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A micelle-based stage-by-stage impelled system for efficient doxorubicin delivery.

ABSTRACT: Chemotherapy remains the mainstay of cancer treatment, benefiting millions of patients each year, but the side effects of chemotherapy drugs severely limit their clinical use. Doxorubicin (DOX) can cause various side effects such as heart damage and treatment-related tumors. The effective use of active and passive targeting will improve the clinical application of DOX. Here, TPGS₃₃₅₀ and bioactive peptides were utilized to construct a micelle-based stage-by-stage impelled efficient system (missiles) for DOX delivery (DOX missiles). By taking advantage of the EPR effect, DOX missiles are efficiently enriched at the tumor site. After being cleaved by matrix metalloproteinase2 (MMP2), the peptide (VRGD) targets tumor cells to facilitate uptake of the missiles by the tumor cells via receptor-mediated endocytosis. The intracellular activated caspase-3-catalyzed explosion of DOX missiles further enables efficient tumor killing. This study provides an efficient approach for DOX delivery and toxicity reduction.

SUBMITTER: Li S

PROVIDER: S-EPMC10086681 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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A micelle-based stage-by-stage impelled system for efficient doxorubicin delivery.

Li Sunfan S Li Fangzhou F Wan Dong D Chen Zuqin Z Pan Jie J Liang Xing-Jie XJ

Bioactive materials 20220715

Chemotherapy remains the mainstay of cancer treatment, benefiting millions of patients each year, but the side effects of chemotherapy drugs severely limit their clinical use. Doxorubicin (DOX) can cause various side effects such as heart damage and treatment-related tumors. The effective use of active and passive targeting will improve the clinical application of DOX. Here, TPGS<sub>3350</sub> and bioactive peptides were utilized to construct a micelle-based stage-by-stage impelled efficient sy ...[more]

PMID: 37056277

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Project description:PurposePolymeric micelles are attractive nanocarriers for tumor-targeted delivery of paclitaxel (PTX). High antitumor efficacy and low toxicity require that PTX mainly accumulated in tumors with little drug exposure to normal tissues. However, many PTX-loaded micelle formulations suffer from low stability, fast drug release, and lack of tumor-targeting capability in the circulation. To overcome these challenges, we developed a micellar formulation that consists of sodium cholate (NaC) and monomethoxy poly (ethylene glycol)-block-poly (d,l-lactide) (mPEG-PDLLA).MethodsPTX-loaded NaC-mPEG-PDLLA micelles (PTX-CMs) and PTX-loaded mPEG-PDLLA micelles (PTX-Ms) were formulated, and their characteristics, particle size, surface morphology, release behavior in vitro, pharmacokinetics and in vivo biodistributions were researched. In vitro and in vivo tumor inhibition effects were systematically investigated. Furthermore, the hemolysis and acute toxicity of PTX-CMs were also evaluated.ResultsThe size of PTX-CMs was 53.61±0.75 nm and the ζ-potential was -19.73±0.68 mV. PTX was released much slower from PTX-CMs than PTX-Ms in vitro. Compared with PTX-Ms, the cellular uptake of PTX-CMs was significantly reduced in macrophages and significantly increased in human cancer cells, and therefore, PTX-CMs showed strong growth inhibitory effects on human cancer cells. In vivo, the plasma AUC0-t of PTX-CMs was 1.8-fold higher than that of PTX-Ms, and 5.2-fold higher than that of Taxol. The biodistribution study indicated that more PTX-CMs were accumulated in tumor than PTX-Ms and Taxol. Furthermore, the significant antitumor efficacy of PTX-CMs was observed in mice bearing BEL-7402 hepatocellular carcinoma and A549 lung carcinoma. Results from drug safety assessment studies including acute toxicity and hemolysis test revealed that the PTX-CMs were safe for in vivo applications.ConclusionThese results strongly revealed that NaC-mPEG-PDLLA micelles can tumor-target delivery of PTX and enhance drug penetration in tumor, suggesting that NaC-mPEG-PDLLA micelles are promising nanocarrier systems for anticancer drugs delivery.

Project description:Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]9 containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)8WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the corresponding physical mixture of the peptide and Dox to evaluate the effectiveness of synthesized conjugate compared to the parent drug alone. [(WR)8WKβA]-Dox conjugate showed higher antiproliferative activity at 10 µM and 5 µM than Dox alone at 5 μM. The conjugate inhibited the cell viability of ovarian adenocarcinoma (SK-OV-3) by 59% and the triple-negative breast cancer cells MDA-MB-231 and MCF-7 by 71% and 77%, respectively, at a concentration of 5 μM after 72 h of incubation. In contrast, Dox inhibited the proliferation of SK-OV-3, MDA-MB-231, and MCF-7 by 35%, 63%, and 57%, respectively. Furthermore, [(WR)8WKβA]-Dox conjugate (5 µM) inhibited the cell viability of Dox-resistant cells (MES-SA/MX2) by 92%, while the viability of cells incubated with free Dox was only 15% at 5 μM. Confocal microscopy images confirmed the ability of both Dox conjugate and the physical mixture of the peptide with the drug to deliver Dox through an endocytosis-independent pathway, as the uptake was not inhibited in the presence of endocytosis inhibitors. The stability of Dox conjugate was observed at different time intervals using analytical HPLC when the conjugate was incubated with 25% human serum. Half-life (t1/2) for [(WR)8WKβA]-Dox conjugate was (∼6 h), and more than 80% of the conjugate was degraded at 12 h. The release of free Dox was assessed intracellularly using the CCRF-CEM cell line. The experiment demonstrated that approximately 100% of free Dox was released from the conjugate intracellularly within 72 h. These data confirm the ability of the cyclic cell-penetrating peptide containing tryptophan and arginine residues as an efficient tool for delivery of Dox and for overcoming resistance to it.

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A micelle-based stage-by-stage impelled system for efficient doxorubicin delivery.

Publications

A micelle-based stage-by-stage impelled system for efficient doxorubicin delivery.

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