Cholesterol-based anionic long-circulating cisplatin liposomes with reduced renal toxicity
Introduction
Platinum compounds play an important role in cancer chemotherapy. Cisplatin, (cis-diammine dichloroplatinum (II); CDDP), the first generation of platinum based chemotherapy drug, is one of the most common anticancer agents and has a broad spectrum of anticancer activity in the treatment of solid tumors including gastrointestinal, head and neck, genitourinary and lung tumors [1], [2], [3], [4], [5]. However, broader therapeutic applications of CDDP are limited by drawbacks such as the low selectivity between malignant and normal cells, the presence of intrinsic or acquired resistance, short time period of retention, rapid inactivation and severe toxic effects (e.g. anemia, deafness, vomiting, nausea and neurotoxicity, particularly nephrotoxicity [6], [7], [8], [9]).
According to the previous research, about 25–35% of patients display a significant decline of renal function following a single dose (50–100 mg/m2) of CDDP [10], [11] due to its preferential accumulation in the kidney, nephrotoxicity consequently becomes the main limit of CDDP in clinical use and to the greater efficacy [12], [13], [14]. Many of the current studies are focus on the underlying cause of cisplatin-induced nephrotoxicity [15], [16], [17], however, the mechanisms are not fully understood. To overcome this shortcoming, enhancement of the hydrophobicity and polymerization of platinum drugs become the mainstream theories of anti-nephrotoxicity strategy. Plenty of related platinum compounds such as carboplatin, oxaliplatin and nedaplatin have been synthesized and tested in the last two decades with the aim of improving the drug efficacy [15]. Also, the anionic carriers such as anionic dendrimers [18], poly (amino acid) [19], anionic polysaccharide [20], anionic polyester [21], alginate and other anionic polymers, were usually designed as the CDDP delivery system in order to load more CDDP in vectors and increase the loading efficiency. Further more, the complex formation of CDDP with the anionic groups could polymerize the platinum drug and the macromolecular drug compounds tend to improve the uptake and effect on retention of CDDP to a higher level in tumors than in the normal tissues indeed in the absence of a targeting group [22]. Such selective targeting which won’t appear in the using of low-molecular weight drugs has been termed “the enhanced permeability and retention effect” (EPR effect) [23].
Specific drug delivery systems (DDS) such as liposomes, micelles, microspheres and other lipid or polymer-based particles have been investigated [24], [25] and designed to polymerize the small molecules so as to endue the polymeric drugs with EPR effect that could reduce drug toxicity and side effects, as well as to prolong the circulation time of encapsulated drugs and improve the in vivo anticancer therapy [26]. It was proved by the advanced clinical studies in patients that liposome is a multifunctional and successful DDS [24] due to the low in vivo toxicity, easily controlled size, high carrying capacity of lipophilic, hydrophilic and amphipathic drugs, membrane-like property, and biocompatibility [27], [28], [29].
In recent years, polyethylene glycol (PEG) modifications were often incorporated into the liposomal system to receive long-circulating stealth liposomes which are able to escape from being phagocytized by the reticuloendothelial system (RES) [30] and can exhibit a prolonged circulation time. Several PEG grafted phospholipids, such as distearoylphosphatidylethanolamine-PEG (DSPE-PEG) [31], phosethanolamine-PEG (PE-PEG) [32] and distearoylglycerol-PEG (DSG-PEG) [33], were designed and successfully maintained the circulation time of drugs. However, the employments of phospholipids-anchored modification induced high cost and inconvenience in the synthesis due to the difficulties in separation of phospholipids and PEG-phospholipids. Another essential constituent of liposomes–cholesterol, which works as the framework in liposomal membrane, could reduce the fluidity of membrane and plays an important role in stabilization and controlling the drug permeability properties of liposomal membrane bilayer [34], [35], [36]. Thus cholesterol was developed as another anchor of modification to obtain materials with the framework-like function as cholesterol and even more specialities. In addition, it was proved that cholesterol anchored PEG-modified liposomes were easily incorporated into the liposomal membranes compared with that of phospholipids-anchored PEG-modified liposomes in the previous report [37].
According to the informations above, the purpose of our work was to design an anionic hydrophobic vector to polymerize the CDDP so as to reduce the nephrotoxicity and increase the loading efficiency. It’s the first time that a simple and efficient long-circulating anionic liposomal nanosystem containing cholesterol-based derivatives was prepared and used in the CDDP delivery. 5-Cholesten-3-beta-ol 3-hemisuccinate (CHO-HS, used as the anionic moiety) and 1-cholesteryl-4-ω-methoxy-polyethylene succinate (CHO-PEG, used as the long-circulating moiety) were selected to be synthesized and incorporated into the liposome system in the interest of EPR effect and reducing the renal toxicity.
