Unified D-α-Tocopherol 5-Fu/SAHA bioconjugates self-assemble as complex nanodrug for optimized combination therapy
Abstract
Aim: To optimize the synergistic efficacy of combination therapy with controlled molar ratio, complex small molecule-based nanodrug (Co-SMND) of 5-fluorouracil (5-Fu)/vorinostat (SAHA) was developed. Materials & methods: Co-SMND with various ratios of 5-Fu-D-α-tocopherol (VE)/SAHA-VE were prepared and characterized including co-assembly mechanism, hydrolytic stability, cytotoxicity, synergistic effect and apoptosis inducing ability. The antitumor activity, systematic toxicity and biodistribution of optimized Co-SMND were evaluated in CT-26 bearing BALB/c mouse. Results: Maximal synergistic effect of Co-SMND could be obtained via simply adjusting the feeding molar ratio. The optimized Co-SMND showed superior in vivo antitumor efficacy, upregulated security and selective intratumoral accumulation. Conclusion: Such Co-SMND is of great significance for future clinical translation, and would be an efficient platform for combination chemotherapy.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . “Combo” nanomedicine: co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy. Adv. Drug Delivery Rev. 98, 3–18 (2016).
- 2 . Codelivery of doxorubicin and paclitaxel by crosslinked multilamellar liposome enables synergistic antitumor activity. Mol. Pharmaceutics 11(5), 1651–1661 (2014). • Proposes the limitations of cocktail administration and solve these problems by crosslinked multilamellar liposome.
- 3 A convergent synthetic platform for single-nanoparticle combination cancer therapy: ratiometric loading and controlled release of cisplatin, doxorubicin, and camptothecin. J. Am. Chem. Soc. 136(16), 5896–5899 (2014). •• First report about the synthesis of polymer nanoparticles that carry precise molar ratio of three different drugs and open a new door for nanomedicine-based combination therapy.
- 4 Coencapsulation of irinotecan and floxuridine into low cholesterol-containing liposomes that coordinate drug release in vivo. Biochim. Biophys. Acta 1768(3), 678–687 (2007).
- 5 Combinational delivery of hydrophobic and hydrophilic anticancer drugs in single nanoemulsions to treat MDR in cancer. Mol. Pharmaceutics 11(8), 2623–2630 (2014).
- 6 . Nanoparticles with precise ratiometric co-loading and co-delivery of gemcitabine monophosphate and cisplatin for treatment of bladder cancer. Adv. Funct. Mater. 24(42), 6601–6611 (2014).
- 7 Cisplatin crosslinked pH-sensitive nanoparticles for efficient delivery of doxorubicin. Biomaterials 35(12), 3851–3864 (2014).
- 8 . Hybrid prodrug nanoparticles with tumor penetration and programmed drug activation for enhanced chemoresistant cancer therapy. ACS Appl. Mater. Interfaces 9(22), 18450–18461 (2017).
- 9 Use of a lipid-coated mesoporous silica nanoparticle platform for synergistic gemcitabine and paclitaxel delivery to human pancreatic cancer in mice. ACS nano. 9(4), 3540–3557 (2015).
- 10 . Combination drug release of smart cyclodextrin-gated mesoporous silica nanovehicles. Chem. Commun. (Cambridge, UK) 51(33), 7203–7206 (2015).
- 11 Dual-pore mesoporous carbon@silica composite core–shell nanospheres for multidrug delivery. Angew. Chem. Int. Ed. 53(21), 5366–5370 (2014).
- 12 Co-delivery of cisplatin prodrug and chlorin e6 by mesoporous silica nanoparticles for chemo-photodynamic combination therapy to combat drug resistance. ACS Appl. Mater. Interfaces 8(21), 13332–13340 (2016).
- 13 . Stimuli-free programmable drug release for combination chemotherapy. Nanoscale 8(25), 12553–12559 (2016).
- 14 Codelivery of doxorubicin-containing thermosensitive hydrogels incorporated with docetaxel-loaded mixed micelles enhances local cancer therapy. Colloids Surf. B 143, 260–270 (2016).
- 15 . Polysaccharide-based micro-/nano-hydrogels for delivering macromolecular therapeutics. J. Control. Rel. 193, 162–173 (2014).
