Abstract
In this article, we have successfully designed and demonstrated a novel continuous process for assembling targeting ligands, peptidic spacers, fluorescent tags and a chelating core for the attachment of cytotoxic molecules, radiotracers, nanomaterials in a standard Fmoc solid-phase peptide synthesis in high yield and purity. The differentially protected Fmoc-Lys-(Tfa)-OH plays a vital role in attaching fluorescent tags while growing the peptide chain in an uninterrupted manner. The methodology is versatile for solid-phase resins that are sensitive to mild and strong acidic conditions when acid-sensitive side chain amino protecting groups such as Trt (chlorotrityl), Mtt (4-methyltrityl), Mmt (4-methoxytrityl) are employed to synthesise the ligand targeted fluorescent tagged bioconjugates. Using this methodology, DUPA rhodamine B conjugate (DUPA = 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid), targeting prostate specific membrane antigen (PSMA) expressed on prostate, breast, bladder and brain cancers and pteroate rhodamine B, targeting folate receptor positive cancers such as ovarian, lung, endometrium as well as inflammatory diseases have been synthesized. In vitro studies using LNCaP (PSMA +ve), PC-3 (PSMA −ve, FR −ve) and CHO-β (FR +ve) cell lines and their respective competition experiments demonstrate the specificity of the newly synthesized bioconstructs for future application in fluorescent guided intra-operative imaging.
Highlights
The understanding of cell processes is indispensable to devise new strategies for diagnosis and treatment of cancer and inflammatory diseases through targeted drug delivery techniques [1]
I) they are cost ineffective, ii) possess low resin loading, iii) incompatible in medium to strongly acidic [30] or basic conditions employed for deprotection of coupled amino acids and iv) undergo premature cleavage of polypeptide chain from solid support resulting in moderate yield during deprotection of acid sensitive side chain protecting moieties to introduce fluorescent tags
The carbonyl oxygen of the urea moiety of DUPA directly coordinates with two zinc atoms present in the active site of prostate specific membrane antigen (PSMA)
Summary
The understanding of cell processes is indispensable to devise new strategies for diagnosis and treatment of cancer and inflammatory diseases through targeted drug delivery techniques [1]. EC17, (λex = 465–490 nm and λem = 520–530 nm) a conjugate of folic acid and fluorescein isothiocyanate has been used for intraoperative surgery of ovarian cancer [17], lung adenocarcinoma [18,19,20], and breast cancer [21] Targeting these biomarkers brings forth new insight to know the cause and treatment for such ailments. These biomarkers belong to a family of cell surface transmembrane proteins [22] over-expressed mainly in diseased tissues and exploited in delivering chemical tools for early diagnosis of malignancy [23] and inflammatory diseases. I) they are cost ineffective, ii) possess low resin loading, iii) incompatible in medium to strongly acidic [30] or basic conditions employed for deprotection of coupled amino acids and iv) undergo premature cleavage of polypeptide chain from solid support resulting in moderate yield during deprotection of acid sensitive side chain protecting moieties to introduce fluorescent tags
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