Liposomal paclitaxel induces fewer hematopoietic and cardiovascular complications than bioequivalent doses of Taxol

Huang,Shih-Ting; Wang,Yi‑Ping; Chen,Yen-Hui; Lin,Chin-Tarng; Li,Wen-Shan; Wu,Han-Chung

doi:10.3892/ijo.2018.4449

Liposomal paclitaxel induces fewer hematopoietic and cardiovascular complications than bioequivalent doses of Taxol

Authors:
- Shih-Ting Huang
- Yi‑Ping Wang
- Yen-Hui Chen
- Chin-Tarng Lin
- Wen-Shan Li
- Han-Chung Wu
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Affiliations: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan, R.O.C., Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, R.O.C., Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, R.O.C., Department of Pathology, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C.
Published online on: June 21, 2018 https://doi.org/10.3892/ijo.2018.4449
Pages: 1105-1117
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Paclitaxel (PTX) exhibits potent antineoplastic activity against various human malignancies; however, clinical application must overcome the inherent hydrophobicity of this molecule. The commercialized Taxol formulation utilizes Cremophor EL (CrEL)/ethanol as a solvent to stabilize and dispense PTX in an aqueous solution. However, adverse CrEL‑induced hypersensitivity reactions have been reported in ~30% of recipients, and 40% of patients receiving premedication may also experience this adverse effect. Therefore, the development of a CrEL-free delivery system is crucial, in order to fully exploit the therapeutic efficacy of PTX. In the present study, a novel liposomal PTX (lipo‑PTX) formulation was optimized with regards to encapsulation rate and long‑term stability, arriving at a molar constituent ratio of soybean phosphatidylcholine:cholesterol:N-(carbonyl-methoxy-poly-ethylene glycol 2000)‑1,2‑distearoyl‑sn-glycero‑3-phosphoethanolamine, sodium salt:PTX at 95:2:1:2. Comparable doses of lipo‑PTX and Taxol were bioequivalent in terms of therapeutic efficacy in xenograft tumor models. However, the systemic side effects, including hematopoietic toxicity, acute hypersensitivity reactions and cardiac irregularities, were significantly reduced in lipo‑PTX‑treated mice compared with those infused with reference formulations of PTX. In conclusion, the present study reported that lipo‑PTX exhibited a higher therapeutic index than clinical PTX formulations.

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1	Kampan NC, Madondo MT, McNally OM, Quinn M and Plebanski M: Paclitaxel and its evolving role in the management of ovarian cancer. BioMed Res Int. 2015.413076:2015.
2	Rowinsky EK and Donehower RC: Paclitaxel (taxol). N Engl J Med. 332:1004–1014. 1995. View Article : Google Scholar : PubMed/NCBI
3	Javeed A, Ashraf M, Riaz A, Ghafoor A, Afzal S and Mukhtar MM: Paclitaxel and immune system. Eur J Pharm Sci. 38:283–290. 2009. View Article : Google Scholar : PubMed/NCBI
4	Hadzic T, Aykin-Burns N, Zhu Y, Coleman MC, Leick K, Jacobson GM and Spitz DR: Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H₂O₂-mediated oxidative stress. Free Radic Biol Med. 48:1024–1033. 2010. View Article : Google Scholar : PubMed/NCBI
5	Alexandre J, Hu Y, Lu W, Pelicano H and Huang P: Novel action of paclitaxel against cancer cells: Bystander effect mediated by reactive oxygen species. Cancer Res. 67:3512–3517. 2007. View Article : Google Scholar : PubMed/NCBI
6	Adams JD, Flora KP, Goldspiel BR, Wilson JW, Arbuck SG and Finley R: Taxol: A history of pharmaceutical development and current pharmaceutical concerns. J Natl Cancer Inst Monogr. 15:141–147. 1993.
