conjugate complexes to enhance absorption (48)(49)(50)(51). These complexes allow daily oral administration with anti-tumor activity and reductions in new blood vessel formation.…”

Section: Discussionmentioning

confidence: 99%

First-in-class multifunctional TYMS nonclassical antifolate inhibitor with potent in vivo activity that prolongs survival

Guijarro¹,

Kellish²,

Dib³

et al. 2023

JCI Insight

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Although thymidylate synthase (TYMS) inhibitors have served as components of chemotherapy regimens, the currently available inhibitors induce TYMS overexpression or alter folate transport/metabolism feedback pathways that tumor cells exploit for drug resistance limiting overall benefit. Here we report a small molecule TYMS inhibitor that i) exhibits enhanced antitumor activity as compared to current fluoropyrimidines and antifolates without inducing TYMS overexpression, ii) is structurally distinct from classical antifolates, iii) extends survival in both pancreatic xenograft tumor models and hTS/Ink4a/Arf null genetically engineered mouse tumor model, iv) and is well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we confirm the compound is a multifunctional non-classical antifolate, and using a series of analogues, we identify structural features allowing direct TYMS inhibition while also maintaining the ability to inhibit dihydrofolate reductase (DHFR). Collectively, this work identifies new non-classical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile highlighting potential for enhanced cancer therapy.

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Oral pemetrexed facilitates low-dose metronomic therapy and enhances antitumor efficacy in lung cancer

Cited by 14 publications

References 35 publications

Transporter-Targeted Bile Acid-Camptothecin Conjugate for Improved Oral Absorption

Transporter-Targeted Bile Acid-Camptothecin Conjugate for Improved Oral Absorption

Apically targeted oral micelles exhibit highly efficient intestinal uptake and oral absorption

First-in-class multifunctional TYMS nonclassical antifolate inhibitor with potent in vivo activity that prolongs survival

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