Elsevier

Biomaterials

Volume 35, Issue 26, August 2014, Pages 7647-7653
Biomaterials

Turning a water and oil insoluble cisplatin derivative into a nanoparticle formulation for cancer therapy

https://doi.org/10.1016/j.biomaterials.2014.05.045Get rights and content

Abstract

The formulation of water insoluble organic compounds into nanoparticles has become a widely established method for enhancing the delivery and efficacy of cancer therapeutics. Therefore, a comparable approach when applied to water insoluble inorganic compounds should also promote similar advantages. Herein, we have successfully formulated insoluble iodinated cisplatin (CDDP-I) into an LPI NPs (lipid-coated iodinated CDDP nanoparticles). Two separate microemulsions were combined, each containing a precursor for the synthesis of CDDP-I. The resulting CDDP-I precipitate was then coated with an anionic lipid and dispersed in water with the help of an additional lipid. This method allows us to effectively encapsulate CDDP-I and was able to achieve a considerable drug loading of 82 wt%. Administered LPI NPs demonstrated high level accumulation in tumor tissues and exhibited an anti-cancer activity comparable to free CDDP in two melanoma xenograft models without inducing nephrotoxicity. The benefits offered through this delivery formulation are not unique to CDDP-I, as this versatile platform may be extended to the formulation of other inorganic compounds that are both water and oil insoluble into nanoparticles for superior anti-cancer efficacy.

Introduction

The application of cisplatin (CDDP), an established anti-cancer drug, is hampered by severe side effects such as neuro- and nephro-toxicity, which limit the maximum tolerated dose (MTD) of cisplatin [1], [2]. To overcome these shortcomings, derivatives incorporating more stable leaving groups, such as carboplatin and oxaliplatin, have been synthesized to reduce side effects. Yet, such modifications inadvertently diminish the efficacy [3], [4]. Another potential strategy has been to alter the halide leaving groups [5]. After this alteration, bromide retains activity and exhibits potent anti-tumor efficacy while iodinated CDDP (CDDP-I) is ineffective, probably due to its insolubility [5], [6].

Nanoparticulate formulations have been developed to enhance the accumulation of CDDP in tumors through the enhanced permeability and retention (EPR) effect while reducing side effects through a restricted drug distribution [7], [8]. Unlike paclitaxel, a water insoluble but oil soluble anti-tumor drug, CDDP-I, is insoluble in any organic solvent and cannot be formulated into nanoparticles (NP) or liposomes. However, formation of CDDP-I nanocrystals may be achieved using “top-down” technology, which involves breakdown of large drug particles through a milling process [9], [10], [11]. Most nanocrystal formulations are administered orally even though nanocrystals dissociate quickly in the blood stream. Taking advantage of this property, we aim to develop a CDDP-I formulation for intravenous administration.

In previous work, CDDP was used to construct LPC NPs [12] in a micro-emulsion reactor using the CDDP precursor and potassium chloride (KCl). Drug loading efficiency for this NP formulation was high (80 ± 5 wt%). CDDP-I was synthesized through a reaction between potassium iodine (KI) and the CDDP precursor in a micro-emulsion to make cores which were dispersed in water (Scheme 1). Dioleoyl phosphatidic acid (DOPA), an anionic lipid, was used to stabilize the CDDP-I cores, which were further dispersed using an outer leaflet lipid layer to obtain LPI NPs (lipid-coated iodinated CDDP nanoparticles). Cell toxicities of LPI NPs and release of CDDP-I from LPI NPs were evaluated then. Tumor accumulation, anti-tumor effect and safety of LPI NPs were also investigated.

Section snippets

Materials

Lipids were purchased from Avanti Polar Lipids (Alabaster, AL). Dulbecco's Modified Eagle Medium (DMEM), l-glutamine, penicillin G sodium, streptomycin and fetal calf serum were purchased from Gibco®. DSPE–PEG–AA was synthesized in our laboratory as previously reported [13]. 1-Hexanol was purchased from Alfa Aesar. Igepal®CO-520, triton™ X-100, cyclohexane, CDDP and silver nitrate were obtained from Sigma–Aldrich (St Louis, MO) without further purification. Pluronic P85 was purchased from BASF

Preparation and characterization of LPI NPs

Due to the insolubility of CDDP-I in water and organic solvents, current drug loading methods including remote loading, double emulsion and nanoprecipitation, cannot be used to formulate CDDP-I into NPs. CDDP and its derivatives are inorganic, poorly soluble and usually synthesized by mixing the precursor and leaving group-donating compounds, which both are water-soluble. These properties make CDDP and its derivatives unique to other anti-cancer drugs. Microemulsion methods have been

Conclusions

The LPI NPs delivery platform was successful in formulating insoluble iodinated CDDP (CDDP-I) into LPI NPs at a significant drug loading efficiency of 82 wt%. In vivo studies showed that LPI NPs had comparable or better anti-tumor activity than free CDDP in two different melanoma xenograft models. LPI NPs exhibited a strong EPR effect and accumulated at 9.5% ID/g in an A375M tumor model and induced significant apoptosis without inducing toxicities. The LPI NPs not only showed activity and

Acknowledgments

This work was supported by NIH grants CA151652, CA151455 and CA149363. We thank Steven Glenn Plonk and Andrew Mackenzie Blair for their assistance in manuscript preparation.

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