Section snippets
Chemicals and materials
Cholesterol (CHO), succinic anhydride (SA), cisplatin (CDDP), 4-dimethylamino pyridine (DMAP), monomethoxy-polyethylene glycol (MPEG) with molecular weight of 550 or 2000, tetrahydrofuran (THF), dimethyl formamide (DMF), ethanol, methanol, acetone and di-stearoylphosphatidylcholine (DSPC) were obtained from Shanghai Chemical Reagent Co., China. All other chemicals were of analytical grade and used as received.
Synthesis of CHO-HS
The CHO-HS was prepared by reaction of the cholesterol with succinic anhydride in
FTIR spectra
Fig. 2 shows the FTIR spectra of cholesterol (spectrum A), CHO-HS (spectrum B) and CHO-PEG (spectrum C). In Fig. 2A, the absorption peaks at 3420 cm−1, 2930 cm−1, 1460 cm−1, 1380 cm−1 are associated with hydroxyl bonds, alkene bonds, methylene and methyl groups of cholesterol, respectively. In Fig. 2B, the broad peak appearing between 3400 and 2500 cm−1 and the peak at 1720 cm−1 are indicative of absorption by O–H bonds and carbonyl bonds in carboxylic acid; absorption peaks appearing at 1660 cm
Conclusion
In this study, mono-cholesteryl succinate (CHO-HS) and 1-cholesteryl-4-ω-methoxy-polyethylene succinate (CHO-PEG) were successfully synthesized and characterized by 1H NMR and FTIR. The synthesized materials have been developed to produce stable and long-circulation liposomes. Physicochemical characteristics of the liposomes were investigated by assessing profiles of the vesicle size, zeta potential, drug encapsulation percentage and loading efficiency, the transmission electron microscopy and
Acknowledgements
The authors are grateful for the financial support of the National Basic Research Program of China (2009CB930300 and 2011CB606202).
References (42)
- et al.
Perspectives in cancer chemotherapy
Eur J Cancer
(2001) - et al.
Clinical development of platinum complexes in cancer therapy
Eur J Cancer
(1998) - et al.
The clinical use of mutagenic anticancer drugs
Mutat Res
(1996) - et al.
Particular aspects of platinum compounds used at present in cancer treatment
Crit Rev Oncol Hematol
(2002) - et al.
Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity
Am J Kidney Dis
(1986) - et al.
Cisplatin nephrotoxicity
Semin Nephrol
(2003) - et al.
Cisplatin nephrotoxicity: mechanisms and renoprotective strategies
Kidney Int
(2008) - et al.
Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: a review of some recent research
Food Chem Toxicol
(2006) - et al.
Poly (methylmetacrylate) (PMMA) core–shell nanospheres act as efficient pharmacophores for the antiproliferative [PtCl3(NH3)] complex by forming ionic couples
Inorganica Chim Acta
(2009) Poly (l-glutamic acid)–anticancer drug conjugates
Adv Drug Deliv Rev
(2002)
The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting
Adv Enzyme Regul
Trends and developments in liposome drug delivery systems
J Pharm Sci
Liposoms: from physics to applications by D. D. Lasic
Biophys J
Novel applications of liposomes
Trends Biotechnol
Folate-PEG coated cationic modified chitosan-cholesterol liposomes for tumor-targeted drug delivery
Biomaterials
Poly(ethylene glycol) on the liposome surface: on the mechanism of polymer-coated liposome longevity
Biochim Biophys Acta
Effect of hybridized liposome by novel modification with some polyethyleneglycol-lipids
Int J Pharm
Permeability properties of phospholipid membranes: effect of cholesterol and temperature
Biochim Biophys Acta
Synthesis, characterization and in vitro degradation of a new family of alternate poly(ester-anhydrides) based on aliphatic and aromatic diacids
Biomaterials
Physico-chemical properties and cytotoxicity assessment of PEG-modified liposomes containing human hemoglobin
Colloids Surf B Biointerfaces
Platinum-based drugs in cancer therapy
Cited by (61)
Toward the boosted loading of cisplatin drug into liposome nanocarriers
2024, European Journal of Pharmaceutics and BiopharmaceuticsAdvances in liposome-based delivery of RNA therapeutics for cancer treatment
2024, Progress in Molecular Biology and Translational SciencePhysiologically-Based Modeling and Interspecies Prediction of Cisplatin Pharmacokinetics
2024, Journal of Pharmaceutical SciencesFlavonoid-liposomes formulations: Physico-chemical characteristics, biological activities and therapeutic applications
2022, European Journal of Medicinal Chemistry ReportsAmino acid coordination complex mediates cisplatin entrapment within PEGylated liposome: An implication in colorectal cancer therapy
2022, International Journal of PharmaceuticsLiposome composition in drug delivery design, synthesis, characterization, and clinical application
2021, Advanced Drug Delivery Reviews