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 acid and polyglutamic acid and loaded with C14-Gemcitabine (GEM C14), showed a size of 40 and 80 nm and a encapsulation efficiency > 90%. These NCs exhibited a capacity to control the release of the encapsulated drug for more than 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-2ʹ-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 formulation reformed instantly into a gel after injection through a needle. Based on these properties, the nanocomposite gel formulation has potential for the intratumoural delivery of anticancer drugs. 1 Abbreviations: low molecular weight gelator (LMWG); nanocapsules (NCs); N4-myristoyl gemcitabine (GEM C14); low molecular weight (LMW); hexadecyltrimethylammonium bromide (CTAB); Sodium hyaluronate (HA); poly-L-glutamic acid (PGA); GEM hydrochloride (GEM-HCl); 9-Diethylamino-5Hbenzo[a]phenoxazine-5-one -Nile Red (NR); Linear visco-elastic (LVE) region; GEM resistant cell line

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Low molecular weight nucleoside gelators hold great promise in drug delivery and particularly for the delivery of biologics due to their excellent biocompatibility. However, the influence of these gelators on protein aggregation inhibition has not yet been studied. Protein aggregation is the most significant cause of protein instability and can severely impact the biological activity of the protein, impairing the quality and safety of the formulation. Herein, we report the ability of a nucleoside based gelator, N4-octanoyl-2ʹ-deoxycytidine to inhibit protein aggregation. Using turbidimetric, spectroscopic and microscopic methods, we demonstrate that protein aggregation inhibition is dependent on gelator concentration. Moreover, we have found that the protein is still functionally active in the hydrogel.