br Abbreviations LMWG low molecular weight gelator NCs nanoc
Abbreviations: LMWG, low molecular weight gelator; NCs, nanocapsules; GEM C14, N4-myristoyl gemcitabine; LMW, low molecular weight; CTAB, hexadecyl-trimethylammonium bromide; HA, Sodium hyaluronate; PGA, poly-L-glutamic acid; GEM-HCl, GEM hydrochloride; NR, 9-Diethylamino-5H-benzo[a]phenoxazine-5-one – Nile Red; LVE, Linear visco-elastic region; GEM R Panc-1, GEM resistant cell line
E-mail addresses: [email protected] (M.J. Alonso), [email protected] (M. Marlow).
Additionally, the fatal dose of Taxol® in this hydrogel was shown to be at least 7.5x higher than that of Taxol® (Wang et al., 2012).
Based on the apparent success of gel formulations for the in-tratumoural delivery of anticancer drugs, the objective of this work was to design and develop a new nanocomposite hydrogel formulation consisting of a nucleoside based LMWG and polymeric coated nano-capsules (NCs). Considering that a variety of late stage cancers cannot be surgically removed, (e.g. pancreatic and oesophageal cancers), it Necrosulfonamide has been hypothesized that their treatment could benefit from such a drug delivery platform. The gel structure should ensure localised drug de-livery over many cell cycles (Wolinsky et al., 2012) and the in-corporation of NCs may provide opportunities for increased tumour permeation of drug, beyond that of diﬀusion from the gel (Strasser et al., 1995). Examples of such nanocomposite gels include: association of poly(ethylene glycol)-block-poly(-lactic acid) (PEG-b-PLA) NPs with hydroxypropylmethylcellulose (HPMC) gels (Appel et al., 2015), Eu-dragit NCs (Contri et al., 2014), poly(d,l- lactide)-b-(ethyleneoxide) (PLA-b-PEO) NPs (Grant et al., 2005) and chitosan NPs (Şenyiğit et al., 2015) with chitosan gels, poly(ε-caprolactone)- poly(ethylene glycol)-poly(ε -caprolactone) (PCEC) NPs with Pluronic F127 gels (Gou et al., 2008) and some liposomal formulations with PEG gels (Lalloo et al.,
2006). In comparison to polymer gels, LMWG are hypothesized to have a diﬀerent mechanism of release and pore structure and hence should be evaluated as a viable alternative to the extensively explored poly-meric nanocomposite gels.
More precisely, in this work the association of N4-octanoyl-2′-deoxycytidine gels with polymer coated NCs loaded with N4-myristoyl gemcitabine (GEM C14), is presented as a delivery strategy of potential application for the treatment of non resectable tumours. A lipophilic (4-(N) position modification) form of gemcitabine was selected to over-come the short half-life and acquired resistance of the parent compound (Mackey et al., 1998; Weizman et al., 2014; Pulido et al., 2014). Ad-ditionally, the hydrophobic modification of gemcitabine further al-lowed its encapsulation in the lipid core of NCs.
The selection of the drug nanocarrier to be include in the gel was based on our previous experience with polymeric NCs (Oyarzun-Ampuero et al., 2013; Rivera-Rodriguez et al., 2013; Lollo et al., 2015), (Janes et al., 2001; Torrecilla et al., 2013),(Rivera-Rodriguez et al., 2013), (Gonzalez-Aramundiz et al., 2017) (PGA-PEG) (Borrajo et al., 2016). Hyaluronic acid (HA) and polyglutamic acid (PGA) nano-capsules were chosen as a good option based on previous studies showing their activity in vitro and in vivo (Oyarzun-Ampuero et al., 2013; Lollo et al., 2015). Firstly these NCs were optimised for our ap-plication and their ability to inhibit cancer cell growth evaluated in vitro using cancer cell lines including a GEM-resistant pancreatic cell line as drug resistance presents a major problem thwarting successful cancer treatment (Hong et al., 2009; Long et al., 2011). Finally, the formation and characterisation of a nanocomposite formulation, of NCs and a LMWG based hydrogel was assessed.