Target engagement and intracellular delivery of mono- and bivalent LDL receptor-binding peptide-cargo conjugates: Implications for the rational design of new targeted drug therapies
“…3b vs Supplementary Table S2 ). The scramble Fc(A680)-VH4Sc conjugate 15 was used as control conjugate. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The Fc(A680)-VH4127 conjugate used in this work shows remarkable properties such as bivalent binding to mouse and human LDLR with excellent affinity (91.8 pM and 60.7 pM, respectively), high proteolytic stability of the VH4127 peptide ligand, and extended serum half-life due to the Fc backbone 15 , 23 . In vitro, this conjugate was mostly taken up by PDAC cells through the LDLR abundantly present at the cell surface and fully functional.…”
Section: Discussionmentioning
confidence: 99%
“…The VH4Sc 15 and VH4127 peptides (Supplementary Table S2 ), were synthesized using an automated micro-wave assisted Fmoc/tBu solid phase peptide synthesis strategy. A rink amide AM resin and hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) were selected as solid support and coupling reagent, respectively.…”
Section: Methodsmentioning
confidence: 99%
“…To this end, we used a peptide-based delivery strategy, that has already proven itself in the early diagnosis, guided-surgery, and targeted therapy of PDAC 12 – 14 . Here, we utilized a fluorescent LDLR-targeting peptide conjugated to a human IgG Fc fragment (i.e., Fc(A680)-VH4127), already validated in engineered cells overexpressing LDLR 15 . We first demonstrate that Fc(A680)-VH4127 retains efficient LDLR-dependent endocytosis in PDAC derived-cancer cells.…”
Despite clinical advances in diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains the third leading cause of cancer death, and is still associated with poor prognosis and dismal survival rates. Identifying novel PDAC-targeted tools to tackle these unmet clinical needs is thus an urgent requirement. Here we use a peptide conjugate that specifically targets PDAC through low-density lipoprotein receptor (LDLR). We demonstrate by using near-infrared fluorescence imaging the potential of this conjugate to specifically detect and discriminate primary PDAC from healthy organs including pancreas and from benign mass-forming chronic pancreatitis, as well as detect metastatic pancreatic cancer cells in healthy liver. This work paves the way towards clinical applications in which safe LDLR-targeting peptide conjugate promotes tumor-specific delivery of imaging and/or therapeutic agents, thereby leading to substantial improvements of the PDAC patient’s outcome.
“…3b vs Supplementary Table S2 ). The scramble Fc(A680)-VH4Sc conjugate 15 was used as control conjugate. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The Fc(A680)-VH4127 conjugate used in this work shows remarkable properties such as bivalent binding to mouse and human LDLR with excellent affinity (91.8 pM and 60.7 pM, respectively), high proteolytic stability of the VH4127 peptide ligand, and extended serum half-life due to the Fc backbone 15 , 23 . In vitro, this conjugate was mostly taken up by PDAC cells through the LDLR abundantly present at the cell surface and fully functional.…”
Section: Discussionmentioning
confidence: 99%
“…The VH4Sc 15 and VH4127 peptides (Supplementary Table S2 ), were synthesized using an automated micro-wave assisted Fmoc/tBu solid phase peptide synthesis strategy. A rink amide AM resin and hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) were selected as solid support and coupling reagent, respectively.…”
Section: Methodsmentioning
confidence: 99%
“…To this end, we used a peptide-based delivery strategy, that has already proven itself in the early diagnosis, guided-surgery, and targeted therapy of PDAC 12 – 14 . Here, we utilized a fluorescent LDLR-targeting peptide conjugated to a human IgG Fc fragment (i.e., Fc(A680)-VH4127), already validated in engineered cells overexpressing LDLR 15 . We first demonstrate that Fc(A680)-VH4127 retains efficient LDLR-dependent endocytosis in PDAC derived-cancer cells.…”
Despite clinical advances in diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains the third leading cause of cancer death, and is still associated with poor prognosis and dismal survival rates. Identifying novel PDAC-targeted tools to tackle these unmet clinical needs is thus an urgent requirement. Here we use a peptide conjugate that specifically targets PDAC through low-density lipoprotein receptor (LDLR). We demonstrate by using near-infrared fluorescence imaging the potential of this conjugate to specifically detect and discriminate primary PDAC from healthy organs including pancreas and from benign mass-forming chronic pancreatitis, as well as detect metastatic pancreatic cancer cells in healthy liver. This work paves the way towards clinical applications in which safe LDLR-targeting peptide conjugate promotes tumor-specific delivery of imaging and/or therapeutic agents, thereby leading to substantial improvements of the PDAC patient’s outcome.
“…The in vitro gene silencing potential of siSOD1-peptide conjugates was investigated in the murine Neuro-2A (N2A) cell line after lipofection, to verify their intrinsic RNAi activity, or free uptake, to evaluate their potential to undergo LDLR-mediated functional uptake, leading to mSOD1 target mRNA knock-down (KD). The ability of both LDLR ligands, including LDL particles (DiI-LDL) and the previously described LDLR-binding VH4127-A680 conjugate (vs. its nonbinding scrambled version VH4sc-A680) 33 , to specifically bind the murine LDLR (mLDLR) expressed by N2A cells was verified beforehand (Supplemental Figure S1). First, transfection experiments clearly demonstrated that most of the tested siSOD1-peptide conjugates induced similar KD effect (c.a.…”
Section: Gene-silencing Potency Of Sisod1-peptide Conjugates In Vitro...mentioning
siRNAs have become one of the most promising therapeutic agents because of their specificity and their potential to modulate the expression of gene-related diseases. Any gene of interest can be potentially up or down-regulated, making RNA-based technology the healthcare breakthrough of our era. However, the functional and specific delivery of siRNAs into tissues of interest and into the cytosol of target cells remains highly challenging, mainly due to the lack of efficient and selective delivery systems. Among the variety of carriers for siRNA delivery, peptides have become essential candidates because of their high selectivity, stability and conjugation versatility. Here, we describe the development of molecules encompassing siRNAs against SOD1, conjugated to peptides that target the LDLR, and their biological evaluation both in vitro and in vivo.
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