Development of paclitaxel-TyroSpheres for topical skin treatment

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Abstract

A potential topical psoriasis therapy has been developed consisting of tyrosine-derived nanospheres (TyroSpheres) with encapsulated anti-proliferative paclitaxel. TyroSpheres provide enhancement of paclitaxel solubility (almost 4000 times greater than PBS) by effective encapsulation and enable sustained, dose-controlled release over 72 h under conditions mimicking skin permeation. TyroSpheres offer potential in the treatment of psoriasis, a disease resulting from over-proliferation of keratinocytes in the basal layer of the epidermis, by (a) enabling delivery of paclitaxel into the epidermis at concentrations > 100 ng/cm2 of skin surface area and (b) enhancing the cytotoxicity of loaded paclitaxel to human keratinocytes (IC50 of paclitaxel-TyroSpheres was approximately 45% lower than that of free paclitaxel). TyroSpheres were incorporated into a gel-like viscous formulation to improve their flow characteristics with no impact on homogeneity, release or skin distribution of the payload. The findings reported here confirm that the TyroSpheres provide a platform for paclitaxel topical administration allowing skin drug localization and minimal systemic escape.

Introduction

Psoriasis is a chronic inflammatory disease of the skin that, according to the National Psoriasis Foundation, affects approximately 125 million people worldwide. The most common form of psoriasis is characterized by pink colored plaques and white flakes appearing on top of the skin. The pathogenesis of psoriasis has still not been completely elucidated. It is generally accepted that initial stimulation of dermal dendritic cells results in a cascade of events that leads to an interaction between epidermal keratinocytes and the immune system [1], [2]. The immune system upregulates the production of cytokines, which in-turn leads to over-proliferation of keratinocytes at the basal layer of the epidermis and the overall inflammation associated with psoriasis lesion formation [2].

Treatment options for psoriasis are based on the severity of the disease. Patients with moderate to severe cases of psoriasis typically receive systemic treatments (e.g. anticancer agents such as methotrexate, immune system suppressants such as cyclosporine, or biological agents) or phototherapy, while those with more mild cases are generally prescribed topical agents including vitamin analogs, corticosteroids, and retinoids [3]. Unfortunately, each treatment option is associated with side effects such as toxicity for systemic options, carcinogenicity associated with phototherapy, and skin thinning and irritation for the topical options. Based on the understanding of the disease pathology and outcomes of the current therapies, the next generation of psoriasis treatments should, most likely, combine the benefits of (a) topical application, which permits significant drug concentration in the skin strata as well as limiting or eliminating side effects associated with systemic exposure, with (b) therapeutics that control and reduce the over-proliferative cellular dysfunction involved in the origination and progression of psoriasis.

Paclitaxel (PTX), a mitotic inhibitor that promotes the assembly and stabilization of microtubules, resulting in eventual cell death [4], is used commonly in cancer chemotherapy to help regulate rapidly proliferating cells. This ability to inhibit cell division should also enable PTX to address the hyperproliferative pathophysiologic process in psoriasis. However, the low aqueous solubility of PTX [5] limits its wide clinical use. In order to address this issue, a number of formulations and delivery systems for PTX including but not limited to Cremophor [6], nanoparticles [4], [7], [8], liposomes [9], emulsions [10], and foams [11] have been investigated. To the best of our knowledge only one instance has been reported using a PTX delivery system for the treatment of psoriasis. In this case, PTX-nanoparticles composed of poly(d,l-lactide) and methoxypolyethylene co-polymers were administered systemically, resulting in the reduction of disease severity and reduced epidermal thickness [12]. Although data showed promise, adverse events were reported including cases of fatigue, infusion reactions, and alopecia [12].

In order to develop a topical, skin-targeted PTX formulation with reduced side effects, we propose the use of the previously reported tyrosine-derived nanospheres for the delivery of PTX. These nanospheres (now referred to as “TyroSpheres” and in previous publications as “NSP”), are composed of the tyrosine-derived block copolymer poly(ethylene glycol)-b-oligo(desaminotyrosyl-tyrosine octyl ester suberate)-b-poly(ethylene glycol), shown in Scheme 1. Several recent studies using TyroSpheres have demonstrated their ability to (a) efficiently encapsulate PTX [13], (b) retain the activity of the encapsulated drug [13], [14], (c) efficiently deliver a wide range of hydrophobic compounds into the skin [15], [16], and (d) cause no detrimental effects to skin morphology [15].

Since the TyroSphere preparation is an aqueous suspension, the flow characteristics are very similar to that of water and are therefore not ideal for topical administration. This has been addressed by increasing the viscosity of the TyroSphere formulation with hydroxypropyl methylcellulose, a pharmaceutically acceptable thickening agent [15].

Based on the potential effectiveness of PTX in the treatment of psoriasis and the safety and effectiveness of TyroSpheres in topical delivery, the aim of this study is to evaluate the applicability of PTX-TyroSpheres for psoriasis treatment. These studies include formulation development and optimization, investigation of cytotoxicity of PTX-TyroSpheres using a keratinocyte cell-line, and quantifying the extent of PTX delivery into the epidermis and dermis via an in vitro method utilizing mass spectrometry.

Section snippets

Materials and methods

  • Glossary of abbreviations:

    PTX: paclitaxel; TyroSpheres: tyrosine-derived nanosphere(s); PTX-TyroSpheres: tyrosine-derived nanospheres containing paclitaxel; DTO-SA/5K: PEG5K-b-oligo(desaminotyrosyl-tyrosine octyl ester suberate)-b-PEG5K; HPMC: hydroxypropyl methylcellulose; BE: binding efficiency; LE: loading efficiency; HPLC: reverse-phase high performance liquid chromatography; SD: standard deviation; SE: standard error; PDI: polydispersity index; LC–MS: liquid chromatography–mass

PTX-TyroSpheres: design, fabrication and characterization

The rationale for choosing the tyrosine-based triblock copolymer system (Scheme 1) used to fabricate TyroSpheres in this study was based on the ability of this amphiphilic copolymer to self-assemble in aqueous media. The middle block oligo(DTO-SA) is composed of naturally occurring metabolites [19] which renders the final degradation products benign, while mPEG end blocks provide a stable dispersion in an aqueous environment. Additionally, this particular formulation has been previously

Conclusions

The aim of this study was to develop and evaluate the potential of tyrosine-derived nanospheres (TyroSpheres) as a topical delivery system for paclitaxel (PTX). Non-cytotoxic TyroSpheres provide greatly enhanced solubility of PTX and PTX-TyroSpheres successfully combine the benefits of: (a) a therapeutic to control the over-proliferation of keratinocytes thereby bringing the system back into equilibrium, (b) dose-controlled delivery of PTX, and (c) preferential deposition of PTX into the

Acknowledgments

The authors wish to thank Dr. Qing Ren (Department of Radiation Oncology at Thomas Jefferson University) for her generous gift of HaCaT cells. We appreciate Dr. Haiyan Zheng (Biological Mass Spectrometry Facility of the UMDNJ-Robert Wood Johnson Medical School and Rutgers, The State University of New Jersey) for fruitful discussions on and assistance with LC–MS work. We acknowledge Ms. Lulu Wang (New Jersey Center for Biomaterials) for her valuable technical contributions and we thank skilled

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