Gold conjugate-based liposomes with hybrid cluster bomb structure for liver cancer therapy

doi:10.1016/j.biomaterials.2015.10.004

Biomaterials

Volume 74, January 2016, Pages 280-291

https://doi.org/10.1016/j.biomaterials.2015.10.004 Get rights and content

Abstract

Hybrid drug delivery system containing both organic and inorganic nanocarriers is expected to achieve its complementary advantages for the aim of improving the performance of antineoplastic drugs in tumor therapy. Here we report the use of liposomes and gold nanoparticles to construct a liposome with a hybrid Cluster Bomb structure and discuss its unique multi-order drug release property for liver tumor treatment. A very simple method is used for the hybrid liposome preparation and involves mixing two solutions containing liposomes loaded with either non-covalent or covalent Paclitaxel (PTX, namely free PTX or PTX-conjugated GNPs, respectively) by different ratio of volume (25:75, 50:50, 25:75, v/v). Various mixed liposomes were tested to determine the optimal conditions for maximum drug delivery. The optimized liposome was then tested using xenograft Heps tumor-bearing mice and showed the best efficacy for chemotherapeutic inhibition of tumor at PTX liposome: PTX-conjugated GNP liposome of 25:75 ratio (v/v). This system allows for simple and easy preparation while providing a more accurate site- and time-release mode for tumor treatment using antitumor drugs.

Introduction

“Soft” organic carriers [1], [2] and “hard” inorganic metal nanoparticles with their oxides [3], [4] are the main platforms for the construction of drug delivery systems (DDSs) at nanoscale [5], [6], [7]. Hybrid therapeutic systems that combine both organic and inorganic nanomaterials are expected to address some of the issues associated with each type of carrier individually while achieving complementary advantages and offering greater number of opportunities to improve the performance of antineoplastic drugs for tumor therapy [8], [9].

Liposomes are the most clinically established nanometer scale systems used to deliver chemical drugs, genes, vaccines, and imaging agents [10], [11], [12]. Coating or encapsulating nanoparticles with lipids offers structural features similar to the cellular membrane [13], [14]. These features promote the biocompatibility of nanoparticles and present a clinically proven platform for further enhancement of the nanoparticle therapeutic efficacy. Although, many nanoparticles of varying chemical compositions, such as gold nanoparticles (GNPs) still remain at their preclinical development stages, they have been tremendously employed to improve the delivery and therapeutic efficacy of gene and small molecule drugs [15], [16]. Nanoparticles encapsulated inside liposomes act as optical probes to track the distribution of systems in vitro and in vivo [8], [9], [17], while simultaneously modulating the drug binding and release of the hybrid delivery systems [18].

Liposome-GNP hybrids have recently attracted the attention of the scientific community for their ability to incorporate applications involving both diagnostic and therapeutic functions in the same delivery system [17]. GNPs of rod and star morphologies [19] loaded in liposomes or gold shell and semi-spherical structures self-assembled by spherical nanoparticles in liposomes would bring the new photothermal therapy (PTT) [20], [21] function to liposomes. Moreover, with the newly introduced PTT function, photothermal-triggered drug release [19], [22], [23], [24], [25], synergistic PPT combined chemotherapy [26] or photodynamic therapy [27] become practical for the liposome-GNP hybrids.

In these systems, the GNPs function as a therapeutic molecule or nanoswitch for killing tumor cells directly or by triggering drug release both spatially and temporally. The liposome-GNP hybrid system maintains the drug delivery properties of liposomes; while the advantages of GNPs in drug delivery, including large specific surface area-induced high drug loading, size-dependent tumor accumulation, and endocytosis-improved cellular uptake, did not receive reasonable consideration in the design of liposome-GNP hybrids. Therefore, a combination involving liposome-GNP hybrid can offer tremendous advantages for improving the performance of antitumor drugs for tumor treatment.

It has previously been demonstrated that paclitaxel (PTX), a mitotic inhibitor, modified with mercapto polyethylene glycol (PEG) and then covalently conjugated to the surface of GNPs can be used for the treatment of liver tumor [28]. The PTX-conjugated GNPs (PTX-PEG@GNPs) were found to demonstrate an overall improvement in performance when compared to free PTX and its commercial formulation Taxol^®, especially in in vivo liver tumor therapeutic efficacy [29]. Furthermore, to protect the drug on the surface of the conjugate, PTX-PEG₄₀₀@GNPs were encapsulated in liposomes to enhance the hydrophilicity, stability, and biocompatibility of nanoconjugates in plasma, as well as to control its pharmacological fate [30]. The results showed that PTX-PEG₄₀₀@GNP-encapsulated liposomes (PTX-PEG₄₀₀@GNP Lips) demonstrated a superior long time drug release in plasma leading to an improved performance of the hybrid system in the liver tumor therapy [29]. This superior long time drug release is very encouraging and prompts one to construct a hybrid system with rapid drug release and sustained treatment efficacy for an extended period of time.

