单蛋白包封的SN38：极其有效且低毒性的抗癌药物

Purpose: SN38 is a potent antineoplastic agent, however, the poor water solubility prohibited its direct clinical applications. At present, only prodrug approach on SN38 has resulted in 2 types of therapeutics approved by the FDA, irinotecan/ONIVYDE and Trodelvy. Furthermore, the poor enzymatic conversion (2-8%) of irinotecan into the active metabolite SN38 severely limits its efficacy. Numerous attempts of drug delivery systems failed to achieve effective SN38 delivery. Therefore, novel approaches are urgently needed for effectively delivering SN38. Methods: Our patented single protein encapsulation (SPE) platform, allowing encapsulation of small-molecule drugs by a single protein (albumins or globulins) without artificial nanoparticles and chemical modifications to drugs and proteins, has made the first drug product, SPEDOX-6 into human phase IB/IIA clinical trial (NCT0764018). The great success of SPEDOX-6 has prompted us to utilize the same SPE technology for encapsulation of SN38 by HSA to create SPESN38-5/8 complexes, which were characterized by membrane dialysis, HPLC, UV and dynamic light scattering. We conducted pharmacological evaluations with respect to MTD, PK, in vitro and in vivo efficacy against various cancers. Results: Lyophilized SPESN38-5/8 complexes can be dissolved in water to form clear and stable solutions. PK of SPESN38‑5 by IV at 55 mg/ kg yielded much higher mouse plasma AUC for SN38 and SN38G, producing a molar ratio of SN38G:SN38 = 1.5:1. We tested in vitro growth-inhibitory effect of SPESN38-8 against SK-ES-1 (Ewing Sarcoma), SK-LMS-1 (soft tissue sarcoma), A204 (rhabdomyosarcoma) and HT1080 (soft tissue sarcoma) with IC50 at 0.1079, 0.1526, 1.023, 1.087 uM, respectively, which is 7 to 60-fold lower than irinotecan. In vivo antitumor efficacy against 5 cancer models was evaluated: (1) SK-ES-1 model, SPESN38-8 at 35 mg/kg vs DOX at 3.0 mg/kg and Doxil at 4.0 mg/kg; led to 8/8 mice tumor free on Day 21, which were monitored for total 230 days, tumor relapse wasn't found for > 209 days, indicative of cancer eradication; (II) A204, SPESN38-8 at 35 mg/kg vs Doxil at 4.0 mg/kg, led to all 4 females free of tumor & 4 males almost tumor free, (III) SK-LMS-1, SPESN38-8 at 35 mg/kg vs DOX at 5.0 mg/kg, led to 6/7 mice free of tumor, indicative of SPESN38-8's superior anticancer efficacy; (IV) HCT-116 (colorectal cancer) model, SPESN38-5 at 55 mg/kg vs irinotecan at 50 mg/kg, SPESN38-5 was much effective to suppress HCT-116 than irinotecan; (V) A549 (non-small cell lung cancer) model, SPESN38-8 at 35 mg/kg vs irinotecan at 50 mg/kg, SPESN38-8 was extremely effective to inhibit A549 than irinotecan. Conclusion: SPESN38 complexes provide a novel water soluble SN38 formulation. SPESN38‑5 and SPESN38‑8 demonstrate better PK values, lower toxicity and superior antitumor efficacy in mouse models, compared with irinotecan, DOX and Doxil. FDA has green-lighted SPESN38-8 (IND #: 164346) for clinical development.