The Therapeutic Effect of Human Serum Albumin Dimer-Doxorubicin Complex against Human Pancreatic Tumors.

Ryo Kinoshita,Masaki Otagiri,Keiichiro Okuhira,Hidenori Ando,Hiroshi Watanabe,Yu Ishima,Tatsuhiro Ishida,Taro Shimizu,Victor T G Chuang,Toru Maruyama

doi:10.3390/pharmaceutics13081209

Abstract

Human serum albumin (HSA) is a versatile drug carrier with active tumor targeting capacity for an antitumor drug delivery system. Nanoparticle albumin-bound (nab)-technology, such as nab-paclitaxel (Abraxane®), has attracted significant interest in drug delivery research. Recently, we demonstrated that HSA dimer (HSA-d) possesses a higher tumor distribution than HSA monomer (HSA-m). Therefore, HSA-d is more suitable as a drug carrier for antitumor therapy and can improve nab technology. This study investigated the efficacy of HSA-d-doxorubicin (HSA-d-DOX) as next-generation nab technology for tumor treatment. DOX conjugated to HSA-d via a tunable pH-sensitive linker for the controlled release of DOX. Lyophilization did not affect the particle size of HSA-d-DOX or the release of DOX. HSA-d-DOX showed significantly higher cytotoxicity than HSA-m-DOX in vitro. In the SUIzo Tumor-2 (SUIT2) human pancreatic tumor subcutaneous inoculation model, HSA-d-DOX could significantly inhibit tumor growth without causing serious side effects, as compared to the HSA binding DOX prodrug, which utilized endogenous HSA as a nano-drug delivery system (DDS) carrier. These results indicate that HSA-d could function as a natural solubilizer of insoluble drugs and an active targeting carrier in intractable tumors with low vascular permeability, such as pancreatic tumors. In conclusion, HSA-d can be an effective drug carrier for the antitumor drug delivery system against human pancreatic tumors.

Highlights

The particle sizes of Human serum albumin (HSA)-mDOX and HSA dimer (HSA-d)-DOX were 3.98 nm and 7.52 nm, and amounts of DOX binding to HSA monomer (HSA-m)-DOX and HSA-d-DOX were 4.08 mol/mol HSA-m and 7.9 mol/mol HSA-d, respectively (Table 1)
These results suggest that HSA-m-DOX and HSA-d-DOX exist as almost homogeneous molecules without aggregated proteins
The stability of HSA-mDOX and HSA-d-DOX after lyophilization was assessed by evaluating the particle sizes and DOX-loading rates

Summary

Introduction

Pancreatic tumors remain one of the most difficult human malignancies to be treated, having the worst mortality rate and the lowest overall survival rate among all tumors. The overall survival rate for pancreatic tumors is extremely low despite rapid advances in tumor diagnosis and treatment. The prognosis of pancreatic tumors is abysmal, with 5-year survival less than 5%. Less than 10% of pancreatic tumor patients are presented with resectable disease or are suitable for potentially curative surgery. Aggressive metastasis often occurs after the operation, which is highly resistant to conventional chemotherapy and radiation therapy. Chemotherapy is the only option in metastatic pancreatic tumor treatment, Pharmaceutics 2021, 13, 1209.

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