In this work, we design and prepare a hybrid liposome (PTX/PTX-PEG₄₀₀@GNP Lips) by a simple mixing method. For example. PTX liposomes (PTX Lips) and PTX-PEG₄₀₀@GNP Lips are mixed with different volume ratio and delivered to the target site at the same time. After delivery, PTX Lips is in charge of the rapid drug release whereas PTX-PEG₄₀₀@GNP Lips is responsible for maintaining drug level at the target site for a long period of time. The reconstruction and formation of a hybrid Cluster Bomb structure (as shown in Fig. 1A) was observed after the mixing process. This integrated hybrid structure provides very unique advantages as mentioned earlier, including increased stability of the system, co-delivery of covalent and non-covalent drugs at designed targets, and more accurate site- and time-controlled release for drug treatment regimens.

Section snippets

Materials and instruments

Hydrogen tetrachloroaurate trihydrate (HAuCl₄·3H₂O) was obtained from the Shanghai Chemical Reagent Company (China). PTX was acquired from Yew Pharmaceutical Co (Jiangsu, China). PEG (the molecular weight of 400 Da) and esterase from porcine liver (lyophilized powder, ≥15 units/mg solid) were purchased from Sigma–Aldrich (USA). Soya phosphatidyl choline (SPC, S100) and cholesterol were supplied by GmbH Lipoid (Ludwigshafen, Germany) and Shanghai Huixing Biochemical Reagent Co., Ltd. (China),

Preparation and characterization

PTX Lips and PTX-PEG₄₀₀@GNP Lips with the same drug content (1 mg/mL) were synthesized and mixed in different volume proportions to form new preparations (PTX/PTX-PEG₄₀₀@GNP Lips, as shown in Fig. 1A). To investigate the possible structural change of mixed liposomes, hydrodynamic size and zeta potentials were determined at 5, 15, and 30 min after mixing. As shown in Fig. 2A, before mixing, the average hydrodynamic diameter of PTX-PEG₄₀₀@GNP Lips (149.2 ± 2.1 nm) is slightly larger than that of

Conclusion

We have developed the gold conjugate-based liposomes with hybrid Cluster Bomb structure by mixing PTX Lips with PTX-PEG₄₀₀@GNP Lips. Depending on the combined effect of PTX Lips and PTX-PEG₄₀₀@GNP Lips and the possible synergistic effect after the reconstruction process, the integrated hybrid liposome (25:75, v/v) has superior properties, including improved stability of whole system, enhanced cellular uptake, and rapid-and-then-sustained drug release, resulting in enhanced tumor cell killing

Acknowledgment

This work was financially supported by the Natural Science Foundation of China (31470916, 31200695, and 31500769), the Program for New Century Excellent Talents in University (NCET-10-0816), the Fundamental Research Funds for the Central Universities (2015PT036, 2016PT014), A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, and the Open Project Program of MOE Key Laboratory of Drug Quality Control and Pharmacovigilance (DQCP2015MS01).

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¹: The first two authors contributed equally to this work.

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Gold conjugate-based liposomes with hybrid cluster bomb structure for liver cancer therapy

Abstract

Introduction

Section snippets

Materials and instruments

Preparation and characterization

Conclusion

Acknowledgment

Biomaterials

Adv. Drug Deliv. Rev.

Trends Pharmacol. Sci.

Adv. Drug Deliv. Rev.

Mol. Ther.

J. Control Release

Colloid Surf. B

Biomaterials

Inter. J. Pharm.

Inter. J. Pharm.

Cancer Lett.

Polymer vesicles

Science

Development of multinuclear polymeric nanoparticles as robust protein nanocarriers

Angew. Chem. Int. Ed.

Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods

J. Am. Chem. Soc.

Nanocarriers as an emerging platform for cancer therapy

Nat. Nanotechnol.

Cancer nanotechnology: opportunities and challenges

Nat. Rev. Cancer

Liposomes versus metallic nanostructures: differences in the process of knowledge translation in cancer

Inter. J. Nanomed.

Recent advances with liposomes as pharmaceutical carriers

Nat. Rev. Drug Discov.