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Intelligent Nanomaterials for Medicine: Carrier Platforms and Targeting Strategies—State of the Art
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Georgette B. Salieb-Beugelaar, Marc Wolf, Roman Lehner, Kegang Liu, Stephan Marsch, Patrick Hunziker
Tumor-penetrating peptides are an option to deal with poor tumor tissue penetration depths. They can open an active trans-cellular transport pathway, C-end Rule (CendR), that is faster than diffusion, with payloads up to NP sizes. The payload does not have to be coupled to the peptide, as the peptide activates a bulk transport system. Tumor-specific accumulation of various payloads was achieved in murine in vivo and human ex vivo studies [177].
Carriers for Nucleic Acid Delivery to the Brain
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Sequence-defined oligoaminoamide oligomers were used for receptor-mediated delivery of siRNA [101] and pDNA [102] into glioma in vivo after systemic injection. For siRNA delivery, an untargeted lipo-oligomer was mixed with a PEGylated oligomer containing an angiopep-2 ligand targeting the LRP-1 receptor, which is overexpressed both on the surface of BCECs and glioma cells [101]. A similar cascade-targeting strategy was used for the delivery of therapeutic pDNA. Here, a nontargeted oligomer was mixed with a PEGylated oligomer containing the heptapeptide I6P7, which binds the interleukin 6 receptor (IL6R). IL6R expression was detected both on the tumour BBB and in various brain tumours such as glioblastoma (Fig. 9.3). Targeted delivery of pDNA encoding inhibitor of growth 4 (pING4) significantly prolonged the survival time of orthotopic U87 glioma-bearing mice [102]. Reporter gene expression was found in the brains of U87 glioblastoma-bearing mice after intracranial injection of pDNA polyplexes formed with bioreducibly linked (cRGDyK)-PEG-ss-PEI. The Arg-Gly-Asp (RGD) sequence binds integrin receptors which are highly expressed in glioma cells, while the cyclic RGD peptide cRGDyK is known to increase the affinity and selectivity of the receptor by providing conformational restraint [32, 103]. PEGPEI polyplexes carrying the therapeutic gene pORF-hTRAIL were targeted with a protease-resistant retro-enantio C-end rule (CendR) peptide-binding neuropilin-1, which plays an important role in tumour angiogenesis, growth and metastasis [104]. Intravenous injection of the polyplexes significantly prolonged the survival time of intracranial U87 glioma-bearing mice from 25 to 30 days. Epidermal growth factor receptor (EGFR)-targeted intratumoural delivery of the synthetic antiproliferative double-stranded RNA polyinosine-cytosine (poly IC) formulated with PEI-PEG-EGF [105–107] induced the complete regression of intracranial tumours in mice, with no obvious adverse toxic effects on normal brain tissue [105]. Several preclinical studies explore the delivery of siRNAs to target genes involved in gliomagenesis, tumour progression and therapy resistance of glial tumours [99]. Tumour growth inhibition and prolonged survival of animals was found after both local application [108–114] and systemic injection [115–120] of siRNA nanoparticles (Table 9.1). Another potentially promising target for glioma-directed delivery of therapeutics is the proangiogenic apelin receptor (APLNR) and its cognate ligand apelin, which play a central role in controlling glioblastoma vascularisation [121]. Apelin and APLNR were found to be dramatically upregulated in glioblastoma-associated microvascular proliferations, but not in the healthy brain [122].
