Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer

Dókus, Levente Endre; Lajkó, Eszter; Ranđelović, Ivan; Mező, Diána; Schlosser, Gitta; Kőhidai, László; Tóvári, József; Mező, Gábor

doi:10.3390/pharmaceutics12060576

Cited by 25 publications

(25 citation statements)

References 34 publications

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“…Dokus and colleagues have proposed a DDS for delivery of GFLG-conjugated daunomycin to the pancreatic adenocarcinoma sites. In vivo studies on PANC-1 tumor-bearing mice resulted in a decrease in cell viability [109].…”

Section: Enzyme-responsive Peptidesmentioning

confidence: 99%

Peptide-Based Drug Delivery Systems

et al. 2021

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Peptide-based drug delivery systems have many advantages when compared to synthetic systems in that they have better biocompatibility, biochemical and biophysical properties, lack of toxicity, controlled molecular weight via solid phase synthesis and purification. Lysosomes, solid lipid nanoparticles, dendrimers, polymeric micelles can be applied by intravenous administration, however they are of artificial nature and thus may induce side effects and possess lack of ability to penetrate the blood-brain barrier. An analysis of nontoxic drug delivery systems and an establishment of prospective trends in the development of drug delivery systems was needed. This review paper summarizes data, mainly from the past 5 years, devoted to the use of peptide-based carriers for delivery of various toxic drugs, mostly anticancer or drugs with limiting bioavailability. Peptide-based drug delivery platforms are utilized as peptide–drug conjugates, injectable biodegradable particles and depots for delivering small molecule pharmaceutical substances (500 Da) and therapeutic proteins. Controlled drug delivery systems that can effectively deliver anticancer and peptide-based drugs leading to accelerated recovery without significant side effects are discussed. Moreover, cell penetrating peptides and their molecular mechanisms as targeting peptides, as well as stimuli responsive (enzyme-responsive and pH-responsive) peptides and peptide-based self-assembly scaffolds are also reviewed.

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Section: Enzyme-responsive Peptidesmentioning

confidence: 99%

Peptide-Based Drug Delivery Systems

et al. 2021

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“…For example, Zhu et al [232] used the sequence CKAAKN, which recognizes the Frizzled receptor of the WNT pathway (see above and below) to functionalize polymeric magnetic nanoparticles which selectively accumulated into pancreatic cancer cells (vs. non-cancerous cells) in vitro. In a recent study by Dókus et al [233] the conjugated drug was daunomycin, connected to the peptide via an aminooxyacetyl moiety, which allows the release of an active metabolite in lysosomes. Various constructs were tested in SCID mice carrying PANC-1 subcutaneous tumors.…”

Section: Peptides As Delivery Agentsmentioning

confidence: 99%

“…The best results were obtained using the sequence SKAAKN (rather than CKAAKN), and linking two molecules of daunomycin to the targeting peptide via the introduction of another lysine. Two copies of the Cathepsin B-sensitive sequence GFLG were also introduced, so that the final molecule (n. 4 in the paper) was (Dau)-GFLG-K(Dau)-GFLG-SKAAKN [233]. However, only a relatively modest decrease of tumor growth was obtained.…”

Section: Peptides As Delivery Agentsmentioning

confidence: 99%

Targeting Pancreatic Ductal Adenocarcinoma (PDAC)

Parrasia

Zoratti

Szabó

et al. 2020

Cell Physiol Biochem

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Pancreatic cancers are among the most ominous, and among the most studied. Their complexities have provided ample material for a huge investigative effort, which is briefly surveyed in this review. Eradication by surgery has proven extremely difficult, and a successful chemotherapeutic approach is desperately needed. Treatment with "traditional" anticancer drugs, such as benchmark gemcitabine or the current standard-of-care FOLFIRINOX quaternary combination increase the mean overall survival by only a few months and often leads to chemoresistance. Much work is therefore currently devoted to potentiating our pharmacological weapons by accurate targeting and, in particular, by acting on the dense tumoral stroma, a distinctive feature of PDAC accounting for much of the therapeutic difficulty. We give an overview of recent developments, touching on the major aspects of PDAC physiology and biochemistry, currently-used and experimental drugs, and targeting technologies under development. A few papers are discussed in some detail to help provide a sense of how the field is moving.

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“…The main fragmentation pathway for daunomycin is the cleavage of the glycosidic bond, with the charge residing either on the aglycon part or on the sugar moiety, which co-occurs with secondary dissociation mechanisms for each fragment [16]. Furthermore, daunomycin conjugates also show extensive fragmentation under the standard ESI-MS workflow that uses slightly acidic solvents [14,[17][18][19]. When the drug moiety is attached via oxime bond to the tumor targeting peptides, the cleavage of the sugar moiety from the daunomycin is the most prominent fragmentation pathway [14].…”

Section: Introductionmentioning

confidence: 99%

Structural Characterization of Daunomycin-Peptide Conjugates by Various Tandem Mass Spectrometric Techniques

Borbély

Pethő

Szabó

et al. 2021

IJMS

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The use of peptide-drug conjugates has generated wide interest as targeted antitumor therapeutics. The anthracycline antibiotic, daunomycin, is a widely used anticancer agent and it is often conjugated to different tumor homing peptides. However, comprehensive analytical characterization of these conjugates via tandem mass spectrometry (MS/MS) is challenging due to the lability of the O-glycosidic bond and the appearance of MS/MS fragment ions with little structural information. Therefore, we aimed to investigate the optimal fragmentation conditions that suppress the prevalent dissociation of the anthracycline drug and provide good sequence coverage. In this study, we comprehensively compared the performance of common fragmentation techniques, such as higher energy collisional dissociation (HCD), electron transfer dissociation (ETD), electron-transfer higher energy collisional dissociation (EThcD) and matrix-assisted laser desorption/ionization–tandem time-of-flight (MALDI-TOF/TOF) activation methods for the structural identification of synthetic daunomycin-peptide conjugates by high-resolution tandem mass spectrometry. Our results showed that peptide backbone fragmentation was inhibited by applying electron-based dissociation methods to conjugates, most possibly due to the “electron predator” effect of the daunomycin. We found that efficient HCD fragmentation was largely influenced by several factors, such as amino acid sequences, charge states and HCD energy. High energy HCD and MALDI-TOF/TOF combined with collision induced dissociation (CID) mode are the methods of choice to unambiguously assign the sequence, localize different conjugation sites and differentiate conjugate isomers.

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Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer

Cited by 25 publications

References 34 publications

Peptide-Based Drug Delivery Systems

Peptide-Based Drug Delivery Systems

Targeting Pancreatic Ductal Adenocarcinoma (PDAC)

Structural Characterization of Daunomycin-Peptide Conjugates by Various Tandem Mass Spectrometric Techniques

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