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Iacobazzi RM, Porcelli L, Lopedota AA, Laquintana V, Lopalco A, Cutrignelli A, Altamura E, Di Fonte R, Azzariti A, Franco M, Denora N. Targeting human liver cancer cells with lactobionic acid-G(4)-PAMAM-FITC sorafenib loaded dendrimers. Int J Pharm 2017. [PMID: 28624661 DOI: 10.1016/j.ijpharm.2017.06.049] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Reported here is the synthesis and biological evaluation of the asialoglycoprotein receptor (ASGP-R) targeted fourth generation poliamidoamine dendrimer (G(4)-PAMAM) loaded with sorafenib. The ASGP-R targeted dendrimer was obtained by conjugation of Lactobionic acid (La) to the G(4)-PAMAM dendrimer, followed by acetylation (Ac) of the free amino groups in order to reduce the non-specific interactions with the cell membrane. Moreover, by additionally grafting fluorescein (FITC), it was easy to characterize the internalization pathway and the intracellular fate of the targeted dendrimer Ac-La-G(4)-PAMAM-FITC. In vitro experiments performed on HepG-2 and HLE cell lines, allowed to study the ability of the dendrimers to affect the cell vitality. Confocal microscopy and cytofluorimetric analysis confirmed higher binding and uptake ability of the Ac-La-G(4)-PAMAM-FITC dendrimer in well differentiated and ASGP-R expressing human liver cancer cell line HepG-2 compared non-expressing HLE cells. Ac-La-G(4)-PAMAM-FITC dendrimer loaded with sorafenib was stable and showed sustained sorafenib release. As evidenced by the cytotoxicity studies, sorafenib included in the dendrimer maintained its effectiveness, and was able to produce a longer lasting effect over the time compared to molar equivalent doses of free sorafenib. This new targeted dendrimer appears to be a suitable carrier for the delivery of sorafenib to liver cancer cells expressing ASGP-R.
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Affiliation(s)
| | - Letizia Porcelli
- Istituto Tumori IRCCS Giovanni Paolo II, viale O. Flacco 65, 70124 Bari, Italy
| | - Angela Assunta Lopedota
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy
| | - Valentino Laquintana
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy
| | - Antonio Lopalco
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy
| | - Annalisa Cutrignelli
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy
| | - Emiliano Altamura
- Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy
| | - Roberta Di Fonte
- Istituto Tumori IRCCS Giovanni Paolo II, viale O. Flacco 65, 70124 Bari, Italy
| | - Amalia Azzariti
- Istituto Tumori IRCCS Giovanni Paolo II, viale O. Flacco 65, 70124 Bari, Italy
| | - Massimo Franco
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy.
| | - Nunzio Denora
- Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy.
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Takano M, Kokudo T, Miyazaki Y, Kageyama Y, Takahashi A, Amikura K, Sakamoto H. Complete response with sorafenib and transcatheter arterial chemoembolization in unresectable hepatocellular carcinoma. World J Gastroenterol 2016; 22:9445-9450. [PMID: 27895433 PMCID: PMC5107709 DOI: 10.3748/wjg.v22.i42.9445] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 08/11/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
Patients with advanced hepatocellular carcinoma (HCC) showing portal vein tumor thrombosis (PVTT) have an extremely poor prognosis. According to treatment guidelines, the only option for HCC patients with PVTT is sorafenib chemotherapy. However, in Asia, various treatments have been attempted and possible prolongation of overall survival has been repeatedly reported. We herein report the first case of a patient with an initially unresectable advanced HCC with PVTT who underwent curative hepatectomy after sorafenib and transcatheter arterial chemoembolization (TACE) showing complete histological response. Two months after induction with sorafenib, a significant decrease in serum alpha-fetoprotein level was observed and computed tomography imaging showed a significant decrease in tumor size. Because of remaining PVTT, TACE and curative resection were performed. The combination of sorafenib and TACE may be an effective treatment for HCC patients with PVTT.
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Kee KM, Hung CH, Wang JH, Lu SN. Serial changes of clinical parameters in a patient with advanced hepatocellular carcinoma with portal vein thrombosis achieving complete response after treatment with sorafenib. Onco Targets Ther 2014; 7:829-34. [PMID: 24920924 PMCID: PMC4043808 DOI: 10.2147/ott.s61740] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The prognosis is usually poor in advanced hepatocellular carcinoma (HCC). Sorafenib is approved for Child-Pugh class A patients with unresectable and advanced HCC. We report here a rare case of a patient with advanced HCC with right portal vein thrombosis (PVT) who achieved a complete response after treatment with sorafenib. This 74-year-old man was a case of non-hepatitis B and C virus-related cirrhosis. Multiphase liver computed tomography showed an 8 cm tumor with early enhance, early wash out, and right PVT at segment 8 of the right lobe. A liver tumor biopsy confirmed the diagnosis of poorly differentiated HCC. Blood tests showed Child-Pugh class A cirrhosis and an alpha-fetoprotein level of 33,058 ng/mL. Sorafenib was initiated at 800 mg/day but was eventually reduced to 400 mg every other day because of a grade 3 hand-foot skin reaction. The alpha fetoprotein (AFP) level decreased rapidly with a linear trend after treatment. After log transformation, the calculated half-life of AFP was 6.84 days. There was no more tumor arterial enhancement, and tumor size was decreased to 3.7 cm on day 42. PVT shrank gradually and localized to the right anterior branch at month 9. There was no recurrence of tumor at the end of follow-up in month 19. Typical serial changes of clinical parameters were demonstrated in this patient.
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Affiliation(s)
- Kwong-Ming Kee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan ; Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan ; Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan ; Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan ; Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Moroni M, Zanlorenzi L. Complete regression following sorafenib in unresectable, locally advanced hepatocellular carcinoma. Future Oncol 2013; 9:1231-7. [PMID: 23902251 DOI: 10.2217/fon.13.86] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Sorafenib (SO) was the first targeted agent to produce significant improvements in overall survival in patients with advanced hepatocellular carcinoma (HCC). We report the case of a cirrhotic patient with chronic hepatitis C virus infection; locally advanced, unresectable, multinodular HCC, and portal vein tumor thrombosis, who achieved complete tumor regression following SO treatment. The patient was treated with SO 400 mg twice daily, which was subsequently reduced to 200 mg twice daily due to the occurrence of hand-foot skin reaction. The patient also received the following concomitant medications: Synchro-Levels(®) (Alphrema, Varese, Italy), silymarin and vitamin E. Long-term treatment with reduced SO dosage and Synchro-Levels resulted in a sustained radiological and clinical response with normalization of α-fetoprotein levels. Observed side effects were mostly low grade and manageable following dose adjustments. After 44 months of treatment the patient was in good physical condition, which suggests that a complete response with long-term SO is achievable in patients with locally advanced HCC.
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Affiliation(s)
- Marco Moroni
- U.O. Malattie Infettive, AO Ospedale di Circolo di Busto Arsizio, Ple Solaro 3, 21052 Busto Arsizio, Italy.
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