7	Goldspiel BR: Clinical overview of the taxanes. Pharmacotherapy. 17:110S–125S. 1997.PubMed/NCBI
8	Gelderblom H, Verweij J, Nooter K and Sparreboom A: Cremophor EL: The drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 37:1590–1598. 2001. View Article : Google Scholar : PubMed/NCBI
9	Szebeni J, Alving CR, Savay S, Barenholz Y, Priev A, Danino D and Talmon Y: Formation of complement-activating particles in aqueous solutions of Taxol: Possible role in hypersensitivity reactions. Int Immunopharmacol. 1:721–735. 2001. View Article : Google Scholar : PubMed/NCBI
10	U.S. Department of Health and Human Services: TAXOL^® (paclitaxel) injection label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf.
11	Weiss RB, Donehower RC, Wiernik PH, Ohnuma T, Gralla RJ, Trump DL, Baker JR Jr, Van Echo DA, Von Hoff DD and Leyland-Jones B: Hypersensitivity reactions from taxol. J Clin Oncol. 8:1263–1268. 1990. View Article : Google Scholar : PubMed/NCBI
12	Sparreboom A, van Tellingen O, Nooijen WJ and Beijnen JH: Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Res. 56:2112–2115. 1996.PubMed/NCBI
13	Sparreboom A, van Zuylen L, Brouwer E, Loos WJ, de Bruijn P, Gelderblom H, Pillay M, Nooter K, Stoter G and Verweij J: Cremophor EL-mediated alteration of paclitaxel distribution in human blood: Clinical pharmacokinetic implications. Cancer Res. 59:1454–1457. 1999.PubMed/NCBI
14	Surapaneni MS, Das SK and Das NG: Designing Paclitaxel drug delivery systems aimed at improved patient outcomes: Current status and challenges. ISRN Pharmacol. 2012.623139:2012.
15	Meng Z, Lv Q, Lu J, Yao H, Lv X, Jiang F, Lu A and Zhang G: Prodrug strategies for Paclitaxel. Int J Mol Sci. 17:7962016. View Article : Google Scholar :
16	Yardley DA: nab-Paclitaxel mechanisms of action and delivery. J Control Release. 170:365–372. 2013. View Article : Google Scholar : PubMed/NCBI
17	Ibrahim NK, Desai N, Legha S, Soon-Shiong P, Theriault RL, Rivera E, Esmaeli B, Ring SE, Bedikian A, Hortobagyi GN, et al: Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res. 8:1038–1044. 2002.PubMed/NCBI
18	Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M and O'Shaughnessy J: Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 23:7794–7803. 2005. View Article : Google Scholar : PubMed/NCBI
19	US Department of Health and Human Services: ABRAXANE^® label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021660s041lbl.pdf.
20	eHealthMe: Abraxane and myocardial infarction. https://www.ehealthme.com/ds/abraxane/myocardial-infarction/.
21	Feng L and Mumper RJ: A critical review of lipid-based nanoparticles for taxane delivery. Cancer Lett. 334:157–175. 2013. View Article : Google Scholar
22	Hong SS, Choi JY, Kim JO, Lee MK, Kim SH and Lim SJ: Development of paclitaxel-loaded liposomal nanocarrier stabilized by triglyceride incorporation. Int J Nanomedicine. 11:4465–4477. 2016. View Article : Google Scholar : PubMed/NCBI
23	Feng Q, Yu MZ, Wang JC, Hou WJ, Gao LY, Ma XF, Pei XW, Niu YJ, Liu XY, Qiu C, et al: Synergistic inhibition of breast cancer by co-delivery of VEGF siRNA and paclitaxel via vapreotide-modified core-shell nanoparticles. Biomaterials. 35:5028–5038. 2014. View Article : Google Scholar : PubMed/NCBI
24	Immordino ML, Brusa P, Arpicco S, Stella B, Dosio F and Cattel L: Preparation, characterization, cytotoxicity and pharma-cokinetics of liposomes containing docetaxel. J Control Release. 91:417–429. 2003. View Article : Google Scholar : PubMed/NCBI
25	Crosasso P, Ceruti M, Brusa P, Arpicco S, Dosio F and Cattel L: Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes. J Control Release. 63:19–30. 2000. View Article : Google Scholar : PubMed/NCBI
