Preclinical antitumor efficacy evaluation of dendrimer-based methotrexate conjugates

Abstract

Our previous studies have demonstrated the in-vitro and in-vivo targeting of a generation-5 (G5) dendrimer-based multifunctional conjugate, which used folic acid (FA) as the targeting agent and methotrexate (MTX) as the chemotherapeutic drug. For the synthesized G5-FA-MTX nanodevice conjugate to be clinically applicable as a cancer therapeutic drug, it is important that the compound elicits cytotoxicity specifically and consistently. The aim of this work was to evaluate four independently synthesized batches of G5-FA-MTX conjugates for their cytotoxic potential and specificity. For determination of specificity, we have used a unique 'coculture' assay in which FA receptor-positive and FA receptor-negative cells were cultured together and have examined the preferential killing of the former. The results of our study show the batch-to-batch consistency and specificity of the G5-FA-MTX nanodevice in the preferential killing of FA receptor-positive cells. The coculture assay shows the consistency of the four different G5-FA-MTX conjugate lots in the specific killing of targeted cells. Further in-vivo studies are, however, necessary to prove the clinical potential of this targeted therapeutic nanodevice.

Folate-conjugated nanoparticles as a potent therapeutic approach in targeted cancer therapy

“…It is reported that conjugation of dendrimers with biological targeting moieties such as FA can significantly increase their specific function on tumor cells in vitro (using KB cells) [132] (Table 4). The selective in vitro cytotoxicity of FA-conjugated methotrexate-loaded dendrimers against tumor cells confirms former report [133]. Kesharwani et al have recently analyzed the anti-tumor potential of different generations of FA-targeted Melphalanloaded poly(propyleneimine) (PPI) dendrimers both in vitro (MCF-7 cells) and in vivo.…”

Pegylated Dendrimer and Its Effect in Fluorouracil Loading and Release for Enhancing Antitumor Activity

“…3 4 Several reports indicated that anticancer drugs (camptothecin, 6-mercaptopurin, methotrexate, adriamycin, 5-fluorouracil, and paclitaxel) were encapsulated into the PAMAM dendrimer exhibiting a significant enhancement of its water solubility, storage stability, and anti-tumor activity. [5][6][7][8][9][10] However, there are a few disadvantages accompanied with PAMAM dendrimer drug-delivery system including hemolytic toxicity and cell lysis due to a strong interaction of the positively charged dendrimer and the negatively charged cell membrane resulting in membrane disruption. 9 11-13 Like other cationic polymers such as polylysine and poly(ethyleneimine), these disadvantages have been solved by conjugating biocompatible and hydrophilic polymers into amine group-terminated dendrimer.…”

Highly lipophilic pluronics-conjugated polyamidoamine dendrimer nanocarriers as potential delivery system for hydrophobic drugs

“…mercaptopurin, methotrexate, 5-FU, and paclitaxel) were encapsulated into the PAMAM dendrimer exhibiting a significant enhancement of its water solubility, storage stability, reduction of side-effects, and anti-tumor activity [17][18][19][20][21]. However, there are a few disadvantages accompanied with the amine-terminated dendrimer-based carriers including hemolytic toxicity and cell lysis due to a strong interaction of its positively charge and a negative charge on cell membrane resulting in disruption of the cellular membrane [22][23][24][25][26].…”