Improving Topical Non-Melanoma Skin Cancer Treatment: In vitro Efficacy of a Novel Guanosine-Analog Phosphonate

Abstract

Actinic keratosis, a frequent carcinoma in situ of non-melanoma skin cancer (NMSC), can transform into life-threatening cutaneous squamous cell carcinoma. Current treatment is limited due to low complete clearance rates and asks for novel therapeutic concepts; the novel purine nucleotide analogue OxBu may be an option. In order to enhance skin penetration, solid lipid nanoparticles (SLN, 136-156 nm) were produced with an OxBu entrapment efficiency of 96.5 ± 0.1%. For improved preclinical evaluation, we combined tissue engineering with clinically used keratin-18 quantification. Three doses of 10^-3 mol/l OxBu, dissolved in phosphate-buffered saline as well as loaded to SLN, were effective on reconstructed NMSC. Tumour response and apoptosis induction were evaluated by an increase in caspase-cleaved fragment of keratin-18, caspase-7 activation as well as by reduced expression of matrix metallopeptidase-2 and Ki-67. OxBu efficacy was superior to equimolar 5-fluorouracil solution, and thus the drug should be subjected to the next step in preclinical evaluation.

The barrier function of organotypic non-melanoma skin cancer models

“…Hoeller Obrigkeit and colleagues use low carcinoma cell counts [16], Commandeur et al seed carcinoma cells only [15], and we used previously a ratio of 3:100 carcinoma to normal cells [11,18]. Albeit their limitations, carcinoma cell lines are Fig.…”

“…Since organotypic NMSC models are developed for preclinical drug evaluation [11,15,16], we investigated the response of cSCC-E and cSCC-ED models to ingenol mebutate in a blinded vehicle-controlled study design (Fig. 4A).…”

“…Ingenol mebutate offers a short-term treatment regimen, but causes rapid and unspecific necrosis [10]. Purine-analog phosphonates showed promising efficacy in monolayer cell cultures, but first attempts to use nanoparticles for enhanced drug delivery show marginal effects [11]. High-molecular-weight cationic membrane-active peptides [12] are theoretically excluded from topical treatment due to their physicochemical properties [13].…”

“…Currently NMSC is reproduced for preclinical drug evaluation by mouse models [14], organotypic skin models [11,15,16], or tumor specimens [17]. Each approach faces distinct limitations: inter alia murine skin morphology considerably differs from human actinic keratosis, organotypic skin models are based on cell lines and tumor specimens originate from invasive carcinomas.…”

Synthesis and Structure-Activity Relationships of Imidazole-Coumarin Conjugates against Hepatitis C Virus

“…Very recently, Gosselin et al [34] reported a 2′-C-methyl branched guanosine pro-nucleotide as a potent liver-targeted HCV polymerase inhibitor. Schaefer–Korting et al [35] found that a guanosine-analog phosphonate can improve topical non-melanoma skin cancer treatment.…”