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Si113-prodrugs selectively activated by plasmin against hepatocellular and ovarian carcinoma
Enrico Rango1, Lucia D'Antona2, Giulia Iovenitti1
1Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy.
Abstract:
Si113, a pyrazolo[3,4-d]pyrimidine derivative, gained more attention as an anticancer agent due to its potent anticancer activity on both in vitro and in vivo hepatocellular carcinomas (HCC) and ovarian carcinoma models. But the drawback is the low water solubility which prevents its further development. In this context, we successfully overcame this limitation by synthesizing two novel prodrugs introducing the amino acid sequence D-Ala-Leu-Lys (TP). Moreover, TP sequence has a high affinity with plasmin, a protease recognized as overexpressed in many solid cancers, including HCC and ovarian carcinoma. The prodrugs were synthesized and fully characterized in terms of in vitro ADME properties, plasma stability and plasmin-induced release of the parent drug. The inhibitory activity against Sgk1 was evaluated and in vitro growth inhibition was evaluated on ovarian carcinoma and HCC cell lines in the presence and absence of human plasmin. In vivo pharmacokinetic properties and preliminary tissue distribution confirmed a better profile highlighting the importance of the prodrug approach. Finally, the prodrug antitumor efficacy was evaluated in an HCC xenografted murine model, where a significant reduction (around 90%) in tumor growth was observed. Treatment with ProSi113-TP in combination with paclitaxel in a paclitaxel-resistant ovarian carcinoma xenografted murine model, resulted in an impressive reduction of tumor volume greater than 95%. Our results revealed a promising activity of Si113 prodrugs and pave the way for their further development against resistant cancer.
Insights
Researchers developed novel Si113 prodrugs to overcome poor water solubility, showing significant anticancer efficacy against hepatocellular carcinoma (HCC) and ovarian cancer models, including drug-resistant types.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Development
Background:
- Si113, a pyrazolo[3,4-d]pyrimidine derivative, exhibits potent anticancer activity against hepatocellular carcinoma (HCC) and ovarian carcinoma.
- Low water solubility of Si113 hinders its clinical development.
- Plasmin, a protease overexpressed in many solid tumors, presents a potential target for drug delivery.
Purpose of the Study:
- To synthesize novel Si113 prodrugs with improved water solubility and targeted delivery.
- To evaluate the in vitro and in vivo anticancer efficacy of the developed prodrugs.
- To assess the potential of the prodrug approach for overcoming drug resistance.
Main Methods:
- Synthesis and characterization of two novel Si113 prodrugs incorporating the D-Ala-Leu-Lys (TP) sequence.
- In vitro assessment of ADME properties, plasma stability, and plasmin-mediated drug release.
- Evaluation of antiproliferative activity against HCC and ovarian cancer cell lines.
- In vivo pharmacokinetic studies, tissue distribution, and antitumor efficacy in HCC xenograft models.
- Assessment of combination therapy in paclitaxel-resistant ovarian cancer models.
Main Results:
- The novel prodrugs demonstrated enhanced water solubility and stability.
- Plasmin-induced release of Si113 was confirmed in vitro.
- Prodrugs showed significant in vitro growth inhibition of cancer cells, enhanced by plasmin.
- In vivo studies revealed improved pharmacokinetic profiles and substantial tumor growth inhibition (approx. 90%) in HCC models.
- Combination therapy with paclitaxel achieved over 95% tumor volume reduction in resistant ovarian cancer models.
Conclusions:
- The developed Si113 prodrugs effectively overcome solubility limitations and exhibit potent anticancer activity.
- The prodrug strategy, leveraging plasmin affinity, shows promise for targeted cancer therapy.
- These prodrugs represent a promising avenue for treating resistant hepatocellular carcinoma and ovarian cancer.
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