Folate-PEG coated cationic modified chitosan – Cholesterol liposomes for tumor-targeted drug delivery

doi:10.1016/j.biomaterials.2010.01.089

Biomaterials

Volume 31, Issue 14, May 2010, Pages 4129-4138

https://doi.org/10.1016/j.biomaterials.2010.01.089 Get rights and content

Abstract

In this paper, a folate-PEG coated polymeric liposome (FPL) formed from octadecyl-quaternized lysine modified chitosan (OQLCS) and cholesterol has been prepared successfully. The OQLCS and its derivatives were characterized using ¹H NMR and infrared spectrum analysis. The FPLs properties were extensively studied by dynamic light scattering (DLS), fluorescence spectroscopy, and transmission electron microscopy (TEM). Due to the amphiphilic property and positive zeta potential of OQLCS, the OQLCS and cholesterol can form stable core-shell FPLs with small size (effective diameter: 163.5 nm) and narrow distribution (polydispersity: 0.108) in aqueous solutions. The PLs could form multi-lamellar structure similar to that of traditional liposomes prepared from phosphatidylcholine/cholesterol (PC/Chol). Compared with traditional liposome, calcein-loaded Polymeric Liposome exhibited high encapsulation efficiency in aqueous solution and slow, controlled release under different pH conditions. Most important, in cellular uptake experiment, folate coated FPLs showed significant higher uptake by MCF-7 cells as compared to FPLs without folate and traditional liposomes, because of the folate-receptor mediated endocytosis. The data suggest that the folate-PEG coated polymeric liposomes (FPLs) may be a useful drug delivery system.

Introduction

One of the most critical challenges in cancer treatment is the design and development of a delivery system with multiple functionalities. Some delivery systems are designed to ensure that they can exhibit a prolonged circulation time in blood and diminish uptake by the reticuloendothelial system (RES) [1], [2], [3]; In blood circulation, some are treated with specific functional groups that target and attach to specific organ or tissue [4], [5], [6]; some possess the transmembrane function to increase the transport efficiency of the nanostructure into targeted cells [7]; Certain particles allow for storage and release of treatment drugs [8], [9], [10]. Thus, there have been few attempts to design and produce a delivery system that meets all of these requirements.

Over the past several decades, there has been a steady growth in the number of available nanoparticles for therapy. Among these products, polymer nanoparticles and liposomes are two dominant classes. The polymers, such as polyethylene glycol (PEG) [11], chitosan (CS) [12], poly(lactic-co-glycolic acid) (PLGA) [13] and so on, have been commonly used to form core-shell structure to encapsulate a variety of drugs [14]. The advantages of liposomes include their multilayer structure to improve the entrapment efficiency of hydrophilic therapeutic agents, protect encapsulated drugs from external conditions and so on.

Recently, the folate-PEG coated polymeric liposome (FPLs) that combined both advantages of polymeric vesicles and liposomes, is developed in our laboratory. The PLs are based on amphiphilic octadecyl-quaternized lysine modified chitosan (OQLCS), folate-conjugated OQLCS, and PEGlated OQLCS. The reasons, why choose these materials, are as follows: First, OQLCS was selected due to its perfect amphiphilicity and its steric stabilizations; Second, PEG chains coated on the PLs surface can protect the nanoparticles from undesired attacks in the biological media, thereby increasing the stability of nanoparticles and prolonging their circulation time in the blood; Third, folate was picked because of folate employed as a targeting moiety of various anti-cancer agents to avoid their non-specific attacks on normal tissues as well as to increase their cellular uptake within target cells.

Herein we report our present study on the synthesis of OQLCS and its derivatives, preparation and characterization of the FPLs. Calcein, a fluorescent molecular, was incorporated into the polymeric liposome systems to investigate relative performance of FPLs.

Section snippets

Materials

Chitosan was supplied by Yuhuan Aoxing Biochemistry Co. Ltd. (Zhejiang, China) with a molecular weight (MW) of 5 × 10⁴. BOC-Lysine and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC) were obtained from Dingguo Biotechnology Co. Ltd. (Shanghai, China). Folate, PEG with a molecular weight (MW) of 2 × 10³ was purchased from Aldrich. Pyrene was purchased from Sigma–Aldrich. Octadecyl dimethylammonium chloride (QA) and lysine modified chitosan (LCS) were all prepared in our

Structural characterization of OQLCS and its derivatives

In the spectrum of OQLCS, the characteristic peak (1604 cm⁻¹) representing NH₂ deformation was weakened and a new peak positioned at 1487 cm⁻¹ (belongs to the methyl groups in the ammonium) was made to appeared, which corresponded to an asymmetric angular bending of methyl groups of quaternary hydrogen. The appearance of new intensive peaks at 717 cm⁻¹ and 2920–2851 cm⁻¹ can be attributed to the long carbon segment of the quaternary ammonium salt [21]. All of these indicated that the formation

Conclusion

A new type of amphiphilic octadecyl-quaternized lysine modified chitosan (OQLCS), FA-OQLCS and PEG-OQLCS were synthesized successfully. In aqueous solutions, these polymer could form Folate-PEG coated polymeric liposomes (FPLs) that showed multi-lamellar structure similar to that of traditional liposomes prepared from phosphatidylcholine/cholesterol (PC/Chol). Compared with traditional liposomes, the FPLs showed smaller particle size (about 160 nm) and lower calcein permeability rate (about

Acknowledgments

The authors gratefully acknowledge National Natural Science Foundation of China (50873076), National High Technology Program of China (863 Program) (2007AA021808), National High Technology Program of China (863 Program) (2007AA021802) and Tianjin Science and Technology Program (09ZCGYSF00900).

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Folate-PEG coated cationic modified chitosan – Cholesterol liposomes for tumor-targeted drug delivery

Abstract

Introduction

Section snippets

Materials

Structural characterization of OQLCS and its derivatives

Conclusion

Acknowledgments

PEG-immunoliposome

Biosci Rep

Large unilamellar liposomes with low uptake into the reticuloendothelial system

FEBS Lett

Sterically stabilized liposomes – improvements in pharmacokinetics and antitumor therapeutic efficacy

Proc Nat Acad Sci U S A

Design of folic acid-conjugated nanoparticles for drug targeting

J Pharm Sci

Liposome-encapsulated doxorubicin targeted to CD44: a strategy to kill CD44-overexpressing tumor cells

Cancer Res

Novel peptide ligand directs liposomes toward EGF-R high-expressing cancer cells in vitro and in vivo

FASEB J

DNA-polycation nanospheres as non-viral gene delivery vehicles

J Control Release

Liposome -encapsulated vincristine, vinblastine and vinorelbine: a comparative study of drug loading and retention

J Control Release

Precise control of PLG microsphere size provides enhanced control of drug release rate

J Control Release

Chitosan microspheres: modification of polymeric chem-physical properties of spray-dried microspheres to control the release of antibiotic drug

J Appl Polym Sci

PEG-based micelles as carriers of contrast agents for different imaging modalities

Adv Drug Deliv Rev