Effects of Surface Charge, PEGylation and Functionalization with Dipalmitoylphosphatidyldiglycerol on Liposome-Cell Interactions and Local Drug Delivery to Solid Tumors Via Thermosensitive Liposomes

Overview

Journal Int J Nanomedicine

Publisher Dove Medical Press

Specialty Biotechnology

Date 2021 Jun 24

PMID 34163158

Citations 6

Authors

Matteo Petrini

Wouter J M Lokerse

Agnieszka Mach

Martin Hossann

Olivia M Merkel

Lars H Lindner

Affiliations

Soon will be listed here.

Abstract

Purpose: Previous studies demonstrated the possibility of targeting tumor-angiogenic endothelial cells with positively charged nanocarriers, such as cationic liposomes. We investigated the active targeting potential of positively charged nanoparticles in combination with the heat-induced drug release function of thermosensitive liposomes (TSL). This novel dual-targeted approach via cationic TSL (CTSL) was thoroughly explored using either a novel synthetic phospholipid 1,2-dipalmitoyl--glycero-3-phosphodiglycerol (DPPG) or a conventional polyethylene glycol (PEG) surface modification. Anionic particles containing either DPPG or PEG were also included in the study to highlight difference in tumor enrichment driven by surface charge. With this study, we aim to provide a deep insight into the main differences between DPPG- and PEG-functionalized liposomes, focusing on the delivery of a well-known cytotoxic drug (doxorubicin; DOX) in combination with local hyperthermia (HT, 41-43°C).

Materials And Methods: DPPG- and PEG-based cationic TSLs (PG-CTSL/PEG-CTSL) were thoroughly analyzed for size, surface charge, and heat-triggered DOX release. Cancer cell targeting and DOX delivery was evaluated by FACS, fluorescence imaging, and HPLC. In vivo particle behavior was analyzed by assessing DOX biodistribution with local HT application in tumor-bearing animals.

Results: The absence of PEG in PG-CTSL promoted more efficient liposome-cell interactions, resulting in a higher DOX delivery and cancer cell toxicity compared with PEG-CTSL. By exploiting the dual-targeting function of CTSLs, we were able to selectively trigger DOX release in the intracellular compartment by HT. When tested in vivo, local HT promoted an increase in intratumoral DOX levels for all (C)TSLs tested, with DOX enrichment factors ranging from 3 to 14-fold depending on the type of formulation.

Conclusion: Cationic particles showed lower hemocompatibility than their anionic counterparts, which was partially mitigated when PEG was grafted on the liposome surface. DPPG-based anionic TSL showed optimal local drug delivery compared to all other formulations tested, demonstrating the potential advantages of using DPPG lipid in designing liposomes for tumor-targeted applications.

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References

Song L, Ahkong Q, Rong Q, Wang Z, Ansell S, Hope M . Characterization of the inhibitory effect of PEG-lipid conjugates on the intracellular delivery of plasmid and antisense DNA mediated by cationic lipid liposomes. Biochim Biophys Acta. 2001; 1558(1):1-13. DOI: 10.1016/s0005-2736(01)00399-6. View

Strieth S, Eichhorn M, Sauer B, Schulze B, Teifel M, Michaelis U . Neovascular targeting chemotherapy: encapsulation of paclitaxel in cationic liposomes impairs functional tumor microvasculature. Int J Cancer. 2004; 110(1):117-24. DOI: 10.1002/ijc.20083. View

Salmaso S, Caliceti P . Stealth properties to improve therapeutic efficacy of drug nanocarriers. J Drug Deliv. 2013; 2013:374252. PMC: 3606770. DOI: 10.1155/2013/374252. View

Haran G, Cohen R, Bar L, Barenholz Y . Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta. 1993; 1151(2):201-15. DOI: 10.1016/0005-2736(93)90105-9. View

Kono Y, Iwasaki A, Fujita T . Effect of surface charge, particle size, and modification by polyethylene glycol of liposomes on their association with Caco-2 cells across an unstirred water layer. Pharmazie. 2018; 73(1):3-8. DOI: 10.1691/ph.2018.7110. View

