Biotherapy of Brain Tumors with Phosphatidylserine-Targeted Radioiodinated SapC-DOPS Nanovesicles

Abstract

Glioblastoma multiforme (GBM), a common type of brain cancer, has a very poor prognosis. In general, viable GBM cells exhibit elevated phosphatidylserine (PS) on their membrane surface compared to healthy cells. We have developed a drug, saposin C-dioleoylphosphatidylserine (SapC-DOPS), that selectively targets cancer cells by honing in on this surface PS. To examine whether SapC-DOPS, a stable, blood–brain barrier-penetrable nanovesicle, could be an effective delivery system for precise targeted therapy of radiation, we iodinated several carbocyanine-based fluorescent reporters with either stable iodine (127I) or radioactive isotopes (125I and 131I). While all of the compounds, when incorporated into the SapC-DOPS delivery system, were taken up by human GBM cell lines, we chose the two that best accumulated in the cells (DiI (22,3) and DiD (16,16)). Pharmacokinetics were conducted with 125I-labeled compounds and indicated that DiI (22,3)-SapC-DOPS had a time to peak in the blood of 0.66 h and an elimination half-life of 8.4 h. These values were 4 h and 11.5 h, respectively, for DiD (16,16)-SapC-DOPS. Adult nude mice with GBM cells implanted in their brains were treated with 131I-DID (16,16)-SapC-DOPS. Mice receiving the radionuclide survived nearly 50% longer than the control groups. These data suggest a potential novel, personalized treatment for a devastating brain disease.

Peptide Dendrimers with Non-Symmetric Bola Structure Exert Long Term Effect on Glioblastoma and Neuroblastoma Cell Lines

“…Consequently, efficacy of various AMPs, alone [ 37 , 38 , 39 ] or as hybrid materials [ 40 , 41 , 42 , 43 , 44 ], was tested against GBM cells and showed their substantial activity along with structure-dependent versatility of mechanism of action [ 45 , 46 , 47 ]. Moreover, PS-targeting was successfully applied for the design of a new delivery systems for brain tumors imaging and therapy [ 48 , 49 ]. Recently, we studied interactions between 2-Cl-Z-terminated dendrimer at relatively low concentration (5.5 μM) with model lipid membranes of different fluidity by combination of neutron reflection (NR)and molecular dynamics (MD).…”

Targeting of elevated cell surface phosphatidylserine with saposin C-dioleoylphosphatidylserine nanodrug as individual or combination therapy for pancreatic cancer

“…Indeed, SapC-DOPS (clinical name: BXQ-350) has shown an exemplary safety profile both preclinically[ 26 ] and in Phase I clinical trials[ 39 , 40 ]. In mice there were no noticeable side effects and SapC-DOPS appeared to attenuate cancer-associated cachexia[ 31 , 41 ]. In the clinical trials, no severe adverse events were observed and most subjects showed no drug linked problems at all.…”

“…Pancreatic cell lines with initially low to moderate surface PS exhibited dose-dependent increases in surface PS by 12 h with a maximum increase by 24 h. In addition, subcutaneous tumors generated in nude mice from the human pancreatic cancer cell line, cfPac-1, nearly doubled their surface PS 48 h following focused exposure to 10 Gy of radiation[ 42 ]. Incidentally, we have recently demonstrated that we can incorporate the therapeutic radioisotope, 131 I into SapC-DOPS nanovesicles and that this radiation enhances the effects of SapC-DOPS to prolong survival in mice bearing glioblastoma multiforme, a type of brain cancer[ 41 ]. In this scenario, the radiation from 131 I, while directly killing the tumor cells may also increase surface PS.…”

SapC–DOPS as a Novel Therapeutic and Diagnostic Agent for Glioblastoma Therapy and Detection: Alternative to Old Drugs and Agents

“…SapC-DOPS selectively targets PS on the tumor cell surface, and, unlike most other therapeutics, its activity is enhanced by the acidic TME. SapC-DOPS binding to the cancer cells leads to ceramide accumulation, caspase activation, and eventual apoptosis [71] via a variety of mechanisms (Figure 1). Importantly, astrocytes in coculture with GBM or metastatic breast cancer cells are not targeted or killed by SapC-DOPS and, critically, do not protect the tumor cells from the effects of SapC-DOPS [72].…”

“…Next, a carbocyanine-based fluorescent probe [DiD (16,16)] with 131 I was incorporated into SapC-DOPS nanovesicles ( 131 I-DiD(16,16)-SapC-DOPS, Figure 1) [71]. 131 I is of great interest for both radiotherapy and imaging applications and was selected for this study because (1) it is an FDA-approved radionuclide for treatment of thyroid cancer [82], (2) it has a short half-life (eight days), and (3) it emits both β and γ radiation.…”