Design and tuning of a cell-penetrating albumin derivative as a versatile nanovehicle for intracellular drug delivery

Ichimizu, Shota; Watanabe, Hiroshi; Maeda, Hitoshi; Hamasaki, Koji; Nakamura, Yuka; Chuang, Victor Tuan Giam; Kinoshita, Ryô; Nishida, Kimiaki; Tanaka, Ryota; Enoki, Yuki; Ishima, Yu; Kuniyasu, Akihiko; Kobashigawa, Yoshihiro; Morioka, Hiroshi; Futaki, Shiroh; Otagiri, Masaki; Maruyama, Toru

doi:10.1016/j.jconrel.2018.02.037

Cited by 28 publications

(25 citation statements)

References 45 publications

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“…These results suggest that HSA-m-DOX and HSA-d-DOX exist as almost homogeneous molecules without aggregated proteins. In the previous report, N -succinimidyl S -acetylthioacetate (SATA) reagent was used to introduce SH to amino groups [ 26 ]. In the case of the SATA reagent, the terminal is thioester after reaction, so a deprotection procedure with hydroxylamine is needed.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, the preparation process was successfully shortened by one step using iminothiolane, where a deprotection operation could be omitted. Fortunately, the DOX loading efficiency using iminothiolane was equivalent to the value in the reference using SATA [ 26 ]. The stability of HSA-m-DOX and HSA-d-DOX after lyophilization was assessed by evaluating the particle sizes and DOX-loading rates.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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“…To validate the relevance of KH-1 system as a potential intracellular delivery vehicle for anticancer agents, we examined the effects of pretargeting and multivalent binding on cell internalization ( Figure 6A). In the absence of Fab'-MORF1, HSA-(MORF2) 11.4 -Cy3 was mostly precluded from cells, due to the macromolecular size of HSA and its poor membrane affinity [28]. Meanwhile, exposure of Fab'-MORF1 pretargeted Raji cells to HSA-(MORF2) 1.4 -Cy3 only resulted in its extracellular binding to cell surface.…”

Section: Internalization and Subcellular Trafficking Of Kh-1: Implicamentioning

confidence: 99%

“…HSA is selected for its superior biocompatibility, stability, blood retention property, and its capability to load a vast array of drugs and ligands [27]. We also take advantage of one disadvantage that HSA exhibits poor penetration into cells for the extracellular actuation [28]. Thus, the multivalent binding of CD20-bound Fab'-MORF1 by HSA-(MORF2) x is expected to act as a surface switch that directly transduces extracellular receptor crosslinking input into intracellular signal activation output, thereby enhancing the apoptosis of drug-treated cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Drug-free albumin-triggered sensitization of cancer cells to anticancer drugs

Yang

Soodvilai

et al. 2019

Journal of Controlled Release

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Chemosensitization strategies have been used to sensitize cancer cells to conventional drugs, but their utility is often obstructed by additional off-target toxicity, limited access to intracellular targets and heterogeneous tumor pathogenesis. To address these challenges, we rationally developed a drug-free human serum albumin (HSA)-based therapeutic (KH-1) that functions extracellularly and exhibits pleiotropic effect on multiple intracellular signaling pathways. It is a two-step touch-trigger system that consists of a pretargeting anchor on surface receptor CD20 (anti-CD20 Fab' conjugated with a morpholino oligonucleotide 1) and a CD20 clustering actuator (HSA grafted with multiple copies of complementary morpholinooligonucleotide 2). The extracellular actuation by surface CD20 crosslinking boosts robust activations of numerous intracellular responses, and promotes cancer cell susceptibility to various anticancer drugs, including docetaxel (microtubule stabilizer), gemcitabine (nucleoside analogue) and GDC-0980 (PI3K/mTOR inhibitor). The broad applicability of KH-1 is demonstrated to result from simultaneous inhibition of survival pathways and augmentation of apoptotic pathways. In addition, KH-1 covalently conjugated with anthracycline anticancer agent, epirubicin, integrates the advantages of both chemosensitization function and improved intracellular drug delivery in a single system and takes effect on the same cell. Therefore, in the present study, we have provided mechanistic demonstration that crosslinking of surface receptors can be leveraged to elicit chemosensitization.

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“…Non-covalent polymer-protein binding studies, sometimes involvingd elivery experiments, is ab road field, and additional reports relatedt ot his topic that highlight various binding interactions and characterization methods can be found in Refs. [58][59][60][61][62][63][64][65][66][67][68][69][70][71].B inding studies showcasing availablet echniques could potentially contain criticali nformation necessary for future protein-delivery optimization studies and should not be overlooked.…”

Section: Other Non-covalent Protein-basedcomplexes For Deliverymentioning

confidence: 99%

Associative and Dissociative Processes in Non‐Covalent Polymer‐Mediated Intracellular Protein Delivery

Posey

Tew

2018

Chemistry An Asian Journal

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Functional protein delivery has created new opportunities for studying intracellular processes and discovering new therapeutics. To that end, researchers have pursued intracellular protein delivery by using an increasing number of methods. This focus review will highlight polymeric carriers that non-covalently bind and deliver protein cargo in vitro. The correlation between polymer-protein binding and delivery as well as the correlation between complex-membrane binding and delivery is reviewed. Finally, binding and its relation to the intracellular function of the protein post-delivery is considered. The purpose of this review is to evaluate the role that binding interactions play in the non-covalent protein-delivery landscape. Presently, the literature does not adequately resolve how binding throughout the process ultimately affects delivery. The field does contain preliminary insights that are expected to impact future delivery applications when developed further.

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Design and tuning of a cell-penetrating albumin derivative as a versatile nanovehicle for intracellular drug delivery

Cited by 28 publications

References 45 publications

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

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

Drug-free albumin-triggered sensitization of cancer cells to anticancer drugs

Associative and Dissociative Processes in Non‐Covalent Polymer‐Mediated Intracellular Protein Delivery

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