Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?

Fu, Chen; Yu, Lifeng; Miao, Yuxi; Liu, Xinli; Yu, Zhaojin; Wei, Minjie

doi:10.1016/j.apsb.2022.07.020

Cited by 58 publications

(46 citation statements)

References 171 publications

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“…However, increasing the number of PEG units in the linker region increased the observed hemolysis of RBCs at high PDC concentrations (e.g., 32 μmol and above), an unexpected result as PEG incorporation is considered to be nontoxic. 18 Hemolysis caused by PDCs containing cell-penetrating peptides has been previously reported, 19,21 reinforcing that careful conjugate design, including discriminant use of linkers, is important to maximize the therapeutic window by improving drug efficacy without increasing harmful effects.…”

Section: ■ Results and Discussionmentioning

confidence: 91%

“…Inspired by the emerging success of drug conjugates in cancer therapeutics, including the demonstrated ability of a PDIP analogue to deliver a cell impermeable peptide cargo inside cancer cells, , we sought to develop peptide–drug conjugates (PDCs) as novel antimalarials. While PDCs have been widely employed for cancer applications, this approach is underexplored in the context of intracellular pathogens such as malaria. − …”

Section: Introductionmentioning

confidence: 99%

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Development of Antiplasmodial Peptide–Drug Conjugates Using a Human Protein-Derived Cell-Penetrating Peptide with Selectivity for Infected Cells

Palombi,

Lawrence,

White

et al. 2023

Bioconjugate Chem.

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Malaria continues to impose a global health burden. Drug-resistant parasites have emerged to each introduced small-molecule therapy, highlighting the need for novel treatment approaches for the future eradication of malaria. Herein, targeted drug delivery with peptide–drug conjugates (PDCs) was investigated as an alternative antimalarial therapy, inspired by the success of emerging antibody–drug conjugates utilized in cancer treatment. A synthetic peptide derived from an innate human defense molecule was conjugated to the antimalarial drug primaquine (PQ) to produce PDCs with low micromolar potency toward Plasmodium falciparum in vitro. A suite of PDCs with different design features was developed to identify optimal conjugation site and investigate linker length, hydrophilicity, and cleavability. Conjugation within a flexible spacer region of the peptide, with a cleavable linker to liberate the PQ cargo, was important to retain activity of the peptide and drug.

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Section: ■ Results and Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Development of Antiplasmodial Peptide–Drug Conjugates Using a Human Protein-Derived Cell-Penetrating Peptide with Selectivity for Infected Cells

Palombi,

Lawrence,

White

et al. 2023

Bioconjugate Chem.

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show abstract

“…In this context, a new self-assembly method to form pectindiydroartemis in hydroxycamptothecin nanoparticles to PDC delivery by the oral route is worth mentioning. It could improve drug loading and release [ 209 , 229 ].…”

Section: Challenges For the Delivery Of Peptide-drug Conjugates: The ...mentioning

confidence: 99%

Peptide-Drug Conjugates: A New Hope for Cancer Management

et al. 2022

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Cancer remains the leading cause of death worldwide despite advances in treatment options for patients. As such, safe and effective therapeutics are required. Short peptides provide advantages to be used in cancer management due to their unique properties, amazing versatility, and progress in biotechnology to overcome peptide limitations. Several appealing peptide-based therapeutic strategies have been developed. Here, we provide an overview of peptide conjugates, the better equivalents of antibody-drug conjugates, as the next generation of drugs for required precise targeting, enhanced cellular permeability, improved drug selectivity, and reduced toxicity for the efficient treatment of cancers. We discuss the basic components of drug conjugates and their release action, including the release of cytotoxins from the linker. We also present peptide-drug conjugates under different stages of clinical development as well as regulatory and other challenges.

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“…These advantages recently led to the authorisation of three PDCs for clinical use in cancer: vipivotide tetraxetan, melphalan flufenamide and a somatostatin derivative, 177 Lu-DOTATATE [ 9 , 10 , 11 , 12 ]. Several others, such as Bicycle Therapeutics’ BT1718, BT5528 and BT8009, Cybrexa’s CBX-12 and Shenogen’s SNG1005, are undergoing clinical trials [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting the Gastrin-Releasing Peptide Receptor (GRP-R) in Cancer Therapy: Development of Bombesin-Based Peptide–Drug Conjugates

Gomena

Vári

Oláh-Szabó

et al. 2023

IJMS

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Targeted tumour therapy has proved to be an efficient alternative to overcome the limitations of conventional chemotherapy. Among several receptors upregulated in cancer cells, the gastrin-releasing peptide receptor (GRP-R) has recently emerged as a promising target for cancer imaging, diagnosing and treatment due to its overexpression on cancerous tissues such as breast, prostate, pancreatic and small-cell lung cancer. Herein, we report on the in vitro and in vivo selective delivery of the cytotoxic drug daunorubicin to prostate and breast cancer, by targeting GRP-R. Exploiting many bombesin analogues as homing peptides, including a newly developed peptide, we produced eleven daunorubicin-containing peptide–drug conjugates (PDCs), acting as drug delivery systems to safely reach the tumour environment. Two of our bioconjugates revealed remarkable anti-proliferative activity, an efficient uptake by all three tested human breast and prostate cancer cell lines, high stability in plasma and a prompt release of the drug-containing metabolite by lysosomal enzymes. Moreover, they revealed a safe profile and a consistent reduction of the tumour volume in vivo. In conclusion, we highlight the importance of GRP-R binding PDCs in targeted cancer therapy, with the possibility of further tailoring and optimisation.

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Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?

Cited by 58 publications

References 171 publications

Development of Antiplasmodial Peptide–Drug Conjugates Using a Human Protein-Derived Cell-Penetrating Peptide with Selectivity for Infected Cells

Development of Antiplasmodial Peptide–Drug Conjugates Using a Human Protein-Derived Cell-Penetrating Peptide with Selectivity for Infected Cells

Peptide-Drug Conjugates: A New Hope for Cancer Management

Targeting the Gastrin-Releasing Peptide Receptor (GRP-R) in Cancer Therapy: Development of Bombesin-Based Peptide–Drug Conjugates

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