d-α-Tocopherol Polyethylene Glycol Succinate-Based Redox-Sensitive Paclitaxel Prodrug for Overcoming Multidrug Resistance in Cancer Cells

Abstract

To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-α-tocopherol polyethylene glycol succinate (TPGS) based PTX prodrug (TPGS-S-S-PTX), was synthesized here to fulfill the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of ∼140 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC50 of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration-time curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors.

Redox-sensitive Pluronic F127-tocopherol micelles: synthesis, characterization, and cytotoxicity evaluation

“…25 A series of F127-SS-TOC micellar solutions with various concentrations ranging from 1.45×10 -6 mg/mL to 0.76 mg/mL were prepared in the presence of pyrene at 6×10 -7 M. The pyrene fluorescence of different micellar solutions was measured with an excitation wavelength of 338 nm and an emission wavelength of 380 nm. On formation of micelles, pyrene moved inside the micelles from the aqueous phase, followed by an alteration in the intensity ratio I 338 /I 333 in a certain micelle concentration range.…”

A novel paclitaxel-loaded poly(D,L-lactide-co-glycolide)-Tween 80 copolymer nanoparticle overcoming multidrug resistance for lung cancer treatment

“…The length and width of tumor were measured using a caliper, and the tumor volume was calculated by the formula, (length × width 2 )/2. 30 When tumors reached 100-150 mm 3 in volume, mice were randomly assigned to four groups (n=10) and injected through the tail vein with saline, Taxol, PTX-loaded PLGA NPs, and PTX-loaded PLGA-Tween 80 NPs at an equivalent PTX concentration of 10 mg mL , respectively. Tumor progression in the mice was measured every 2 days, and then animals were sacrificed at the end of the experiment.…”

“…21 It may be attributed to the tumor heterogeneity, complexity of drug resistance, and barriers of NPs circulating and crossing in vivo. 19,29,30 There are already substantial efforts to incorporate multiple functionalities and moieties within the nanoparticle design. The design for site-specific delivery of therapeutics will be considered in future such as inducing the targeting agent.…”

D-α-tocopherol polyethylene glycol succinate-based derivative nanoparticles as a novel carrier for paclitaxel delivery

“…17 The CAC value was essential to evaluate the formation of NP. It was anticipated that the NP with low CAC value would be intact even on high dilution by a much larger volume of blood in vivo.…”

“…16 In addition, TPGS has also been utilized as a P-glycoprotein inhibitor to overcome multidrug resistance and to greatly improve the oral bioavailability of anticancer drugs. [17][18][19][20] In the past decade, TPGS-based derivatives, which can significantly enhance the solubility and stability of the formulated drug and realize sustained, controlled, and targeted drug delivery, have been widely investigated. 21 Nevertheless, the application of independent TPGS micelles for drug delivery is limited by the disadvantage that they were not stable enough in physiological environments.…”