Screening of Polymer-Based Drug Delivery Vehicles Targeting Folate Receptors in Triple-Negative Breast Cancer

Das, Debarshi; Koirala, Nischal; Li, Xin; Khan, Nazir Ahmad; Dong, Franklin; Zhang, William; Mulay, Prajakatta; Shrikhande, Gayatri; Puskás, Judit E.; Drazba, Judy; McLennan, Gordon

doi:10.1016/j.jvir.2020.05.010

Cited by 8 publications

(8 citation statements)

References 27 publications

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“…FA-targeted compounds have been shown to be internalized by FR-mediated endocytosis [ 2 , 3 , 21 , 22 , 24 ]. The cellular uptake mechanism was not investigated in detail in this work, but based on Luo et al’s work [ 31 ], we theorize that the main pathway is clathrin-mediated endocytosis due to the size of the dPEG [ 32 ], perhaps assisted by caveolae-mediated endocytosis as suggested.…”

Section: Resultsmentioning

confidence: 99%

“…Against this background, we set out to investigate monodisperse PDCs with precise functionalities and covalently attached drugs. This new class of PDCs is based on monodisperse functionalized poly(ethylene glycol) (“discrete” or dPEG), carrying exactly two FA-targeting groups and two doxorubicin (DOX) on each molecule, and are to be produced by patented chemo-enzymatic routes [ 2 , 24 , 25 , 26 , 27 ]. The design was based on the University of Michigan’s fundamental studies and our own investigations.…”

Section: Introductionmentioning

confidence: 99%

“…FA-FL-FA had better endocytosis than FA-FL. Comparison of FA-FL-PEG-FL-FA-containing PEG with M n = 1000 and 2000 g/mol and dPEG 20 (“discreet” PEG with precisely 20 repeat units with no polydispersity) demonstrated the best uptake for dPEG in both MDA-MB-231 (Caucasian) and MDA-MB-468 (African American, less FR) triple-negative breast cancer (TNBC) cell lines [ 2 , 24 ]. This was the first example of using dPEG in FR-targeted PDCs.…”

Section: Introductionmentioning

confidence: 99%

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Folate-Targeted Monodisperse PEG-Based Conjugates Made by Chemo-Enzymatic Methods for Cancer Diagnosis and Treatment

Nagy

Tóth

Pállinger

et al. 2021

IJMS

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This paper focuses on preliminary in vitro and in vivo testing of new bivalent folate-targeted PEGylated doxorubicin (DOX) made by modular chemo-enzymatic processes (FA2-dPEG-DOX2). A unique feature is the use of monodisperse PEG (dPEG). The modular approach with enzyme catalysis ensures exclusive γ-conjugation of folic acid, full conversion and selectivity, and no metal catalyst residues. Flow cytometry analysis showed that at 10 µM concentration, both free DOX and FA2-dPEG-DOX2 would be taken up by 99.9% of triple-negative breast cancer cells in 2 h. Intratumoral injection to mice seemed to delay tumor growth more than intravenous delivery. The mouse health status, food, water consumption, and behavior remained unchanged during the observation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Folate-Targeted Monodisperse PEG-Based Conjugates Made by Chemo-Enzymatic Methods for Cancer Diagnosis and Treatment

Nagy

Tóth

Pállinger

et al. 2021

IJMS

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“…In the United States, 1 in every 8 women (13%) is at risk of developing BC in their lifetime, and 1 in every 39 women (3%) is at risk of dying from BC [ 2 , 3 ]. While BC may commonly be perceived as a single disease, it is heterogeneous and phenotypically diverse, with a prognosis widely dependent on the underlying genetic aberration(s) [ 4 ]. Based on the molecular subtypes (gene expression), BC can be classified into four main molecular subtypes: Luminal A (ER+ (ER: estrogen receptor] and/or PR+ (PR: progesterone receptor), HER2− (HER2: human epidermal growth factor receptor 2), and low Ki67 (<14%)); Luminal B (ER+ and/or PR+ and HER2+(luminal HER2 group); ER+ and/or PR+, HER2−, and high Ki67 (>14%)); HER2-enriched (ER−, PR−, and HER2+); and basal-like or triple-negative (TNBC) (ER−, PR−, HER2−, and CK5/6 and/or EGFR+) [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity

