Palmitoyl Carnitine-Anchored Nanoliposomes for Neovasculature-Specific Delivery of Gemcitabine Elaidate to Treat Pancreatic Cancer

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2023 Jan 8

PMID 36612178

Authors

Akanksha Patel

Aishwarya Saraswat

Harsh Patel

Zhe-Sheng Chen

Ketan Patel

Affiliations

Soon will be listed here.

Abstract

Being the fourth most fatal malignancy worldwide, pancreatic cancer is on track to become the second leading cause of cancer-related deaths in the United States by 2030. Gemcitabine is a first-line chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine Elaidate (Gem Elaidate) is a lipophilic derivative which allows hENT1-independent intracellular delivery of gemcitabine and better pharmacokinetics and entrapment in a nanocarrier. Cancer cells and neovasculature are negatively charged compared to healthy cells. Palmitoyl-DL-carnitine chloride (PC) is a Protein kinase C (PKC) inhibitor which also provides a cationic surface charge to nanoliposomes for targeting tumor neovasculature and augmented anticancer potency. The objectives of our study are: (a) to develop and characterize a PKC inhibitor-anchored Gem Elaidate-loaded PEGylated nanoliposome (PGPLs) and (b) to investigate the anticancer activity of Gem Elaidate and PGPLs in 2D and 3D models of pancreatic cancer. The optimized PGPLs resulted in a particle size of 80 ± 2.31 nm, a polydispersity index of 0.15 ± 0.05 and a ζ-potential of +31.6 ± 3.54 mV, with a 93.25% encapsulation efficiency of Gem Elaidate in PGPLs. Our results demonstrate higher cellular uptake, inhibition in migration, as well as angiogenesis potential and significant apoptosis induced by PGPLs in 3D multicellular tumor spheroids of pancreatic cancer cells. Hence, PGPLs could be an effective and novel nanoformulation for the neovasculature-specific delivery of Gemcitabine Elaidate to treat PDAC.

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References

Spyridopoulos I, Luedemann C, Chen D, Kearney M, Chen D, Murohara T . Divergence of angiogenic and vascular permeability signaling by VEGF: inhibition of protein kinase C suppresses VEGF-induced angiogenesis, but promotes VEGF-induced, NO-dependent vascular permeability. Arterioscler Thromb Vasc Biol. 2002; 22(6):901-6. DOI: 10.1161/01.atv.0000020006.89055.11. View

Campbell R, Fukumura D, Brown E, Mazzola L, Izumi Y, Jain R . Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors. Cancer Res. 2002; 62(23):6831-6. View

Mochly-Rosen D, Das K, Grimes K . Protein kinase C, an elusive therapeutic target?. Nat Rev Drug Discov. 2012; 11(12):937-57. PMC: 3760692. DOI: 10.1038/nrd3871. View

Yang K, Yu G, Yang Z, Yue L, Zhang X, Sun C . Supramolecular Polymerization-Induced Nanoassemblies for Self-Augmented Cascade Chemotherapy and Chemodynamic Therapy of Tumor. Angew Chem Int Ed Engl. 2021; 60(32):17570-17578. DOI: 10.1002/anie.202103721. View

Nordh S, Ansari D, Andersson R . hENT1 expression is predictive of gemcitabine outcome in pancreatic cancer: a systematic review. World J Gastroenterol. 2014; 20(26):8482-90. PMC: 4093699. DOI: 10.3748/wjg.v20.i26.8482. View

Maniotis A, Folberg R, Hess A, Seftor E, Gardner L, Peer J . Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol. 1999; 155(3):739-52. PMC: 1866899. DOI: 10.1016/S0002-9440(10)65173-5. View

Zhou Q, Kiosses W, Liu J, Schimmel P . Tumor endothelial cell tube formation model for determining anti-angiogenic activity of a tRNA synthetase cytokine. Methods. 2008; 44(2):190-5. PMC: 3835186. DOI: 10.1016/j.ymeth.2007.10.004. View

Saffari M, Hoseini Shirazi F, Moghimi H . Terpene-loaded Liposomes and Isopropyl Myristate as Chemical Permeation Enhancers Toward Liposomal Gene Delivery in Lung Cancer cells; A Comparative Study. Iran J Pharm Res. 2016; 15(3):261-267. PMC: 5149012. View

Heinemann V . Gemcitabine in the treatment of advanced pancreatic cancer: a comparative analysis of randomized trials. Semin Oncol. 2003; 29(6 Suppl 20):9-16. DOI: 10.1053/sonc.2002.37372. View

10.

