Rerouting Native HDL to Predetermined Receptors for Improved Tumor-Targeted Gene Silencing Therapy

Ding, Yang; Han, Yue; Wang, Ruoning; Wang, Yazhe; Chi, Cheng; Zhao, Ziqiang; Zhang, Huaqing; Wang, Wei; Yin, Lifang; Zhou, Jianping

doi:10.1021/acsami.7b10047

Cited by 16 publications

(10 citation statements)

References 50 publications

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“…Although lipid conjugation as a delivery platform has many strengths, it also has limitations, chief among them being difficulty in achieving cell type-specific delivery. This concern is being addressed in various forums, including the redirection of endogenous HDL and its therapeutic cargo via modification of surface apolipoprotein residues 49 .…”

Section: Discussionmentioning

confidence: 99%

Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways

Osborn

Coles

Biscans

et al. 2018

Preprint

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Efficient delivery of therapeutic RNA is the fundamental obstacle preventing its clinical utility. Lipid conjugation improves plasma half-life, tissue accumulation, and cellular uptake of small interfering RNAs (siRNAs). However, the impact of conjugate structure and hydrophobicity on siRNA pharmacokinetics is unclear, impeding the design of clinically relevant lipid-siRNAs. Using a panel of biologically-occurring lipids, we show that lipid conjugation modulates siRNA hydrophobicity and governs spontaneous partitioning into distinct plasma lipoprotein classes in vivo. Lipoprotein binding influences siRNA distribution by delaying renal excretion and promoting uptake into lipoprotein receptor-enriched tissues. Lipid-siRNAs elicit mRNA silencing without causing toxicity in a tissue-specific manner. Lipid-siRNA internalization occurs independently of lipoprotein endocytosis, and is mediated by siRNA phosphorothioate modifications. Although biomimetic lipoprotein nanoparticles have been considered for the enhancement of siRNA delivery, our findings suggest that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation. IntroductionFor over a decade, the underlying obstacle preventing the widespread clinical use of small interfering RNA (siRNA)-based therapies has been efficient and safe in vivo delivery. siRNAs are large (~14 kDa), polyanionic macromolecules that require extensive modifications to improve their inherently-poor pharmacological properties (e.g. plasma half-life of <5 min before renal excretion) 1,2 . Lipid-and polymer-based nanoparticles, which are effective transfection agents in vitro, can prolong circulation time and improve stability and bioavailability in vivo. However, nanoparticle delivery is typically limited to clearance organs with fenestrated and/or discontinuous endothelium (e.g. liver, spleen, and certain tumors). Moreover, nanoparticles can interact with opsonin proteins that enhance clearance by macrophage phagocytosis.

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Section: Discussionmentioning

confidence: 99%

Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways

Osborn

Coles

Biscans

et al. 2018

Preprint

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“…The cytotoxicity of RHE, DOX, RHE/DOX and RD NPs against 4T1 cells was evaluated in MTT assays [2,18]. Briefly, cells were seeded and cultured.…”

Section: In Vitro Cytotoxicity Assaymentioning

confidence: 99%

“…Up to now, though the great quantity of nanomedicine drug delivery systems were reported, only a few have been used in clinical. One major disadvantage for clinical usage is that current nanomedicines are always applying new materials or chemical modifications to agents [18][19][20]. The intensive clinical trials and final FDA approvals should be needed for these materials as excipients.…”

Section: Introductionmentioning

confidence: 99%

Synergistic inhibition of metastatic breast cancer by dual-chemotherapy with excipient-free rhein/DOX nanodispersions

