Combretastatin A-4

Although breast cancer mortality rates have declined, effective localized delivery systems to reduce post-surgical recurrence remains challenging. We developed an injectable in situ forming hybrid hydrogel incorporating liposomal combretastatin A4 (CA4) and plasmid green fluorescent protein (pGFP) lipoplexes for prolonged simultaneous drug and gene delivery to the tumor microenvironment. Cationic liposomes were synthesized using cholesterol/DOTAP² (1:1 M ratio) and complexed with pGFP as the reporter gene. CA4 loaded liposomes made of HSPC³/DSPE⁴/DPPG⁵/Cholesterol/CA4 (molar ratios: 5/20/5/15/55) were synthesized with 84 % encapsulation efficiency. The hydrogel was injectable at room temperature, gelling after 30 min at 37 °C, with 18.38 % swelling index and 14.21 % degradation rate over 30 days. Drug release studies showed 32.22 % CA4 release over 21 days. In vivo studies in BALB/c mice demonstrated significant tumor growth reduction in the treatment group. Histopathological studies revealed that the administration of the hybrid hydrogel induced the highest tumor necrosis with no severe damage to other organs. Notably, animal imaging studies indicated prolonged and enhanced gene expression, surpassing that of the PEI 25 kDa standard. These findings underscore the hybrid hydrogel as a potent delivery platform, facilitating localized simultaneous drug and gene delivery, enhancing anti-angiogenic effects, sustained gene expression and ensuring formulation stability for extended therapeutic benefits.

The combination therapy could overcome the limitation of monotherapy to inhibit tumor recurrence and metastasis, but is usually constrained by complex fabrication processes. Here, a tunable hydrogel platform was developed using different silk nanocarriers, which independently achieve flexible functional optimization of various drugs. Silk nanorods (SNR) were modified with cRGDfK peptides to achieve targeting ability to tumor vessels and then loaded with hydrophobic vascular inhibitor Combretastatin A4 (CA4). The loading of CA4 and the targeted modification could be tuned to enhance the destruction of tumor vessels. Both hydrophilic doxorubicin (DOX) and hydrophobic paclitaxel (PTX) were co-loaded on silk nanofibers (SNF) to form injectable hydrogels with optimized combination chemotherapy. The drug-laden SNR and SNF were blended directly to form injectable hydrogels without the compromise of drug biological activity. Both the targeting modification of SNR and the optimized co-delivery of DOX and PTX improved the therapeutic efficiency in vitro and in vivo. The long-term inhibition of tumor recurrence and metastasis was achieved through the injectable silk nanocarriers, which are superior to previous combination chemotherapy systems of DOX and PTX. The gradual modular fabrication process and simple physical blending endowed the systems with high flexibility and tunability, suggesting a suitable platform for designing a drug cocktail system.