A novel low molecular weight nanocomposite hydrogel formulation for intra-tumoural delivery of anti-cancer drugs

Tracey D. Bradshaw,Ana Cadete,Haneen Abuzaid,Maria J. Alonso,Bhanu Teja Surikutchi,Ivana Štaka,Maria Marlow

doi:10.1016/j.ijpharm.2019.04.070

Abstract

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 >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 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.

Highlights

30 Supramolecular gels are formed from low molecular weight (LMW) molecules
The composite consist of Hyaluronic acid (HA) NCs dispersed in a low molecular weight gelators (LMWG)
The charge of the NCs depended on the polymer coating with zeta 230 potential values closer to neutral when polyglutamic acid (PGA) was used (-10 to -4 mV) while more negative charge was observed for HA NCs (-19 to -9 mV)

Summary

Introduction

30 Supramolecular gels are formed from low molecular weight (LMW) molecules (typically < 3 kDa). DOX was physically entrapped 45 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 (4T1) 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 injectable hydrogel and impeded tumour growth 2-fold compared to an i.v. injection of Taxol® in the breast (4T1) tumour model in mice. 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)

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Conclusion