Fabrication of 3D-Printed Fish-Gelatin-Based Polymer Hydrogel Patches for Local Delivery of PEGylated Liposomal Doxorubicin.

Jin Liu,Tetsuya Ozeki,Tatsuaki Tagami

doi:10.3390/md18060325

Abstract

3D printing technology has been applied to various fields and its medical applications are expanding. Here, we fabricated implantable 3D bio-printed hydrogel patches containing a nanomedicine as a future tailored cancer treatment. The patches were prepared using a semi-solid extrusion-type 3D bioprinter, a hydrogel-based printer ink, and UV-LED exposure. We focused on the composition of the printer ink and semi-synthesized fish gelatin methacryloyl (F-GelMA), derived from cold fish gelatin, as the main component. The low viscosity of F-GelMA due to its low melting point was remarkably improved by the addition of carboxymethyl cellulose sodium (CMC), a pharmaceutical excipient. PEGylated liposomal doxorubicin (DOX), as a model nanomedicine, was incorporated into the hydrogel and liposome stability after photo-polymerization was evaluated. The addition of CMC inhibited particle size increase. Three types of 3D-designed patches (cylinder, torus, gridlines) were produced using a 3D bioprinter. Drug release was dependent on the shape of the 3D-printed patches and UV-LED exposure time. The current study provides useful information for the preparation of 3D printed nanomedicine-based objects.

Highlights

Liposomes are biocompatible lipid vesicles extensively used as drug carriers for nanomedicine [1,2,3].Liposomes can encapsulate anticancer drugs with a narrow therapeutic window and reduce non-specific drug distribution in organ tissues
The phosphoric acid groups of the liposomes formed micro-crosslinks with gelatin methacryloyl (GelMA) molecules, as described by Cheng et al, who prepared liposome-modified hydrogels stabilized by hydrogen alone had a larger particle size than that containing 20% fish gelatin methacryloyl (F-GelMA) + 7% carboxymethyl cellulose sodium (CMC) (Figure S1b) and the polydispersity index (PDI) of hydrogel formulations containing F-GelMA tended to be larger than those containing FGelMA + CMC. These results suggested that PEGylated liposomal DOX in a mixture of CMC and FGelMA is more stable than that of F-GelMA alone, stabilizing the liposomes in the hydrogel
In vivo experiments are necessary to demonstrate the therapeutic efficacy of these patches in treating cancer, patches prepared using a 3D bioprinter will be useful for implantation and may be applicable for treating cancer tissues in patients or in sites of surgical removal

Summary

Introduction

Liposomes are biocompatible lipid vesicles extensively used as drug carriers for nanomedicine [1,2,3]. Liposomes can encapsulate anticancer drugs with a narrow therapeutic window and reduce non-specific drug distribution in organ tissues. PEGylated liposomal DOX, Doxil® , was the first nanomedicine approved by the US Food and Drug Administration for cancer treatment and has remarkably reduced cardiotoxicity compared to free DOX solution [4]. The implantation of drug-loaded devices, and the application of nanomedicine, are useful strategies for controlling and maintaining the required drug concentration in the target tissue. Compared to systemic drug delivery, local drug delivery allows the local, surgical administration of drugs directly to cancer tissue. Nanomaterial implantation has been investigated for preventing infection after orthopedic surgery, and for diagnosis and cancer therapy [8]

Methods

Discussion

Conclusion