Koirala

Dey

Aske

et al. 2022

IJMS

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The development of HER2-targeted therapies has dramatically improved patient survival and patient management and increased the quality of life in the HER2+ breast cancer patient population. Due to the activation of compensatory pathways, patients eventually suffer from resistance to HER2-directed therapies and develop a more aggressive disease phenotype. One of these mechanisms is the crosstalk between ER and HER2 signaling, especially the CDK4/6-Cyclin D-Rb signaling axis that is commonly active and has received attention for its potential role in regulating tumor progression. CDK 4/6 inhibitors interfere with the binding of cell-cycle-dependent kinases (CDKs) with their cognate partner cyclins, and forestall the progression of the cell cycle by preventing Rb phosphorylation and E2F release that consequentially leads to cancer cell senescence. CDK 4/6 inhibitors, namely, palbociclib, ribociclib, and abemaciclib, in combination with anti-estrogen therapies, have shown impressive outcomes in hormonal receptor-positive (HR+) disease and have received approval for this disease context. As an extension of this concept, preclinical/clinical studies incorporating CDK 4/6 inhibitors with HER2-targeted drugs have been evaluated and have shown potency in limiting tumor progression, restoring therapeutic sensitivity, and may improving the management of the disease. Currently, several clinical trials are examining the synergistic effects of CDK 4/6 inhibitors with optimized HER2-directed therapies for the (ER+/-) HER2+ population in the metastatic setting. In this review, we aim to interrogate the burden of HER2+ disease in light of recent treatment progress in the field and examine the clinical benefit of CDK 4/6 inhibitors as a replacement for traditional chemotherapy to improve outcomes in HER2+ breast cancer.

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“…We investigated monodisperse PDCs based on PEG, specifically, dPEG (discrete PEG with Đ = 1). First, we synthesized fluorescein (FL)-labeled PEGs containing two FA (FA-FL-PEG-FL-FA, in comparison with compounds with one or two FA (FA-FL, and FA-FL-FA), all made by chemo-enzymatic methods with excellent yield (95%+) and selectivity (100%) [ 21 ]. FA-FL-FA with two FA showed better endocytosis in both MDA-MB-231 (Caucasian) and MDA-MB-468 (African American, less FR) triple-negative breast cancer (TNBC) cell lines than FA-FL with a single targeting group.…”

Section: Introductionmentioning

confidence: 99%

Multifunctional PEG Carrier by Chemoenzymatic Synthesis for Drug Delivery Systems: In Memory of Professor Andrzej Dworak

Puskás

Shrikhande²,

Krisch

et al. 2022

Polymers

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This paper describes the synthesis and characterization of new bivalent folate-targeted PEGylated doxorubicin (FA2-dPEG-DOX2) made by modular chemo-enzymatic processes using Candida antarctica lipase B (CALB) as a biocatalyst. Unique features are the use of monodisperse PEG (dPEG) and the synthesis of thiol-functionalized folic acid yielding exclusive γ-conjugation of folic acid (FA) to dPEG. The polymer-based drug conjugate is built up by a series of transesterification and Michael addition reactions all catalyzed be CALB. In comparison with other methods in the literature, the modular approach with enzyme catalysis leads to selectivity, full conversion and high yield, and no transition metal catalyst residues. The intermediate product with four acrylate groups is an excellent platform for Michael-addition-type reactions for a wide variety of biologically active molecules. The chemical structures were confirmed by nuclear magnetic resonance spectroscopy (NMR). Flow cytometry analysis showed that, at 10 µM concentration, both free DOX and FA2-dPEG-DOX2 were taken up by 99.9% of triple-negative breast cancer cells in 2 h. Fluorescence was detected for 5 days after injecting compound IV into mice. Preliminary results showed that intra-tumoral injection seemed to delay tumor growth more than intravenous delivery.

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Screening of Polymer-Based Drug Delivery Vehicles Targeting Folate Receptors in Triple-Negative Breast Cancer

Cited by 8 publications

References 27 publications

Folate-Targeted Monodisperse PEG-Based Conjugates Made by Chemo-Enzymatic Methods for Cancer Diagnosis and Treatment

Folate-Targeted Monodisperse PEG-Based Conjugates Made by Chemo-Enzymatic Methods for Cancer Diagnosis and Treatment

Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity

Multifunctional PEG Carrier by Chemoenzymatic Synthesis for Drug Delivery Systems: In Memory of Professor Andrzej Dworak

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