pH-Sensitive Nanoformulated Triptolide as a Targeted Therapeutic Strategy for Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) has one of the worst prognoses for survival as it is poorly responsive to both conventional chemotherapy and mechanism-directed therapy. This results from a lack of therapeutic concentration in the tumor tissue coupled with the highly toxic off-site effects exhibited by these compounds. Consequently, we believe the best packaging for holistic therapy for HCC will involve three components: a potent therapeutic, a rationally designed drug delivery vehicle to enrich the target site concentration of the drug, and a surface ligand that can enable a greater propensity to internalization by tumor cells compared to the parenchyma. We screened a library containing hundreds of compounds against a panel of HCC cells and found the natural product, triptolide, to be more effective than sorafenib, doxorubicin, and daunorubicin, which are the current standards of therapy. However, the potential clinical application of triptolide is limited due to its poor solubility and high toxicity. Consequently, we synthesized tumor pH-sensitive nanoformulated triptolide coated with folate for use in an HCC-subpopulation that overexpresses the folate receptor. Our results show triptolide itself can prevent disease progression, but at the cost of significant toxicity. Conversely, our pH-sensitive nanoformulated triptolide facilitates uptake into the tumor, and specifically tumor cells, leading to a further increase in efficacy while mitigating systemic toxicity.

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

“…However, the clinical applications have been limited by poor solubility and extreme side effects. Hence, Ling et al 13 synthesized smart pH-sensitive nanoformulated triptolide (Nf-Trip) coated with folate as a targeted therapeutic strategy for HCC. The hepatoma cells BEL-7402 with positive FRs and normal hepatocyte MIHA with negative FRs were selected to investigate the in vitro cellular uptake.…”

“…The NTDDS involves three essential components: a potent therapeutic such as chemotherapeutic agent, gene, or photosensitizer; a rational delivery vehicle to transport therapeutics in high concentration into tumor cells with long circulation time and excellent stability; and a surface ligand that mediates delivery vehicle to interact with and internalize into hepatoma cells with high specificity and efficiency. [13][14][15] Targeted delivery could overcome the deficiencies of conventional administration routes as mentioned earlier. As NPs for targeted delivery of therapeutics and small interfering RNAs (siRNA) in HCC have been reviewed in a recent review, 16 this review focuses on the latest NTDDS for HCC and summarizes the ligands that can specifically bind with the matching receptors on hepatoma cell membrane and trigger the receptor-mediated endocytosis, to provide some insight into future research in nanomedicine for HCC.…”

Polyethylenimine-functionalized silver nanoparticle-based co-delivery of paclitaxel to induce HepG2 cell apoptosis

“…4,5 Meanwhile, as most cases with HCC are metastatic or advanced at the time of diagnosis, the local therapies including liver transplantation and surgical excision are unsuitable. 6,7 Furthermore, chemotherapeutic is generally ineffective against advanced HCC, which has high metastatic potential. 8 Finally, most conventional cancer therapeutics have a relatively short half-life and poor permeability, which may influence curative effect.…”

Fabrication of novel vesicles of triptolide for antirheumatoid activity with reduced toxicity in vitro and in vivo

“…[19][20][21][22] Delivery systems are innovative ways for administering to alleviate the disadvantages of the drug. [23][24][25] In order to reduce the adverse effects of TP, hydrophilic, biodegradable, and high drug-loading content efficiency drug carriers need to be developed. Among the drug carriers, poly-γ-glutamic acid (γ-PGA) is a very promising one.…”