Implication of linker length on cell cytotoxicity, pharmacokinetic and toxicity profile of gemcitabine-docetaxel combinatorial dual drug conjugate

Kushwah, Varun; Katiyar, Sameer S.; Agrawal, Ashish Kumar; Saraf, Isha; Singh, Inder Pal; Gupta, Ramesh C.; Jain, Sanyog

doi:10.1016/j.ijpharm.2018.07.016

Cited by 18 publications

(8 citation statements)

References 43 publications

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“…One of the problems in applying vcMMAE, especially in conjugates with high drug loading, is its hydrophobicity, a factor greatly influencing tissue penetration and specificity of cellular internalization. − We previously found that an FGF2 conjugate containing three vcMMAE molecules (FGF2 3xC -(vcMMAE) 3 ) at a concentration higher than 125 nM exhibits nonspecific cytotoxicity toward the FGFR1-negative U2OS cell line . However, there are numerous chemical derivatives of auristatin, i.e., MMAE, MMAF, MMAU, and AY, which differ in hydrophobicity, charge, and cytotoxicity. ,,, Taking into account the plan to load FGF2 with three auristatin molecules, we decided to use more hydrophilic AY.…”

Section: Discussionmentioning

confidence: 99%

Site-Specific, Stoichiometric-Controlled, PEGylated Conjugates of Fibroblast Growth Factor 2 (FGF2) with Hydrophilic Auristatin Y for Highly Selective Killing of Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1 (FGFR1)

2020

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In spite of significant progress in the field of targeted anticancer therapy, the FDA has approved only five ADC-based drugs. Hence the search for new targeted anticancer agents is an unfulfilled necessity. Here, we present novel types of protein–drug conjugates (PDCs) that exhibit superior anticancer activities. Instead of a monoclonal antibody, we used fibroblast growth factor 2 (FGF2) as a targeting molecule. FGF2 is a natural ligand of fibroblast growth factor receptor 1 (FGFR1), a transmembrane receptor overproduced in various types of cancers. We synthesized site-specific and stoichiometric-controlled conjugates of FGF2 with a highly potent, hydrophilic derivative of auristatin called auristatin Y. To increase the hydrophilicity and hydrodynamic radius of conjugates, we employed PEG4 and PEG27 molecules as a spacer between the targeting molecule and the cytotoxic payload. All conjugates were selective to FGFR1-positive cell lines, effectively internalized via the FGFR1-dependent pathway, and exhibited a highly cytotoxic effect only on FGFR1-positive cancer cell lines.

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Section: Discussionmentioning

confidence: 99%

Site-Specific, Stoichiometric-Controlled, PEGylated Conjugates of Fibroblast Growth Factor 2 (FGF2) with Hydrophilic Auristatin Y for Highly Selective Killing of Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1 (FGFR1)

2020

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“…Drug resistance of cancer cells can lead to a severe decrease in the efficiency of therapy. , The clinical and preclinical studies show that the use of drug combinations with different modes of action brings substantial improvement in antitumor activity. − One possible approach for improvement of targeted anticancer strategies could be generation of a conjugate based on targeting protein and two drugs showing different modes of cellular action. Only a few examples of dual-warhead conjugates are found in the literature. − In 2013, Sutro Biopharma presented the first data involving a dual-warhead ADC. In the developed technology, Sutro Biopharma employs incorporation of two different unnatural amino acid residues in monoclonal antibody and then coupling two distinct payloads via click-chemistry reaction .…”

Section: Discussionmentioning

confidence: 99%

Novel Method for Preparation of Site-Specific, Stoichiometric-Controlled Dual Warhead Conjugate of FGF2 via Dimerization Employing Sortase A-Mediated Ligation