Mourtas S, Michanetzis G, Missirlis Y, Antimisiaris S . Haemolytic activity of liposomes: effect of vesicle size, lipid concentration and polyethylene glycol-lipid or arsonolipid incorporation. J Biomed Nanotechnol. 2010; 5(4):409-15. DOI: 10.1166/jbn.2009.1050. View

11.

Alavi M, Hamidi M . Passive and active targeting in cancer therapy by liposomes and lipid nanoparticles. Drug Metab Pers Ther. 2019; 34(1). DOI: 10.1515/dmpt-2018-0032. View

12.

Fu Y, Rathod D, Abo-Ali E, Dukhande V, Patel K . EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAF Mutated Parent- and Vemurafenib-Resistant Melanoma. Pharmaceutics. 2019; 11(10). PMC: 6836218. DOI: 10.3390/pharmaceutics11100504. View

13.

Venugopal B, Awada A, Evans T, Dueland S, Hendlisz A, Rasch W . A first-in-human phase I and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analogue, in patients with advanced solid tumours. Cancer Chemother Pharmacol. 2015; 76(4):785-92. DOI: 10.1007/s00280-015-2846-0. View

14.

Stylianopoulos T, Soteriou K, Fukumura D, Jain R . Cationic nanoparticles have superior transvascular flux into solid tumors: insights from a mathematical model. Ann Biomed Eng. 2012; 41(1):68-77. PMC: 3886728. DOI: 10.1007/s10439-012-0630-4. View

15.

Primassin S, Ter Veld F, Mayatepek E, Spiekerkoetter U . Carnitine supplementation induces acylcarnitine production in tissues of very long-chain acyl-CoA dehydrogenase-deficient mice, without replenishing low free carnitine. Pediatr Res. 2008; 63(6):632-7. DOI: 10.1203/PDR.0b013e31816ff6f0. View

16.

Matsumoto T, Komori T, Yoshino Y, Ioroi T, Kitahashi T, Kitahara H . A Liposomal Gemcitabine, FF-10832, Improves Plasma Stability, Tumor Targeting, and Antitumor Efficacy of Gemcitabine in Pancreatic Cancer Xenograft Models. Pharm Res. 2021; 38(6):1093-1106. PMC: 8217058. DOI: 10.1007/s11095-021-03045-5. View

17.

Scotti M, Bamlet W, Smyrk T, Fields A, Murray N . Protein kinase Ciota is required for pancreatic cancer cell transformed growth and tumorigenesis. Cancer Res. 2010; 70(5):2064-74. PMC: 2881466. DOI: 10.1158/0008-5472.CAN-09-2684. View

18.

Storz P . Targeting protein kinase C subtypes in pancreatic cancer. Expert Rev Anticancer Ther. 2015; 15(4):433-8. PMC: 4577234. DOI: 10.1586/14737140.2015.1003810. View

19.

Singh R, OReilly E . New Treatment Strategies for Metastatic Pancreatic Ductal Adenocarcinoma. Drugs. 2020; 80(7):647-669. PMC: 7466866. DOI: 10.1007/s40265-020-01304-0. View

20.

Anderson E, Thomassian S, Gong J, Hendifar A, Osipov A . Advances in Pancreatic Ductal Adenocarcinoma Treatment. Cancers (Basel). 2021; 13(21). PMC: 8583016. DOI: 10.3390/cancers13215510. View