New insights into the role of co-receptor neuropilins in tumour angiogenesis and lymphangiogenesis and targeted therapy strategies
Published in Journal of Drug Targeting, 2021
Lin Zhao, Hongyuan Chen, Lu Lu, Lei Wang, Xinke Zhang, Xiuli Guo
CendR peptides are primarily used to optimise the targeting of drug delivery systems without anti-tumour activity. Another heptapeptide A7R was screened by phage display technology and its sequence ATWLPPR was originally thought to be an antagonist of VEGFR2 [109]. It has been demonstrated that A7R is highly targeted to VEGFR2 and NRP1 on cell membranes resulting in decreasing the VEGFA-165/VEGFR2/NRP1 complex [110]. The LPPR sequence of A7R is considered to be a core amino acid fragment of the blocking effect, and it can also be similarly defined as a CendR peptide that specifically targets the NRP1 b1 domain because its C-terminus is an arginine residue. In vitro, A7R can inhibit endothelial cells proliferation and tube formation, but has no effect on non-endothelial cells. In vivo, A7R also significantly inhibited the formation of new blood vessels in the presence of VEGF stimulation [111]. A7R is considered to be a potent anti-angiogenic peptide, but it can be easily destroyed by proteolytic enzymes. It has been investigated that the retro-inverso peptide (DA7R) or glycosylation modification of A7R can greatly improve its in vivo half-life and anti-tumour activity [112,113]. As an NRP1 targeting peptide, A7R blocks the VEGFA-165-induced VEGFR2 signalling pathways and can also be used in the modification of drug delivery systems which is similar to the application of CendR peptides [114].
Recent advances in drug delivery systems for enhancing drug penetration into tumors
Published in Drug Delivery, 2020
Bin He, Xin Sui, Bing Yu, Song Wang, Youqing Shen, Hailin Cong
Targeted groups of nanoparticles can specifically identify tumor cells, trigger receptor-mediated endocytosis, accelerate the distribution of nano-drugs in tumor tissues, and promote their deep penetration (Liu et al., 2015; Ruoslahti, 2017; Zhang et al., 2020). Many peptides that are effective for penetration in tumor tissues contain the sequence: (R/K)XX(R/K) (Figure 13(a)(1)), where X represents an amino acid other than lysine or arginine. These peptides are also known as CendR peptides. As shown in Figure 13(a)(2), the principle of rapid infiltration of CendR peptides into tumor tissues is as follows: (i) the peptide binds to the primary receptor on the surface of tumor endothelial cells. For example, the primary receptor of iRGD is an αvβ3/αvβ5 integrin, and that of the Lyp-1 peptide sequence is p32/gC1qR. (ii) the CendR sequence of the polypeptide becomes exposed by hydrolysis of the protease (C-terminal); (iii) the CendR sequence binds to neuropilin-1 (NRP-1) on the cell surface, which becomes rapidly integrated into the cell to be subsequently excreted out by exosmosis, where it ‘infects’ other adjacent tumor cells for rapid infiltration into the tumor tissue.
Recent progress in LyP-1-based strategies for targeted imaging and therapy
Published in Drug Delivery, 2019
Ningning Song, Lingzhou Zhao, Meilin Zhu, Jinhua Zhao
LyP-1 not only shows the characteristics of homing to certain pathological cells expressing p32 on their surface, but also can be internalized by these target cells, which is important for the transport of attached cargo into cells. The potential mechanism of this cell-internalizing and tumor-penetrating activity is presumably due to the C-terminal C-end rule (CendR) motif existing on LyP-1 (Sugahara et al., 2009; Teesalu et al., 2009; Sugahara et al., 2010; Roth et al., 2012). CendR peptides are defined by the sequence of (R/K)XX(R/K) (in which X represents any amino acid), which can activate transvascular transport, cell internalization, and parenchymal penetration through a high affinity with neuropilin-1/2 (NRP1/2) on pathological cells. The LyP-1 internalization through CendR pathway is shown Figure 1. When LyP-1 (CGNKRTRGC, the bolded residues show the CendR segment) combines with the p32 receptor, and it undergoes proteolytic processing to expose the CendR peptide (CGNKRTR, also called tLyP-1). Subsequently, the CendR peptide is able to bind to NRP1 or NRP2, the second receptor with an ability of triggering the transport pathway for extravasation and tissue penetration (Hamzah et al., 2011). The internalization capacity of LyP-1 gifted by CendR sequence allows LyP-1 and its modified cargoes to enter not only the inside of tumor tissues but also the cell nucleus, which makes it more effective in imaging and treatment of diseases.