Wang

Yang

Yuan

et al. 2020

Preprint

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Background: The treatment of metastatic cancer continues to be very challenging worldwide. Notably, excipient-free nanodispersions that are entirely composed of pharmaceutically active molecules are regarded as promising candidates for the next generation of drug formulations. These molecules are mainly formulated from the self-assembly of drug molecules that enable the safe and effective delivery of therapeutic drugs to local diseased lesions. Herein, we developed a novel and green approach for preparing nanoparticles via the self-assembly of rhein (RHE) and doxorubicin (DOX) molecules, named RHE/DOX nanoparticles (RD NPs); this assembly was associated with π−π stacking interactions and did not involve any organic solvents. Results：Molecular dynamics (MD) simulations showed that DOX molecules tend to assemble around RHE molecules through intermolecular forces. With the advantage of nanosizing, RD NPs improved the intracellular drug retention of DOX. As a dual-drug-loaded nanoformulation, the toxicity of RD NPs to tumor cells in vitro was synergistically enhanced. The combination of DOX and RHE in nanoparticles exhibited a synergistic effect with a combination index (CI) value of 0.51 and showed a stronger ability to induce cell apoptosis compared to that of free DOX. Furthermore, RD NPs treatment not only effectively suppressed primary tumor growth but also successfully inhibited tumor metastasis both in vitro and in vivo, with a good safety profile. Conclusion: The generation of pure nanodrugs via a self-assembly approach might be an option and may provide inspiration for the fabrication of new excipient-free nanodispersions, especially for two small molecular antitumor drugs that could potentially have synergistic antiproliferation effects against metastatic breast cancer.

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“…The cytotoxicity of RHE, DOX, RHE/DOX and RD NPs toward 4T1 cells was evaluated using MTT assays [3,23]. Brie y, cells were seeded and cultured.…”

Section: In Vitro Cytotoxicity Assaymentioning

confidence: 99%

Synergistic inhibition of metastatic breast cancer by dual-chemotherapy with excipient-free rhein/DOX nanodispersions

Wang

Yang

Yuan

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: The management of metastatic cancer remains a major challenge in cancer therapy worldwide. The targeted delivery of chemotherapeutic drugs through rationally designed formulations is one potential therapeutic option. Notably, excipient-free nanodispersions that are entirely composed of pharmaceutically active molecules have been evaluated as promising candidates for the next generation of drug formulations. Formulated from the self-assembly of drug molecules, these nanodispersions enable the safe and effective delivery of therapeutic drugs to local disease lesions. Here, we developed a novel and green approach for preparing nanoparticles via the self-assembly of rhein (RHE) and doxorubicin (DOX) molecules, named RHE/DOX nanoparticles (RD NPs); this assembly was associated with the interaction force and did not involve any organic solvents. Results: According to molecular dynamics (MD) simulations, DOX molecules tend to assemble around RHE molecules through intermolecular forces. This intermolecular retention of DOX was further improved by the nanosizing effect of RD NPs. Compared to free DOX, RD NPs exerted a slightly stronger inhibitory effect on 4T1 cells in the scratch healing assay. As a dual drug-loaded nanoformulation, the efficacy of RD NPs against tumor cells in vitro was synergistically enhanced. Compared to free DOX, the combination of DOX and RHE in nanoparticles exerted a synergistic effect with a combination index (CI) value of 0.51 and showed a stronger ability to induce cell apoptosis. Furthermore, the RD NP treatment not only effectively suppressed primary tumor growth but also significantly inhibited tumor metastasis both in vitro and in vivo, with a better safety profile. Conclusions: The generation of pure nanodrugs via a self-assembly approach might hold promise for the development of more efficient and novel excipient-free nanodispersions, particularly for two small molecular antitumor drugs that potentially exert synergistic antiproliferative effects on metastatic breast cancer.

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Rerouting Native HDL to Predetermined Receptors for Improved Tumor-Targeted Gene Silencing Therapy

Cited by 16 publications

References 50 publications

Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways

Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways

Synergistic inhibition of metastatic breast cancer by dual-chemotherapy with excipient-free rhein/DOX nanodispersions

Synergistic inhibition of metastatic breast cancer by dual-chemotherapy with excipient-free rhein/DOX nanodispersions

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