Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis

Huang, Jialin; Jiang, Gan; Song, Qing; Gu, Xiao; Meng, Hu; Wang, Xiaolin; Song, Huahua; Chen, Lepei; Lin, Yingying; Jiang, Di; Chen, Jun; Feng, Junfeng; Qiu, Yongming; Jiang, Jiyao; Jiang, Xinguo; Chen, Hongzhuan; Gao, Xiaoling

doi:10.1038/ncomms15144

Cited by 157 publications

(95 citation statements)

References 67 publications

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“…Cross-linked albumin may stabilize and improve upon existing nab-paclitaxel; upon systemic administration, nab-paclitaxel dissociates from particulate form into monomeric albumin and thereby limits the amount of drug delivery without incurring systemic toxicities 18,20,26 . From the MFI values, oncogenic KRAS MDA-MB-231 cells exhibited greater uptake of both monomeric albumin and cross-linked albumin NPs than control MDA-MB-468 cells.…”

Section: Resultsmentioning

confidence: 99%

Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis

Liu

Ghosh

2019

Preprint

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11The RAS family of oncogenes (KRAS, HRAS, NRAS) are the most frequent mutations in 12 cancers and regulate key signaling pathways that drive tumor progression. As a result, drug 13 delivery targeting RAS-driven tumors has been a long-standing challenge in cancer therapy. 14 Mutant RAS activates cancer cells to actively take up nutrients, including glucose, lipids, and 15 albumin, via macropinocytosis to fulfill their energetic requirements to survive and proliferate. 16Here, we exploit this mechanism to deliver nanoparticles in cancer cells harboring activating 17 KRAS mutations. We have synthesized stable albumin nanoparticles that demonstrate 18 significantly greater uptake in cancer cells with activating mutations of KRAS than monomeric 19 albumin (i.e. dissociated form of clinically-used nab-paclitaxel). From pharmacological inhibition 20 and semi-quantitative fluorescent microscopy studies, these nanoparticles exhibit significantly 21 increased uptake in mutant KRAS cancer cells than wild-type KRAS cells by macropinocytosis. 22Importantly, we demonstrate that their uptake is driven by KRAS. This nanoparticle-based 23 strategy targeting RAS-driven macropinocytosis is a facile approach towards improved delivery 24into KRAS-driven cancers. 25 26 28 29 3 Background 30Mutations of the RAS oncogenes (HRAS, NRAS, and KRAS) are the most frequent 31 mutations in human cancers and are present in 25% of all cancers. Among the three isoforms of 32 RAS genes, KRAS is the most frequent mutated (85% in all RAS driven cancers). In particular, 33 hyperactivated mutations of RAS oncogenes initiate and drive tumor progression in a significant 34 subset of lung, colorectal, and pancreatic cancers 1 . Patients with oncogenic RAS mutations 35 have poor prognosis in colorectal 2 and pancreatic cancers 3 . As a result, drug delivery targeting 36 RAS-driven tumors has been a long-standing goal for cancer therapy 1,4 . However, targeting 37 cancers with RAS mutations has been a significant challenge due to the poor therapeutic index 38 of existing RAS inhibitors 1 . Consequently, approaches that enhance delivery and accumulation 39 of RAS-targeting therapeutics would greatly advance and significantly improve patient 40 outcomes. 41RAS hyperactivation drives cancer cell survival and proliferation by altering metabolic 42 requirements of the cells to upregulate intracellular uptake; as a result, mutant RAS drives the 43 uptake of numerous solutes. RAS proteins are GTPases that act as "molecular switches", 44 effectively cycling between binding to guanosine triphosphatase (GTP) and guanosine 45 diphosphatase (GDP) 5 . During homeostasis, RAS protein toggle between binding to GTP in its 46 active state and GDP in its non-stimulated, inactive state. At rest, RAS protein is bound to GDP 47

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Section: Resultsmentioning

confidence: 99%

Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis

Liu

Ghosh

2019

Preprint

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“…Prior studies have established that cholesterol-conjugated siRNAs have 8-to 15-fold higher activity when pre-complexed into purified HDL than when injected alone, leading to a surge in the exploration of biomimetic lipoprotein nanoparticles as siRNA delivery vehicles [39][40][41][42][43][44] . One caveat to those reports is the use of unmodified or partially 2'-substituted siRNA scaffolds, which are inherently unstable in serum 45,46 .…”

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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“…Also, adding of specific ligands into the complex may result in the efficient and specific transferring of drugs into the cancer cells, thus leading to suppression of tumor growth . On the other hand, by manipulating the content of different lipids and apolipoproteins, it is possible to change the physicochemical properties of synthetic HDLs that can affect the stability of these particles, the amounts of loaded drugs and their therapeutic efficacy …”

Section: High‐density Lipoproteins and Targeted Drug Delivery In Cancermentioning

confidence: 99%

“…35 On the other hand, by manipulating the content of different lipids and apolipoproteins, it is possible to change the physicochemical properties of synthetic HDLs that can affect the stability of these particles, the amounts of loaded drugs and their therapeutic efficacy. [36][37][38][39][40][41][42][43] In general, targeted drug delivery into tumor tissue can be divided into three main categories: passive, active, and physical. In the following section, we will discuss the use of HDL particles in drug delivery by each of these three applications.…”

Section: High-density Lipoproteins and Targeted Drug Delivery In Camentioning

confidence: 99%

The role of high‐density lipoproteins in antitumor drug delivery

et al. 2019

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High‐density lipoproteins (HDLs) are the smallest lipoprotein with the highest level of protein in their surface. The main role of HDLs are reverse transport of cholesterol from peripheral tissues to the liver. More recently, HDLs have been considered as a new drug delivery system because of their small size, proper surface properties, long circulation time, biocompatibility, biodegradability, and low immune stimulation. Delivery of anticancer drug to the tumor tissue is a major obstacle against successful chemotherapy, which is because of the toxicity and poor aqueous solubility of these drugs. Loading chemotherapeutic drugs in the lipid core of HDLs can overcome the aforementioned problems and increase the efficiency of drug delivery. In this review, we discuss the use of HDLs particles in drug delivery to the tumor tissue and explain some barriers and limitations that exist in the use of HDLs as an ideal delivery vehicle.

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Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis

Cited by 157 publications

References 67 publications

Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis

Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis

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

The role of high‐density lipoproteins in antitumor drug delivery

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