Kono Y, Jinzai H, Kotera Y, Fujita T . Influence of Physicochemical Properties and PEG Modification of Magnetic Liposomes on Their Interaction with Intestinal Epithelial Caco-2 Cells. Biol Pharm Bull. 2017; 40(12):2166-2174. DOI: 10.1248/bpb.b17-00563. View

Zhao W, Zhuang S, Qi X . Comparative study of the in vitro and in vivo characteristics of cationic and neutral liposomes. Int J Nanomedicine. 2011; 6:3087-98. PMC: 3235029. DOI: 10.2147/IJN.S25399. View

Augustin H, Braun K, Telemenakis I, Modlich U, Kuhn W . Ovarian angiogenesis. Phenotypic characterization of endothelial cells in a physiological model of blood vessel growth and regression. Am J Pathol. 1995; 147(2):339-51. PMC: 1869809. View

Maruyama K, Yuda T, Okamoto A, Kojima S, Suginaka A, IWATSURU M . Prolonged circulation time in vivo of large unilamellar liposomes composed of distearoyl phosphatidylcholine and cholesterol containing amphipathic poly(ethylene glycol). Biochim Biophys Acta. 1992; 1128(1):44-9. DOI: 10.1016/0005-2760(92)90255-t. View

10.

Peller M, Willerding L, Limmer S, Hossann M, Dietrich O, Ingrisch M . Surrogate MRI markers for hyperthermia-induced release of doxorubicin from thermosensitive liposomes in tumors. J Control Release. 2016; 237:138-46. DOI: 10.1016/j.jconrel.2016.06.035. View

11.

Knudsen K, Northeved H, Kumar P, Permin A, Gjetting T, Andresen T . In vivo toxicity of cationic micelles and liposomes. Nanomedicine. 2014; 11(2):467-77. DOI: 10.1016/j.nano.2014.08.004. View

12.

Miller C, Bondurant B, McLean S, McGovern K, OBrien D . Liposome-cell interactions in vitro: effect of liposome surface charge on the binding and endocytosis of conventional and sterically stabilized liposomes. Biochemistry. 1998; 37(37):12875-83. DOI: 10.1021/bi980096y. View

13.

Overgaard J . Combined adriamycin and hyperthermia treatment of a murine mammary carcinoma in vivo. Cancer Res. 1976; 36(9 pt.1):3077-81. View

14.

Klibanov A, Maruyama K, Torchilin V, Huang L . Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett. 1990; 268(1):235-7. DOI: 10.1016/0014-5793(90)81016-h. View

15.

Campbell R, Ying B, Kuesters G, Hemphill R . Fighting cancer: from the bench to bedside using second generation cationic liposomal therapeutics. J Pharm Sci. 2008; 98(2):411-29. DOI: 10.1002/jps.21458. View

16.

Wu J, Lee A, Lu Y, Lee R . Vascular targeting of doxorubicin using cationic liposomes. Int J Pharm. 2007; 337(1-2):329-35. DOI: 10.1016/j.ijpharm.2007.01.003. View

17.

Manzoor A, Lindner L, Landon C, Park J, Simnick A, Dreher M . Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors. Cancer Res. 2012; 72(21):5566-75. PMC: 3517817. DOI: 10.1158/0008-5472.CAN-12-1683. View

18.

Dan N . Effect of liposome charge and PEG polymer layer thickness on cell-liposome electrostatic interactions. Biochim Biophys Acta. 2002; 1564(2):343-8. DOI: 10.1016/s0005-2736(02)00468-6. View

19.

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

20.

Nagy J, Senger D, Dvorak H, Dvorak A . Ultrastructural localization of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) to the abluminal plasma membrane and vesiculovacuolar organelles of tumor microvascular endothelium. J Histochem Cytochem. 1995; 43(4):381-9. DOI: 10.1177/43.4.7534783. View