- 16 Development and evaluation of oxaliplatin and irinotecan co-loaded liposomes for enhanced colorectal cancer therapy. J. Control. Rel. 238, 10–21 (2016).
- 17 . A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy. Int. J. Nanomed. 11, 6003–6022 (2016). •• Proposes the concept of small molecule based nanodrug.
- 18 . Building nanostructures with drugs. Nano. Today 11(1), 13–30 (2016). • Reviews the design, development and advantages of small molecule nanodrug.
- 19 Temperature sensitive semi-IPN microspheres from sodium alginate and N-isopropylacrylamide for controlled release of 5-fluorouracil. J. Appl. Polym. Sci. 107(5), 2820–2829 (2008).
- 20 . Blend microspheres of poly(3-hydroxybutyrate) and cellulose acetate phthalate for colon delivery of 5-fluorouracil. Ind. Eng. Chem. Res. 50(18), 10414–10423 (2011).
- 21 . Colon targeting of 5-fluorouracil using polyethylene glycol crosslinked chitosan microspheres enteric coated with cellulose acetate phthalate. Ind. Eng. Chem. Res. 50(21), 11797–11807 (2011).
- 22 Inter-polymer complex microspheres of chitosan and cellulose acetate phthalate for oral delivery of 5-fluorouracil. Polym. Bull. 71(8), 2113–2131 (2014).
- 23 . A randomized Phase II study of two doses of vorinostat in combination with 5-FU/LV in patients with refractory colorectal cancer. Cancer Chemother. Pharmacol. 69(3), 743–751 (2012).
- 24 A Phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy. Cancer Chemother. Pharmacol. 65(5), 979–988 (2010). • Fails to determine the MTD of combining vorinostat (SAHA) with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer in a Phase I/II clinical trial.
- 25 South China University of Technology. CN102531964B (2014).
- 26 A unique highly hydrophobic anticancer prodrug self-assembled nanomedicine for cancer therapy. Nanomedicine (NY, USA) 12(8), 2273–2282 (2016). • The conjugate of hydrophobic docetaxel and D-α-tocopherol succinate (VE) was able to self-assemble into nanoparticle.
- 27 Preparation of intravenous injection nanoformulation of VESylated gemcitabine by co-assembly with TPGS and its anti-tumor activity in pancreatic tumor-bearing mice. Int. J. Pharm. 495(2), 792–797 (2015).
- 28 . A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46(12 Pt 1), 6387–6392 (1986).
- 29 . Comparison of simple potential functions for simulating liquid water. J. Phys. Chem. 79(2), 926–935 (1983).
- 30 Gaussian 09, Revision A.1. Gaussian, Inc., Wallingford CT, USA (2009).
- 31 . A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model. J. Phys. Chem. 97, 10269–10280 (1993).
- 32 The amber biomolecular simulation programs. J. Comput. Chem. 26(16), 1668–1688 (2005).
- 33 . Routine microsecond molecular dynamics simulations with AMBER on GPUs. 1. generalized born. J. Chem. Theory Comput. 8(5), 1542–1555 (2012).
- 34 . Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J. Comput. Phys. 23(3), 327–341 (1977).
- 35 . Efficient multiple time step method for use with Ewald and particle mesh Ewald for large biomolecular systems. J. Chem. Phys. 115(5), 2348–2358 (2001).
- 36 . Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70(2), 440–446 (2010).
- 37 Combination of small molecule prodrug and nanodrug delivery: amphiphilic drug–drug conjugate for cancer therapy. J. Am. Chem. Soc. 136(33), 11748–11756 (2014).
- 38 . Direct detection of CH/pi interactions in proteins. Nat. Chem. 2(6), 466–471 (2010).
- 39 . Preclinical evaluation of antitumor activity of acid-sensitive PEGylated doxorubicin. ACS Appl. Mater. Interfaces 6(23), 21202–21214 (2014).
- 40 An investigation of antitumor efficiency of novel sustained and targeted 5-fluorouracil nanoparticles. Eur. J. Med. Chem. 92, 882–889 (2015).
- 41 . Cytotoxicity and antitumour activity of 5-fluorouracil-loaded polyhydroxybutyrate and cellulose acetate phthalate blend microspheres. J. Microencapsulation 30(4), 356–368 (2013).