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  • M Kurihara A Shiraishi H Satake A P Kimura

    2019-10-22

    [33] M. Kurihara, A. Shiraishi, H. Satake, A.P. Kimura, A conserved noncoding sequence can function as a spermatocyte-specific enhancer and a bidirectional promoter for a ubiquitously expressed gene and a testis-specific long noncoding RNA, J. Mol. Biol. 426 (2014) 3069–3093.
    Contents lists available at ScienceDirect
    International Journal of Pharmaceutics
    journal homepage: www.elsevier.com/locate/ijpharm
    A novel low molecular weight nanocomposite hydrogel formulation for intra-tumoural delivery of anti-cancer drugs 
    T
    Ivana Štakaa,b,c, Ana Cadetea, Bhanu Teja Surikutchic, Haneen Abuzaidb, Tracey D. Bradshawb, Maria J. Alonsoa, , Maria Marlowc,
    a CIMUS Research University, University of Santiago de Compostela, 15706 Campus Vida, Spain
    b Centre for Biomolecular Sciences, University of Nottingham, NG7 2RD, UK
    c Boots Science Building, School of Pharmacy, University of Nottingham, NG7 2RD, UK
    Keywords:
    Gel-nanocomposite
    Polymeric nanocapsules
    Low molecular weight gelators Local delivery 
    Herein, an injectable formulation composed of a low molecular weight gelator (LMWG) based hydrogel and drug-loaded polymeric nanocapsules (NCs) is described. The NCs, made of hyaluronic Paclitaxel (Taxol) and polyglutamic acid and loaded with C14-Gemcitabine (GEM C14), showed a size of 40 and 80 nm and a encapsulation effi-ciency > 90%. These NCs exhibited a capacity to control the release of the encapsulated drug for > 1 month. GEM C14-loaded NCs showed activity against various cancer cell lines in vitro; cell growth inhibition by 50% (GI50) values of 15 ± 6, 10 ± 9, 13 ± 3 and 410 ± 463 nM were obtained in HCT 116, MIA PaCa-2, Panc-1 and Panc-1 GEM resistant cell lines respectively. Nanocomposite hydrogels were prepared using the LMWG – N4-octanoyl-2′-deoxycytidine and loaded for the first time with polymeric NCs. 2% and 4% w/v nanocapsule concentrations as compared to 8% w/v NC concentrations with 2% and 3% w/v gelator concentrations gave mechanically stronger gels as determined by oscillatory rheology. Most importantly, the nanocomposite for-mulation reformed instantly into a gel after injection through a needle. Based on these properties, the nano-composite gel formulation has potential for the intratumoural delivery of anticancer drugs.
    1. Introduction
    Supramolecular gels are formed from low molecular weight (LMW) molecules (typically < 3 kDa). The main characteristic of low mole-cular weight gelators (LMWG) is their ability to gel solvent (water in the case of hydrogels) at concentrations as low as 0.5% wt through the process of self-assembly and the formation of fiber networks (Sangeetha and Maitra, 2005). The self-assembly is governed by non-covalent physical interactions whose dynamic nature can bring two features: viscous flow under shear stress (shear-thinning) and time-dependent recovery upon relaxation (self-healing) (Skilling et al., 2016). These properties make supramolecular gels appropriate for an injectable for-mulation.
    The design of LMWGs for cancer therapy has been increasingly re-ported over the last decade. Specifically, peptide-type LMWGs have been extensively investigated and used for incorporation of various cancer drugs such as doxorubicin (DOX) (Naskar et al., 2009),
    campthothecin (Cheetham et al., 2013), paclitaxel (Wang et al., 2011) and many others (Tian and Niu, 2014). Additionally, LMWG gel for-mulations, oligopeptides, lanreotide and degarelix composed of 8 and 10 amino acids respectively, are used clinically as hormone therapy in patients with neuroendocrine tumours (Pokuri et al., 2016; Steinberg 2009; Klotz et al., 2008; Vlieghe et al., 2010). Several LMWG for-mulations, specifically designed for intra-tumoural delivery of antic-ancer drugs have shown inhibition of tumour growth. For example, DOX was physically entrapped in a gel made of L-alanine hydrazide gelator and was reported to reduce the tumour burden by 40% as compared to an untreated control when injected into a breast (4 T1) tumour model in mice, whereas DOX alone had negligible antitumour effects upon injection (Singh et al., 2014). In another example, a Taxol derivative (succinic acid – glutathione) self-assembled into an in-jectable hydrogel and impeded tumour growth 2-fold compared to an i.v. injection of Taxol® in the breast (4 T1) Paclitaxel (Taxol) tumour model in mice. Furthermore, the Taxol hydrogel was able to prevent metastasis.