A novel topical treatment for bone metastases using a gelatin hydrogel incorporating cisplatin as a sustained release system

Abstract

Management of bone metastasis is becoming increasingly important. Thus, local and systemic treatment options have been developed for control. Although systemic administration of anticancer agents is effective for bone metastasis, it is often stopped because of poor general conditions or side effects. Therefore, it is highly desirable to develop a more effective and safer local treatment for bone metastasis. The purpose of the current study was to investigate the antitumor effects and safety of gelatin hydrogel microspheres incorporating cisplatin (GM‐CDDP), which we developed as a sustained release system without harmful substances. First, we assessed GM‐CDDP for its in vitro degradability and potential for sustained release. Second, in vivo antitumor and side effects were evaluated using a murine bone metastasis model of MDA‐MB‐231 human breast cancer cells incorporating GFP. In vitro, initial bursts were observed within 2 h and CDDP was released gradually with gelatin hydrogel degradation, which reached 100% at 48 h. In vivo, local administration of GM‐CDDP (2 mg/kg) significantly suppressed tumor growth and bone osteolysis compared with the control, and local and systemic administration of free CDDP (2 mg/kg; p < 0.05). Local administration of GM‐CDDP significantly reduced loss of body weight and elevation of blood urea nitrogen compared with the systemic administration of free CDDP (p < .05). The current study suggests that local administration of GM‐CDDP achieves higher antitumor effects with a potential for lesser side effects compared with local or systemic administration of free CDDP.

Platinum-based drugs and hydrogel: a promising anti-tumor combination

“…Gelatin and other proteins are nontoxic and biodegradable substances. The CDDP release rate from gelatin hydrogels depends on the cross-linking degree; more cross-linking means slower drug release (Kanda et al., 2021 ). Gelatin hydrogel granules (GHG) were made by cross-linking gelatin solution with glutaraldehyde.…”

“…The results showed that GM-CDDP exhibited more remarkable antitumor effect than free CDDP. In addition, local administration of GM-CDDP resulted in the maximum amount of bone residue, reducing the damage to surrounding healthy tissue caused by free administration and preserving the integrity and mechanical strength of bone tissues as much as possible (Kanda et al., 2021 ). For peritumoral injection, a CDDP-loaded thermosensitive polypeptide hydrogel displayed more significant tumor inhibition than free CDDP group with the same dose (10 mg/kg) during weekly injection to MCF-7 cell transplanted tumor model, supporting the effectiveness of targeted delivery (Yu et al., 2017 ).…”

Next-Generation 3D Scaffolds for Nano-Based Chemotherapeutics Delivery and Cancer Treatment

“…Injectable microspheres are fabricated by co-axial electrospinning and can be used for minimally invasive delivery of drugs inside bone-like rigid structures without surgery. Due to the excellent microarchitecture of the microsphere, researchers nowadays tend to use injectable microspheres to treat bone metastasis [129]. In bone metastasis, cancer cells induce osteoblast expression to release an apoptotic regulatory gene (RANKL) so that the RANKL may bind to the osteoclast and increase proliferation.…”