Novel Injectable Hydrogel-based Drug Delivery System For Localized Cancer Therapy

Supramolecular hydrogels formed by intermolecular interactions are an interesting class of soft material materials.Their gelation conditions are mild and easy to operate,and its properties such as stimulation response and self-healing make this type of materials show a broad application prospect in biomedical field.Cisplatin(CDDP),as a chemotherapeutic drug widely used in clinic,has broad-spectrum anticancer activity.However,its poor selectivity and side effects restrict its clinical efficacy.On the other hand,intravenous injection has obvious disadvantages,such as frequency administration,high systemic side effects and low drug bioavaliability.In order to overcome the above drawbacks,we designed and prepared a new injectable supramolecular hydrogel for in situ solid tumor treatment with mouse breast cancer cell(4T1)as a tumor model.Furthermore,the gelation mechanism and properties of the supramolecular hydrogel were also investigated in detail.In this work,poly(ethylene glycol)grafted poly(glutamic acid)(PLG-g-mPEG)modified by arginine glycine aspartic cyclic peptide(cRGDfk)was developed,and the drug loaded micelles were formed through cisplatin coordinated bond.Further,the supramolecular hydrogel was formed by the interaction between alpha cyclodextrin(?-CD)and the poly(ethylene glycol)(PEG)chain on PLG-g-mPEG.In the process of hydrogel formation,the hydrogel showed good gelation properties in vitro and in vivo.Rheological studies have shown that the strength of hydrogels can be regulated by the concentration of ?-CD.In addition,due to the coordination effect of CDDP and carboxyl groups,the mechanical strength of drug loaded hydrogels has been improved some degree.The results of circular dichroism show that the secondary structure of PLG-g-mPEG can be regulated by the changing of the cisplatin concentration.Furthermore,the supramolecular hydrogel drug delivery system was applied to treating 4T1 and B16F10 cells in vitro.The results showed that cRGDfk modified drug loaded gel exhibited higher inhibitory effect of tumor cell growth compared to the control group.Flow cytometry showed that endocytosis of the cRGDfk modified CDDP NPs were stronger.The anti-tumor effect of 4T1 mouse tumor model indicated that the nanomedicine released from the gel had a highest inhibitory effect on tumor comparing with the other treated groups.