Enhanced Tumor Delivery of Gemcitabine via PEG-DSPE/TPGS Mixed Micelles

Abstract

Gemcitabine is a potent anticancer drug approved for the treatment of pancreatic, non-small-cell lung, breast, and ovarian cancers. The major deficiencies of current gemcitabine therapy, however, are its rapid metabolic inactivation and narrow therapeutic window. Herein, we employed polyethylene glycol-b-distearoylphosphatidylethanolamine (PEG-DSPE)/tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles as a delivery system, to improve the pharmacokinetic characteristics of gemcitabine and enhance its antitumor efficacy. By conjugating stearic acid to gemcitabine and subsequently encapsulating stearoyl gemcitabine (GemC18) within PEG-DSPE/TPGS mixed micelles, the deamination of gemcitabine was delayed in vitro and in vivo. Importantly, compared to free gemcitabine, GemC18-loaded micelles pronouncedly prolonged the circulation time of gemcitabine and elevated its concentration in the tumor by 3-fold, resulting in superior antitumor efficacy in mice bearing human pancreatic cancer BxPC-3 xenografts. Our findings demonstrate the promise of PEG-DSPE/TPGS mixed micelles as a nanocarrier system for the delivery of gemcitabine to achieve safer and more efficacious therapeutic outcomes.

Development and evaluation of vitamin E D-α-tocopheryl polyethylene glycol 1000 succinate-mixed polymeric phospholipid micelles of berberine as an anticancer nanopharmaceutical

“…25,26,32 The efficient cellular delivery of Brb, via TPGS-mMics, seems to have triggered apoptotic death machinery in both cancer models, potentially with the involvement of mitochondrial depolarization, as emphasized previously. 10,11,29,35 In fact, analogous to the apoptosis assay positive control, CCCP, the Brb-mMic treatment was also associated with maximum elevation of influential caspase proteins, caspase-3 and -7, which are commonly recognized as the chief effector caspases involved in driving the different pathways of apoptosis in tumors.…”

“…[22][23][24] In vivo, owing to their extended plasma circulation half-life (typically .36 hours in mice), the small size of PEG-PE micelles allows also for their effective accumulation in tumorous tissues with leaky vasculature, via the enhanced permeability and retention effect. [23][24][25] Here, mixed micelle (mMic) formulation of Brb is investigated in order to enhance the solubilization efficacy of PEG-PE micellar carriers, by including d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as an additional component -a PEGylated derivative of natural Vitamin E (VE), (α-tocopherol) commonly utilized as a pharmaceutical solubilizer, absorption enhancer, and a vehicle for lipidic drug formulations (Figure 1). [25][26][27][28][29] Such a mixed micellar system would not only improve Brb solubilization capacity, owing to increased core volume of mMics, created by the planar chromane moiety of VE, but would also provide better protection for the active isoquinolone structure of Brb (Figure 1), effectively enhancing both Brb encapsulation and stability.…”

“…[23][24][25] Here, mixed micelle (mMic) formulation of Brb is investigated in order to enhance the solubilization efficacy of PEG-PE micellar carriers, by including d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as an additional component -a PEGylated derivative of natural Vitamin E (VE), (α-tocopherol) commonly utilized as a pharmaceutical solubilizer, absorption enhancer, and a vehicle for lipidic drug formulations (Figure 1). [25][26][27][28][29] Such a mixed micellar system would not only improve Brb solubilization capacity, owing to increased core volume of mMics, created by the planar chromane moiety of VE, but would also provide better protection for the active isoquinolone structure of Brb (Figure 1), effectively enhancing both Brb encapsulation and stability. 30 Based on recent reports, TPGS has shown notable proapoptotic activity as well as a strong ability to overcome drug resistance by inhibiting Pgp efflux pumps.…”

Lipid prodrug nanocarriers in cancer therapy

“…Classification of the anticancer drugs, lipids used for their derivatization and the nanoscale drug delivery system based on these prodrugs are reported in Table 1. A C C E P T E D M A N U S C R I P T Liposomes [37][38][39] Stearic acid C18 (stearoyl) Liposomes [36][37][38][39] Micelles [40,41] Polymer nanoparticles [42] Solid lipid nanoparticles [43][44][45][46] Self-assembled nanoparticles [47] Squalene Nanoparticles [50][51][52][53] [54-57, 59-63, 66, 67] Isoprenoids (monoisoprenoyl, geranyl farnesyl,polyisoprenoyl) Nanoparticles [68,69] Squalene Liposomes [58] Gemcitabine monofosfate Squalene Nanoparticles [64,65] Cytosine arabinoside Oleic acid Palmitic acid Liposomes [73] Cholesterol Liposomes [74] Glycerol substituted Liposomes [75] Phospholipids Thioether lipids (1-Salkylthioglycerols) Micelles [76] Squalene Liposomes [77][78] 5-fluorouracil Stearic acid Solid lipid nanoparticles [79] Floxuridine Octanoic acid; palmitic acid Liposomes [80][81][82] Octanoic acid; Solid lipid nanoparticles [84] Capecitabine Palmitic acid, Phytic acid,Oleic acid, Stearic acid, Linoleic acid, Linolenic acid Solid lipid nanoparticles, cubosomes, gyroids, double diamonds [85][86]…”

Desenvolvimento de carreador lipídico nanoestruturado (CLN) como sistema de co-encapsulação de curcuminóides e timol para aplicação tópica

“…Nas formulações farmacêuticas pode aumentar a biodisponibilidade de fármacos com baixa solubilidade tanto pelo aumento na solubilidade como pela modulação do efluxo de fármacos dependente de glicoproteína-P (Johnson et al, 2002;Wang et al, 2014), além de poder ser utilizado na formulação de emulsões O/A como tensoativo. Também atua reduzindo a sensibilidade da pele a certos fármacos, como carreador em aplicações tópicas e como ligante em tecnologias de "hot-melt granulation" e "hot-melt extrusion" (Guo et al, 2013;Lee et al, 2015;Lamm et al, 2016).…”