Multivalent protein-drug conjugates – An emerging strategy for the upgraded precision and efficiency of drug delivery to cancer cells

Porębska, Natalia; Ciura, Krzysztof; Chorążewska, Aleksandra; Zakrzewska, Małgorzata; Otlewski, Jacek; Opaliński, Łukasz

doi:10.1016/j.biotechadv.2023.108213

Cited by 10 publications

(3 citation statements)

References 214 publications

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“…Points to consider when investigating this approach for drug delivery to cancer cells include the following: the specificity of the tumor target, whether the target is found on healthy cells, and is it the only or predominant moiety recognized by the binding protein; is it affected by the number of binding antibodies/number of receptors expressed on the surface of target cells; is the carrier taken up readily by tumor cells and the drug readily released within them; how long does the drug remain effective; are other cells affected by released drug; do patients that fall into different classifications of the cancer respond similarly; and how easily can the particles be made, purified, and transported. As of 2023, 14 antibody-drug combinations had received FDA approval, and many more protein-drug combinations are under investigation [165]. An example of this approach is the use of a humanized murine IgG4 anti-CD33 (siglec 3) antibody to target gemtuzumab ozogamicin (GO) in acute myeloid leukemia cells.…”

Section: Use and Possible Advantages Of Multivalency When Targeting B...mentioning

confidence: 99%

The Ying and Yang of Ganglioside Function in Cancer

Schengrund

2023

Cancers

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The plethora of information about the expression of cancer cell-associated gangliosides, their role(s) in signal transduction, and their potential usefulness in the development of cancer treatments makes this an appropriate time to review these enigmatic glycosphingolipids. Evidence, reflecting the work of many, indicates that (1) expression of specific gangliosides, not generally found in high concentrations in most normal human cells, can be linked to certain types of cancer. (2) Gangliosides can affect the ability of cells to interact either directly or indirectly with growth factor receptors, thereby changing such things as a cell’s mobility, rate of proliferation, and metastatic ability. (3) Anti-ganglioside antibodies have been tested, with some success, as potential treatments for certain cancers. (4) Cancer-associated gangliosides shed into the circulation can (a) affect immune cell responsiveness either positively or negatively, (b) be considered as diagnostic markers, and (c) be used to look for recurrence. (5) Cancer registries enable investigators to evaluate data from sufficient numbers of patients to obtain information about potential therapies. Despite advances that have been made, a discussion of possible approaches to identifying additional treatment strategies to inhibit metastasis, responsible for the majority of deaths of cancer patients, as well as for treating therapy-resistant tumors, is included.

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Section: Use and Possible Advantages Of Multivalency When Targeting B...mentioning

confidence: 99%

The Ying and Yang of Ganglioside Function in Cancer

Schengrund

2023

Cancers

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“…The evolution of ADCs has greatly expanded personalized tumor therapy, leveraging their unique structure for precise targeting and minimal off-target toxicity in ideal conditions. In the structural design of ADCs, the majority are either based on IgG design or created utilizing multivalent proteins [ 12 ], peptides [ 13 , 14 ], multi-structured fusion proteins [ 15 ], and other small-molecule proteins [ 16 ] or mini-peptides [ 11 ]. However, in actual clinical research, the bind site barrier is a pivotal impediment hindering the development of ADCs [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

A humanized trivalent Nectin-4-targeting nanobody drug conjugate displays potent antitumor activity in gastric cancer

