Amino Acid Metabolism Abnormity and Microenvironment Variation Mediated Targeting and Controlled Glioma Chemotherapy

Abstract

Energy metabolism abnormity is one of the most significant hallmarks of cancer. As a result, large amino acid transporter 1 (LAT1) is remarkably overexpressed in both blood-brain-barrier and glioma tumor cells, leading a rapid and sufficient substrate transportation. 3CDIT and 4CDIT are originally synthesized by modifying the existing most potent LAT1 substrate. 3CDIT is selected as its higher glioma-targeting ability. Since the microenvironment variation in tumor cells is another important feature of cancer, a great disparity in adenosine-5'-triphosphate (ATP) and glutathione (GSH) levels between extracellular and intracellular milieu can provide good possibilities for dual-responsive drug release in tumor cells. Doxorubicin (DOX) is successfully intercalated into the ATP aptamer DNA scaffolds, compressed by GSH-responsive polymer pOEI, and modified with 3CDIT to obtain 3CDIT-targeting pOEI/DOX/ATP aptamer nanoparticles (NPs). Enhanced NP accumulation and rapid GSH & ATP dual-responsive DOX release in glioma are demonstrated both in vitro and in vivo. More efficient therapeutic effects are shown with 3CDIT-targeting pOEI/DOX/ATP aptamer NPs than free DOX and no systemic toxicity is observed. Therefore, glioma-targeting delivery and GSH & ATP dual-responsive release guarantee an adequate DOX accumulation within tumor cells and ensure a safe and efficient chemotherapy for glioma.

The expression of the aminoacid transporters ASCT2 (SLC1A5) and LAT1 (SLC7A5) in astrocytomas

“…[28][29][30] LAT1 (isolated in 1998) was the first discovered transporter of L-system; it transports Gln and asparagine despite its low affinity (Km of 1.6 and 2.1 μM, respectively). Increased LAT1 expression has also been described in several types of cancer, namely colorectal, 31,32 glioma, 33,34 esophageal, [35][36][37] ovarian, 38,39 neuroendocrine 40 and others. 41 Moreover, a high expression of LAT1 has been associated to bad prognosis in prostate carcinoma, 42,43 lung adenocarcinoma 44 and non-small-cell lung carcinoma.…”

Aptamer-Based In Vivo Therapeutic Targeting of Glioblastoma

“…An and co-authors [ 39 ] developed a targeting delivery system based on an ATP aptamer coupled with a modified substrate of the amino acid transporter LAT1 and a GSH responsive molecule [ 39 ] acting as dual-release regulating factors for the efficient doxorubicin (DOX) delivery into GBM cells. The ATP DNA aptamer is a 25-base single-stranded oligodeoxynucleotide selected from a random-sequence DNA pool and showing high affinity for ATP [ 39 ]. To regulate DOX delivery, the ATP aptamer was hybridized with its cDNA, forming a DNA scaffold as a DOX carrier.…”

“…DOX can specifically intercalate into the GC pairs of the DNA scaffold, yielding DOX/ATP aptamer complex without changing the duplex structure of the DNA scaffold and allowing DOX release depending on ATP concentration. Indeed, in vitro, only the ATP amount of tumor cells was able to trigger the DOX release, while it was not induced by the low extracellular concentration, ensuring DOX release only to the tumor cells [ 39 ].…”

“…The system was then improved using another targeting molecule named 3CDIT, a substrate derivate of LAT1 that is an amino acid transporter expressed by both the BBB and glioma cells [ 39 ]. Then, considering the great disparity in GSH levels between extracellular and intracellular compartments, the 3CDIT substrate was decorated onto a GSH-responsive polymer (pOEI), yielding a 3CDIT-targeting pOEI complex that was afterwards condensed with the DOX/ATP complex forming the 3CDIT-pOEI/DOX/ATP aptamer delivery system [ 39 ].…”

“…Aptamers have been largely tested in vitro, showing multiple anticancer properties in GBM cell lines [ 10 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. However, only some of the GBM aptamers, able to reach the tumor site in vivo, are capable of efficiently treating this cancer [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ].…”