3D Printed Core-Shell Structured Scaffolds with NIR-Triggered Dual Release for Cancer Therapy and Uterine Tissue Regeneration

Gynecologic cancers and uterine fibroids can cause dysfunction of the uterus and hence result in female infertility. Various treatment options, including surgical resection, radiation therapy, chemotherapy and hormone therapy, are available for treating gynecologic cancers and uterine fibroids, aiming to restore fertility for women of the child-bearing age. Surgical resection is one of the most used treatments for cancerous tissues and uterine fibroids. However, insufficient clinical intervention can result in tumor recurrence, and the residual defective tissue after surgery can cause intrauterine adhesion (IUA) and further affect women’s reproductive ability. Therefore, new and novel treatments that can effectively kill residual tumor cells and at the same time, regenerate new and healthy uterine tissues should be developed. In the current study, a dual drug/biomolecule release system, with the release being triggered by a near-infrared (NIR) laser that would deliver anticancer drug and biomolecules (for promoting uterine tissue regeneration) in a chronological manner, was designed and fabricated for the affected uterus. Specifically, gelatin (Gel) hydrogel/poly(L-lactide-<i>co</i>-trimethylene carbonate) (PLLA-co-TMC, “PTMC” in short) core-shell structured scaffolds with NIR-triggered dual releases of anticancer drug doxorubicin hydrochloride (DOX) and hormone estradiol (E2) were constructed via 3D printing for providing cancer therapy and for promoting uterine regeneration for postoperative females. DOX is a commonly used antineoplastic agent for treating many cancers and has been clinically used for uterine cancers. E2 is an estrogen steroid hormone extensively used to facilitate uterine regeneration. In our fabrication, Gel and DOX were homogeneously mixed first and 3D printed to form Gel-DOX scaffolds. E2-containing polydopamine (PDA@E2) microspheres were synthesized and homogeneously dispersed in PTMC-dichloromethane (DCM) solution. Gel-DOX scaffolds were then soaked in the PTMC-PDA@E2 solution for fabricating Gel-DOX/PTMC-PDA@E2 core-shell structured scaffolds. It was observed that the PTMC-PDA@E2 coating layer significantly enhanced mechanical properties of the scaffolds, making them comparably strong with the native uterine tissue. Furthermore, the coating layer protected the Gel-DOX core from rapid biodegradation and thus inhabited the burst release of DOX. Moreover, Gel-DOX/PTMC-PDA@E2 scaffolds could release DOX and E2 in a chronological manner, firstly delivering DOX together with photothermal therapy (PTT) to effectively kill Hela cells used in the <i>in vitro</i> experiments and then sustainably releasing E2 over 28 days of the experiment duration to promote uterine tissue regeneration. The <i>in vitro </i>experiments showed that DOX could be quickly released in 3 days and that the core-shell scaffolds exhibited excellent anticancer ability through the synergy of DOX release and hyperthermia cancer cell ablation. E2 via controlled release over the 28 days promoted the proliferation of bone marrow-derived mesenchymal stem cells (BMSCs) and induced their differentiation. The novel Gel-DOX/PTMC-PDA@E2 core-shell scaffolds have shown their high potential for postoperative management for female patients.