26	National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals: Guide for the Care and Use of Laboratory Animals. 8th edition. The National Academies Press; Washington, DC: 2011
27	Gregoriadis G: Drug entrapment in liposomes. FEBS Lett. 36:292–296. 1973. View Article : Google Scholar : PubMed/NCBI
28	Allen TM and Chonn A: Large unilamellar liposomes with low uptake into the reticuloendothelial system. FEBS Lett. 223:42–46. 1987. View Article : Google Scholar : PubMed/NCBI
29	Lee TY, Lin CT, Kuo SY, Chang DK and Wu HC: Peptide-mediated targeting to tumor blood vessels of lung cancer for drug delivery. Cancer Res. 67:10958–10965. 2007. View Article : Google Scholar : PubMed/NCBI
30	Wu CH, Kuo YH, Hong RL and Wu HC: α-Enolase-binding peptide enhances drug delivery efficiency and therapeutic efficacy against colorectal cancer. Sci Transl Med. 7:290ra912015. View Article : Google Scholar
31	Bartlett GR: Phosphorus assay in column chromatography. J Biol Chem. 234:466–468. 1959.PubMed/NCBI
32	Fiandaca MS, Berger MS and Bankiewicz KS: The use of convection-enhanced delivery with liposomal toxins in neuroon-cology. Toxins (Basel). 3:369–397. 2011. View Article : Google Scholar
33	Hillaireau H and Couvreur P: Nanocarriers' entry into the cell: Relevance to drug delivery. Cell Mol Life Sci. 66:2873–2896. 2009. View Article : Google Scholar : PubMed/NCBI
34	Eiseman JL, Eddington ND, Leslie J, MacAuley C, Sentz DL, Zuhowski M, Kujawa JM, Young D and Egorin MJ: Plasma pharmacokinetics and tissue distribution of paclitaxel in CD2F1 mice. Cancer Chemother Pharmacol. 34:465–471. 1994. View Article : Google Scholar : PubMed/NCBI
35	Howarth FC, Calaghan SC, Boyett MR and White E: Effect of the microtubule polymerizing agent taxol on contraction, Ca²⁺ transient and L-type Ca²⁺ current in rat ventricular myocytes. J Physiol. 516:409–419. 1999. View Article : Google Scholar
36	Zhang K, Heidrich FM, DeGray B, Boehmerle W and Ehrlich BE: Paclitaxel accelerates spontaneous calcium oscillations in cardiomyocytes by interacting with NCS-1 and the InsP3R. J Mol Cell Cardiol. 49:829–835. 2010. View Article : Google Scholar : PubMed/NCBI
37	Boehmerle W, Splittgerber U, Lazarus MB, McKenzie KM, Johnston DG, Austin DJ and Ehrlich BE: Paclitaxel induces calcium oscillations via an inositol 1,4,5-trisphosphate receptor and neuronal calcium sensor 1-dependent mechanism. Proc Natl Acad Sci USA. 103:18356–18361. 2006. View Article : Google Scholar : PubMed/NCBI
38	Boehmerle W, Zhang K, Sivula M, Heidrich FM, Lee Y, Jordt SE and Ehrlich BE: Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation. Proc Natl Acad Sci USA. 104:11103–11108. 2007. View Article : Google Scholar : PubMed/NCBI
39	Drummond DC, Meyer O, Hong K, Kirpotin DB and Papahadjopoulos D: Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev. 51:691–743. 1999.PubMed/NCBI
40	McIntosh TJ: The effect of cholesterol on the structure of phosphatidylcholine bilayers. Biochim Biophys Acta. 513:43–58. 1978. View Article : Google Scholar : PubMed/NCBI
41	Deniz A, Sade A, Severcan F, Keskin D, Tezcaner A and Banerjee S: Celecoxib-loaded liposomes: Effect of cholesterol on encapsulation and in vitro release characteristics. Biosci Rep. 30:365–373. 2010. View Article : Google Scholar
42	Sharma A, Mayhew E, Bolcsak L, Cavanaugh C, Harmon P, Janoff A and Bernacki RJ: Activity of paclitaxel liposome formulations against human ovarian tumor xenografts. Int J Cancer. 71:103–107. 1997. View Article : Google Scholar : PubMed/NCBI