2019

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Targeted therapies are rapidly evolving modalities of cancer treatment. The largest group of currently developed biopharmaceuticals is antibody−drug conjugates (ADCs). Here, we developed a new modular strategy for the generation of cytotoxic bioconjugates, containing a homodimer of targeting protein and two highly potent anticancer drugs with distinct mechanisms of action. Instead of antibody, we applied human fibroblast growth factor 2 (FGF2) as a targeting protein. We produced a conjugate of FGF2 with either monomethyl auristatin E (MMAE) or α-amanitin (αAMTN) as a cytotoxic agent and subsequently applied a sortase A-mediated ligation to obtain a dimeric conjugate containing both MMAE and αAMTN. The developed method ensures site-specific conjugation and a controlled drug-to-protein ratio. We validated our approach by demonstrating that dimeric dual warhead conjugate exhibits higher cytotoxic potency against fibroblast growth factor receptorpositive cell lines than single-warhead conjugates. Our modular technology can be applied to other targeting proteins or drugs and thus can be used for preparation of different bioconjugates.

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“…Using different lengths of PEG to modify nanoparticles can significantly influence the in vivo profiles of nanoparticles . Here, two self-illuminating photocleavable nanoprodrugs, PCLP1000 (with PEG1000 modification) and PCLP2000 (with PEG2000 modification), were synthesized, as shown in Figure A.…”

Section: Results and Discussionmentioning

confidence: 99%

Self-Illuminating Triggered Release of Therapeutics from Photocleavable Nanoprodrug for the Targeted Treatment of Breast Cancer

Sun

Wang

et al. 2022

ACS Appl. Mater. Interfaces

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Photocleavable biomaterials and bioconjugates have been widely researched for tissue engineering, cell culture, and therapeutics delivery. However, most in vivo applications of these materials or conjugates require external irradiation, and some of the light sources used such as ultraviolet (UV) light have poor tissue penetration. To address these key limitations, we synthesized a photocleavable nanoprodrug using luminol (a luminescent donor), chlorambucil (CHL, i.e., an antitumor drug with a photocleavable linker), and polyethylene glycol–folic acid conjugates (a targeted moiety) loaded onto polyamidoamine (PAMAM). The synthesized nanoprodrug can smartly release its payloads through photocleavage of photoresponsive linker by UV light, which was produced in situ by reacting luminol with pathological reactive oxygen species (ROS). The luminescence performance and absorption spectrum of this nanoprodrug was characterized in detail. In vitro cellular assays verified that the nanoprodrugs could be efficiently internalized by 4T1 and MDA-MB-231 cells, and the CHL released from the nanoprodrugs could distinctly decrease cell viability through the damage of DNA in cells. In vivo animal experiments demonstrated that the nanoprodrugs were mainly accumulated at tumor sites, and the antitumor drug CHL could be smartly released from the nanoprodrugs through cleavage of photosensitive linkers at a high level of ROS. The released CHL significantly inhibited the growth of tumors without any obvious adverse effects. Our results provide a practicable strategy to expand the in vivo application of photocleavable biomaterials and bioconjugates.

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Implication of linker length on cell cytotoxicity, pharmacokinetic and toxicity profile of gemcitabine-docetaxel combinatorial dual drug conjugate

Cited by 18 publications

References 43 publications

Site-Specific, Stoichiometric-Controlled, PEGylated Conjugates of Fibroblast Growth Factor 2 (FGF2) with Hydrophilic Auristatin Y for Highly Selective Killing of Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1 (FGFR1)

Site-Specific, Stoichiometric-Controlled, PEGylated Conjugates of Fibroblast Growth Factor 2 (FGF2) with Hydrophilic Auristatin Y for Highly Selective Killing of Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1 (FGFR1)

Novel Method for Preparation of Site-Specific, Stoichiometric-Controlled Dual Warhead Conjugate of FGF2 via Dimerization Employing Sortase A-Mediated Ligation

Self-Illuminating Triggered Release of Therapeutics from Photocleavable Nanoprodrug for the Targeted Treatment of Breast Cancer

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