Development of paclitaxel-TyroSpheres for topical skin treatment
Graphical abstract
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
References (34)
- et al.
Review of treatment options for psoriasis in pregnant or lactating women: from the Medical Board of the National Psoriasis Foundation
J. Am. Acad. Dermatol.
(2012) - et al.
Paclitaxel nanoparticles for the potential treatment of brain tumors
J. Control. Release
(2004) - et al.
Solid-state characterization of paclitaxel
J. Pharm. Sci.
(1997) - et al.
A novel controlled release formulation for the anticancer drug paclitaxel (Taxol): PLGA nanoparticles containing vitamin E TPGS
J. Control. Release
(2003) - et al.
Abraxane in the treatment of ovarian cancer: the absence of hypersensitivity reactions
Gynecol. Oncol.
(2006) - et al.
Paclitaxel delivery from PLGA foams for controlled release in post-surgical chemotherapy against glioblastoma multiforme
Biomaterials
(2009) - et al.
Micellar paclitaxel improves severe psoriasis in a prospective phase II pilot study
J. Am. Acad. Dermatol.
(2004) - et al.
Paclitaxel in tyrosine-derived nanospheres as a potential anti-cancer agent: in vivo evaluation of toxicity and efficacy in comparison with paclitaxel in Cremophor
Eur. J. Pharm. Sci.
(2012) - et al.
Topical drug delivery by a polymeric nanosphere gel: formulation optimization and in vitro and in vivo skin distribution studies
J. Control. Release
(2011) - et al.
Tyrosine-derived nanospheres for enhanced topical skin penetration
Int. J. Pharm.
(2008)
Polymers derived from the amino acid L-tyrosine: polycarbonates, polyarylates and copolymers with poly(ethylene glycol)
Adv. Drug Deliv. Rev.
Particle size of liposomes influences dermal delivery of substances into skin
Int. J. Pharm.
Skin penetration and distribution of polymeric nanoparticles
J. Control. Release
Novel mechanisms and devices to enable successful transdermal drug delivery
Eur. J. Pharm. Sci.
A review of the formation and classification of amphiphilic block copolymer nanoparticulate structures: micelles, nanospheres, nanocapsules and polymersomes
Eur. J. Pharm. Biopharm.
Nanoparticles and microparticles for skin drug delivery
Adv. Drug Deliv. Rev.
Review paper: preclinical models of psoriasis
Vet. Pathol.
Cited by (81)
Tacrolimus and paclitaxel co-loaded O/O ointment without surfactant: Synergistic combinations for the treatment of psoriasis
2023, European Journal of Pharmaceutics and BiopharmaceuticsNanosphere size control by varying the ratio of poly(ester amide) block copolymer blends
2022, Journal of Colloid and Interface ScienceNanovesicles delivery approach for targeting steroid mediated mechanism of antipsoriatic therapeutics
2021, Journal of Drug Delivery Science and TechnologyStatistically optimized calcipotriol fused nanostructured lipid carriers for effectual topical treatment of psoriasis
2021, Journal of Drug Delivery Science and TechnologyPart 1. Evaluation of Epigallocatechin Gallate or Tannic Acid Formulations of Hydrophobic Drugs for Enhanced Dermal and Bladder Uptake or for Local Anesthesia Effects
2021, Journal of Pharmaceutical SciencesCitation Excerpt :For all drugs, EGCG outperformed TA formulations and PG pastes provided improved drug transfer. Researchers have previously tried to deliver PTX across the skin to treat psoriasis.18–20 Using gallate based formulations in this study very high levels of PTX (5000 μg/g tissue) observed for EGCG-PG in this study.