Viale Maurizio, Rossi Marta, Russo Eleonora, Cilli Michele, Aprile Anna, Profumo Aldo, Santi Pierluigi, Fenoglio Carla, Cafaggi Sergio, Rocco Mattia
U.O.C. Bioterapie, IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 10, 16132, Genova, Italy.
S.C. Farmacia Interna, E.O. Ospedali Galliera, Mura delle Cappuccine 14, 16128, Genova, Italy.
Invest New Drugs. 2015 Dec;33(6):1151-61. doi: 10.1007/s10637-015-0291-x. Epub 2015 Oct 7.
Fibrin gels are attractive biomaterials for local delivery of a variety of agents, from drugs to proteins. Similarly, polymer-anticancer-drug conjugates and nanoparticles are emerging as potential candidates for cancer treatment. Combining these different approaches, we have studied the efficacy of fibrin gels loaded with cisplatin (DDP) and a complex of DDP with hyaluronate (DDP-HA) for tumor growth inhibition in a melanoma model. Loaded gels prepared at relatively high fibrinogen concentration (22 mg/ml) showed good in vitro antiproliferative activities, prolonged release of the anticancer drug, and a long persistence (10-15 days) in vivo when implanted subcutaneously (sc) in immunodeficient mice. Gels loaded with DDP or DDP-HA containing 1/3 or even 1/6 of their systemic dose (6 mg/kg) and positioned under the tumor mass in mice bearing a sc human SK-Mel-28 tumor showed an antitumor activity better than that of the original parent compound given intraperitoneally (ip). Moreover, in an additional experiment in vivo, fibrin gels loaded with N-trimethyl chitosan-based nanoparticles containing a DDP-HA complex were assayed, resulting in a further 8 % improvement of anticancer activity, with lesser adverse systemic toxic effects. Taken together, these results suggest that the combination of fibrin gels and drugs complexed with suitable macromolecules holds great promise for loco-regional anticancer therapy of melanoma and other surgically removable cancer types.
纤维蛋白凝胶是用于多种药物（从药物到蛋白质）局部递送的有吸引力的生物材料。同样，聚合物 - 抗癌药物缀合物和纳米颗粒正成为癌症治疗的潜在候选物。结合这些不同方法，我们研究了负载顺铂（DDP）和DDP与透明质酸复合物（DDP - HA）的纤维蛋白凝胶在黑色素瘤模型中抑制肿瘤生长的功效。在相对高的纤维蛋白原浓度（22mg/ml）下制备的负载凝胶在体外显示出良好的抗增殖活性、抗癌药物的延长释放，并且当皮下（sc）植入免疫缺陷小鼠体内时具有较长的持久性（10 - 15天）。在携带皮下人SK - Mel - 28肿瘤的小鼠中，负载含有其全身剂量（6mg/kg）的1/3甚至1/6的DDP或DDP - HA且置于肿瘤块下方的凝胶显示出比腹腔内（ip）给予的原始母体化合物更好的抗肿瘤活性。此外，在另一项体内实验中，对负载含有DDP - HA复合物的基于N - 三甲基壳聚糖的纳米颗粒的纤维蛋白凝胶进行了测定，结果抗癌活性进一步提高了8%，且全身不良毒性较小。综上所述，这些结果表明纤维蛋白凝胶与与合适大分子复合的药物的组合在黑色素瘤和其他可手术切除的癌症类型的局部区域抗癌治疗中具有巨大潜力。