43	Liu Y, Ran R, Chen J, Kuang Q, Tang J, Mei L, Zhang Q, Gao H, Zhang Z and He Q: Paclitaxel loaded liposomes decorated with a multifunctional tandem peptide for glioma targeting. Biomaterials. 35:4835–4847. 2014. View Article : Google Scholar : PubMed/NCBI
44	Li XY, Zhao Y, Sun MG, Shi JF, Ju RJ, Zhang CX, Li XT, Zhao WY, Mu LM, Zeng F, et al: Multifunctional liposomes loaded with paclitaxel and artemether for treatment of invasive brain glioma. Biomaterials. 35:5591–5604. 2014. View Article : Google Scholar : PubMed/NCBI
45	Ruttala HB and Ko YT: Liposomal co-delivery of curcumin and albumin/paclitaxel nanoparticle for enhanced synergistic antitumor efficacy. Colloids Surf B Biointerfaces. 128:419–426. 2015. View Article : Google Scholar : PubMed/NCBI
46	Barbosa MV, Monteiro LO, Carneiro G, Malagutti AR, Vilela JM, Andrade MS, Oliveira MC, Carvalho-Junior AD and Leite EA: Experimental design of a liposomal lipid system: A potential strategy for paclitaxel-based breast cancer treatment. Colloids Surf B Biointerfaces. 136:553–561. 2015. View Article : Google Scholar : PubMed/NCBI
47	Assanhou AG, Li W, Zhang L, Xue L, Kong L, Sun H, Mo R and Zhang C: Reversal of multidrug resistance by co-delivery of paclitaxel and lonidamine using a TPGS and hyaluronic acid dual-functionalized liposome for cancer treatment. Biomaterials. 73:284–295. 2015. View Article : Google Scholar : PubMed/NCBI
48	Schmitt-Sody M, Strieth S, Krasnici S, Sauer B, Schulze B, Teifel M, Michaelis U, Naujoks K and Dellian M: Neovascular targeting therapy: Paclitaxel encapsulated in cationic liposomes improves antitumoral efficacy. Clin Cancer Res. 9:2335–2341. 2003.PubMed/NCBI
49	Strieth S, Eichhorn ME, Werner A, Sauer B, Teifel M, Michaelis U, Berghaus A and Dellian M: Paclitaxel encapsulated in cationic liposomes increases tumor microvessel leakiness and improves therapeutic efficacy in combination with Cisplatin. Clin Cancer Res. 14:4603–4611. 2008. View Article : Google Scholar : PubMed/NCBI
50	Fetterly GJ, Grasela TH, Sherman JW, Dul JL, Grahn A, Lecomte D, Fiedler-Kelly J, Damjanov N, Fishman M, Kane MP, et al: Pharmacokinetic/pharmacodynamic modeling and simulation of neutropenia during phase I development of liposome-entrapped paclitaxel. Clin Cancer Res. 14:5856–5863. 2008. View Article : Google Scholar : PubMed/NCBI
51	Slingerland M, Guchelaar HJ, Rosing H, Scheulen ME, van Warmerdam LJ, Beijnen JH and Gelderblom H: Bioequivalence of Liposome-Entrapped Paclitaxel Easy-To-Use (LEP-ETU) formulation and paclitaxel in polyethoxylated castor oil: A randomized, two-period crossover study in patients with advanced cancer. Clin Ther. 35:1946–1954. 2013. View Article : Google Scholar : PubMed/NCBI
52	Yeh ET and Bickford CL: Cardiovascular complications of cancer therapy: Incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 53:2231–2247. 2009. View Article : Google Scholar : PubMed/NCBI
53	Gardner ER, Dahut W and Figg WD: Quantitative determination of total and unbound paclitaxel in human plasma following Abraxane treatment. J Chromatogr B Analyt Technol Biomed Life Sci. 862:213–218. 2008. View Article : Google Scholar : PubMed/NCBI
54	Sparreboom A, Scripture CD, Trieu V, Williams PJ, De T, Yang A, Beals B, Figg WD, Hawkins M and Desai N: Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol). Clin Cancer Res. 11:4136–4143. 2005. View Article : Google Scholar : PubMed/NCBI
55	Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, Tao C, De T, Beals B, Dykes D, et al: Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 12:1317–1324. 2006. View Article : Google Scholar : PubMed/NCBI