A prodrug micellar carrier assembled from polymers with pendant farnesyl thiosalicylic acid moieties for improved delivery of paclitaxel

Abstract

In order to achieve enhanced and synergistic delivery of paclitaxel (PTX), a hydrophobic anticancer agent, two novel prodrug copolymers, POEG15-b-PFTS6 and POEG15-b-PFTS16 composed of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) and hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist) blocks, were synthesized. Both POEG-b-PFTS polymers were able to form micelles with intrinsic antitumor activity in vitro and in vivo. Employing these micelles as a carrier to load PTX, their drug loading capacity, stability, in vivo biodistribution and tumor inhibition effect were evaluated. PTX/POEG15-b-PFTS16 mixed micelles exhibited an excellent stability of 9 days at 4°C with a PTX loading capacity of 8.2%, which was more effective than PTX/POEG15-b-PFTS6 mixed micelles. In vivo biodistribution data showed that DiR-loaded POEG-b-PFTS micelles were more effectively localized in the tumor than in other organs. Moreover, both PTX/POEG-b-PFTS micelles showed significantly higher antitumor activity than Taxol in a 4T1.2 murine breast tumor model, and the tumor inhibition and animal survival followed the order of PTX/POEG15-b-PFTS16 > PTX/POEG15-b-PFTS6 > POEG15-b-PFTS16 > Taxol ≈ POEG15-b-PFTS6. Our data suggest that POEG-b-PFTS micelles are a promising anticancer drug carrier that warrants more studies in the future.

In vitro and in vivo evaluation of macromolecular prodrug GC-FUA based nanoparticle for hepatocellular carcinoma chemotherapy

“…For overcoming these shortcoming, many researchers have been doing many try, with the development of nanotechnology in cancer therapy, the nanosystems of nanoparticles, liposomes, micelles are commonly applied in this field. In recent years, a promising approach to increase the aqueous solubility and enhance bioavailability of antitumor drugs is to form polymerbased prodrugs through the conjugation with polymeric carriers (Dragojevic et al, 2015;Magaña et al, 2016;Sun et al, 2016). The macromolecular prodrugs also possess other preponderance such as sustained drug release and reduced toxicity before the metabolization occurs (Yu et al, 2016).…”

Doxorubicin delivered by a redox-responsive dasatinib-containing polymeric prodrug carrier for combination therapy

“…First, POEG macroCTA ( M n = 9 KDa, n=18) was synthesized by reversible addition-fragmentation transfer (RAFT) polymerization as reported previously with some modification [34]. By using POEG macroCTA as RAFT chain transfer agent, MBA and MBC monomers were polymerized respectively to yield POEG- b -PMBA and POEG- b -PMBC polymers, and the polymerization kinetics was studied.…”

“…Dulbecco’s Modified Eagle’s Medium (DMEM), trypsin-EDTA solution, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), Triton X-100, Hoechst 33342 and LysoTracker Green DND-26 were all purchased from Sigma-Aldrich. N -methacryloyl- N -( tert -butoxycarbonyl)aminohexyl methacrylamide (MBA) [39], N -methacryloyl- N ′-( t -butyoxycarbonyl)cystamine (MBC) [40], POEG macroCTA [34], and 4-nitrophenyl-actived dasatinib Das-NO 2 [41] were prepared according to the literatures. All other reagents were of analytical or chromatographic grade.…”

“…Other groups include cells treated with Das, blank POEG- b -PCCDas and POEG- b -PSSDas micelles at equivalent Das concentrations as in corresponding drug-loaded groups. After incubation for 72 h, the cell viability was measured via MTT assay as reported before [34]. Untreated cells were included as a control.…”

“…Moreover, prodrug polymers with amphiphilic properties could be used as dual-functional carriers to co-load other drugs and achieve synergistic effect [34]. Furthermore, polymeric prodrug carriers can realize controlled release of both conjugated drugs and encapsulated drugs in response to a particular stimulus via introducing stimuli-responsive linkages between the drug and the polymer backbone.…”