Dual-responsive, Methotrexate-loaded, Ascorbic acid-derived Micelles Exert Anti-tumor and Anti-metastatic Effects by Inhibiting NF-κB Signaling in an Orthotopic Mouse Model of Human Choriocarcinoma

Abstract

Gestational trophoblastic neoplasia (GTN), the most aggressive form of which is choriocarcinoma, can result from over-proliferation of trophoblasts. Treating choriocarcinoma requires high doses of systemic chemotherapeutic agents, which result in nonspecific drug distribution and severe toxicity. To overcome these disadvantages and enhance chemotherapeutic efficacy, we synthesized redox- and pH-sensitive, self-assembling, ascorbic acid-derived (PEG-ss-aAPP) micelles to deliver the drug methotrexate (MTX). Methods : We developed and tested self-assembling PEG-ss-aAPP micelles, which release their drug cargo in response to an intracellular reducing environment and the acidity of the early lysosome or tumoral microenvironment. Uptake into JEG3 choriocarcinoma cancer cells was examined using confocal microscopy and transmission electron microscopy. We examined the ability of MTX-loaded PEG-ss-aAPP micelles to inhibit metastasis in an orthotopic mouse model of human choriocarcinoma. Results : Drug-loaded micelles had encapsulation efficiency above 95%. Particles were spherical based on transmission electron microscopy, with diameters of approximately 229.0 nm based on dynamic light scattering. The drug carrier responded sensitively to redox and pH changes, releasing its cargo in specific environments. PEG-ss-aAPP/MTX micelles efficiently escaped from lysosome/endosomes, and they were effective at producing reactive oxygen species, strongly inducing apoptosis and inhibiting invasion and migration. These effects correlated with the ability of PEG-ss-aAPP/MTX micelles to protect IκBα from degradation, which in turn inhibited translocation of NF-κB p65 to the nucleus. In an orthotopic mouse model of human choriocarcinoma, PEG-ss-aAPP/MTX micelles strongly inhibited primary tumor growth and significantly suppressed metastasis without obvious side effects. Conclusions : Our results highlight the potential of PEG-ss-aAPP micelles for targeted delivery of chemotherapeutic agents against choriocarcinoma.

Characterization of an Amphiphilic Phosphonated Calixarene Carrier Loaded With Carboplatin and Paclitaxel: A Preliminary Study to Treat Colon Cancer in vitro and in vivo

“…Nanomedicine is an emerging, dynamic branch of therapeutics that continues to gain prominence as a viable treatment alternative for many cancers, including colon cancer (Zhang Q. et al, 2019). Nanomedicine encompasses the application of nanotechnology (construction of functional structures on the nanometer scale) to the treatment, diagnosis, monitoring, and control of biological systems (Yang et al, 2015; Li et al, 2019; Wei et al, 2019). This field has seen the development of a number of drug delivery platforms, including polymer-drug conjugates (Li and Wallace, 2008; Karolczak-Bayatti et al, 2019), liposomes (Paasonen et al, 2010; Shen and Ye, 2019), micelles (Dehghan Kelishady et al, 2014; Alliot et al, 2019), nanoshells (Huschka et al, 2012; Russo et al, 2019), and dendrimers (Modi et al, 2014; Zhao et al, 2017).…”

DPP4 Regulates DHCR24-Mediated Cholesterol Biosynthesis to Promote Methotrexate Resistance in Gestational Trophoblastic Neoplastic Cells

“…Sitagliptin solution (100 mg/kg per day for 9 days) was administered by oral gavage ( 32 ). MTX was administered at a dose of 5 mg/kg every other day until day 20 by intraperitoneal injection ( 33 ). Phosphate buffered saline (PBS) was used as negative control.…”

Metal ion-responsive nanocarrier derived from phosphonated calix[4]arenes for delivering dauricine specifically to sites of brain injury in a mouse model of intracerebral hemorrhage

“…We hypothesized that we could couple DRC with an appropriate carrier that would be responsive to metal ions such as Fe 2+ that are more abundant at hematoma sites than in normal tissue. As a drug delivery system, we focused on the calixarene macrocyle and its derivatives, which have antiviral, antibacterial, antifungal, antitubercular, anticancer, and anti-oxidant activities [10][11][12][13]. We have shown that a p-methylenebisphosphonic calix [4] arene derivative can assemble into micelles to form host-guest complexes with small molecules in the cavity, such as the drug carboplatin [14,15].…”