Wu,

Zhu,

Sun

et al. 2024

J Nanobiotechnol

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Background Gastric cancer represents a highly lethal malignancy with an elevated mortality rate among cancer patients, coupled with a suboptimal postoperative survival prognosis. Nectin-4, an overexpressed oncological target for various cancers, has been exploited to create antibody-drug conjugates (ADCs) to treat solid tumors. However, there is limited research on Nectin-4 ADCs specifically for gastric cancer, and conventional immunoglobulin G (IgG)-based ADCs frequently encounter binding site barriers. Based on the excellent tumor penetration capabilities inherent in nanobodies (Nbs), we developed Nectin-4-targeting Nb drug conjugates (NDCs) for the treatment of gastric cancer. Results An immunized phage display library was established and employed for the selection of Nectin-4-specific Nbs using phage display technology. Subsequently, these Nbs were engineered into homodimers to enhance Nb affinity. To prolong in vivo half-life and reduce immunogenicity, we fused an Nb targeting human serum albumin (HSA), resulting in the development of trivalent humanized Nbs. Further, we site-specifically conjugated a monomethyl auristatin E (MMAE) at the C-terminus of the trivalent Nbs, creating Nectin-4 NDC (huNb26/Nb26-Nbh-MMAE) with a drug-to-antibody ratio (DAR) of 1. Nectin-4 NDC demonstrated excellent in vitro cell-binding activities and cytotoxic efficacy against cells with high Nectin-4 expression. Subsequent administration of Nectin-4 NDC to mice bearing NCI-N87 human gastric cancer xenografts demonstrated rapid tissue penetration and high tumor uptake through in vivo imaging. Moreover, Nectin-4 NDC exhibited noteworthy dose-dependent anti-tumor efficacy in in vivo studies. Conclusion We have engineered a Nectin-4 NDC with elevated affinity and effective tumor uptake, further establishing its potential as a therapeutic agent for gastric cancer. Graphical abstract

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“…Therefore, developing thermoresponsive and multifunctional nanosystems is novel and propagatory towards nanobioapplications as well real real-time industrial usage. Until now, quantum dots (QDTs) [11][12][13][14][15], carbon nanotubes (CNTs) [16][17][18], nanowires, nanorods, coreshell nanoparticles, micelles, etc., have been reported to their kind but thermoresponsive and morphologically modifiable [(PLA)-b-(Car)] based 1) frustum shaped nanoparticles, 2) elliptical cone shaped nanoparticles and 3) dome-shaped nanoparticles with huge porosity is newer and interesting concept to evaluate the catalytic activity for biomedical regulations [19][20][21]. Consequently, Scheme 1 deliberates steps involved in the synthesis of [(PLA)-b-(Car)] followed by the design and development of different types of nanoparticles and their stimuliresponsive catalytic activity through the fluorescence measurement of [(Cys)-(Au + )] [22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Thermoresponsive [(PLA)-b-(Car)] based frustum-shaped capsules with extended porosity for biosensing and biomedical applications

Pawar,

Luo,

Rokkala

et al. 2024

Preprint

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We present, a facile method for the synthesis of block co-polymer of [(PLA)-b-(Car)], (PLA-Poly Lactic acid and Car-Carbazole) followed by the development of cone and ice-cream cup-shaped frustums with nanoporous capsules for bio-sensing and drug loading applications. Thermoplastic polyester PLA aminated with an aromatic heterocyclic organic compound Car gives the desired shape and characteristics of the capsules with extended porosity on the surface. The size, shape, and morphology of the capsules are tunable concerning solvents and thermal treatment. Interestingly, the synthesis and development of nanoporous hollow (half-broken coconut type) capsules has been carried out without using any precursors and surfactants. Synthesis of [(PLA)-b-(Car)] has been confirmed through the Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR; 1H and 13C). However, the morphology and surface properties of capsules were confirmed through field emission scanning electron microscopy (FE-SEM), Bruner Emmett Teller (BET), and atomic force microscopy (AFM) characterizations. The capsule size ranges from ~200 nm to 1 µm (in diameter) and porosity scales from ~60 to 80 nm. The hollow and porous surface of the capsules with biosensing and biomedical applications can be considered as a unique and novel characteristic property of our invention. This kind of novel cone and ice cream cup-shaped hollow frustums can be used as a stimuli-responsive catalytic activity through the fluorescence measurement of cysteine and gold nanoparticle [(Cys)-(Au+)] for enhanced payload and biomedical applications.

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Multivalent protein-drug conjugates – An emerging strategy for the upgraded precision and efficiency of drug delivery to cancer cells

Cited by 10 publications

References 214 publications

The Ying and Yang of Ganglioside Function in Cancer

The Ying and Yang of Ganglioside Function in Cancer

A humanized trivalent Nectin-4-targeting nanobody drug conjugate displays potent antitumor activity in gastric cancer

Thermoresponsive [(PLA)-b-(Car)] based frustum-shaped capsules with extended porosity for biosensing and biomedical applications

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