Effective doxorubicin-based nano-therapeutics for simultaneous malignant lymphoma treatment and lymphoma growth imaging

Etrych, Tomáš; Daumová, Lenka; Pokorná, Eva; Tuskova, Diana; Lidický, Ondřej; Kolarova, V.; Pankrác, Jan; Šefc, Luděk; Chytil, Petr; Klener, Pavel

doi:10.1016/j.jconrel.2018.09.018

Cited by 33 publications

(17 citation statements)

References 25 publications

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“…First, the fluorescently labeled star copolymer was synthesized by Cy7-NHS-ester attachment to hydrazide groups of polymer 2, thus forming a hydrazide bond, which is stable in a physiological environment. Afterward, the polymer conjugate pHPMA-Dox-Cy7, containing Dox bound via pH-sensitive hydrazone bond, was synthesized using the condensation of hydrazide groups of the Cy7-labeled polymer precursors 2 with keto group of Dox, according to the previously described procedure [ 24 ]. The final star polymer was freed of unbound Dox and fluorescence dye using GPC chromatography, using columns filled with Sephadex LH-20 and methanol as eluent.…”

Section: Methodsmentioning

confidence: 99%

Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment

Noack

Lucas

Chytil

et al. 2020

IJMS

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Stimulus-sensitive polymer drug conjugates based on high molecular weight N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers carrying doxorubicin via a pH-dependent cleavable bond (pHPMA-Dox) were previously shown to be able to overcome multi-drug resistance. Nevertheless, a tumor type dependent differential response was observed. Although an improved and more selective tumor accumulation of pHPMA-Dox is generally achieved due to the enhanced permeability and retention (EPR) effect, little is known about the fate of these conjugates upon entering the tumor tissue, which could explain the different responses. In this study, we compared in vitro and in vivo accumulation and Dox-activation of pHPMA-Dox in three cancer cell line models (1411HP, A2780cis, HT29) and derived xenograft tumors using a near-infrared fluorescence-labeled pHPMA-Dox conjugate. Firstly, cytotoxicity assays using different pH conditions proved a stepwise, pH-dependent increase in cytotoxic activity and revealed comparable sensitivity among the cell lines. Using multispectral fluorescence microscopy, we were able to track the distribution of drug and polymeric carrier simultaneously on cellular and histological levels. Microscopic analyses of cell monolayers confirmed the assumed mechanism of cell internalization of the whole conjugate followed by intracellular cleavage and nuclear accumulation of Dox in all three cell lines. In contrast, intratumoral distribution and drug release in xenograft tumors were completely different and were associated with different tissue substructures and microenvironments analyzed by Azan- and Hypoxisense®-staining. In 1411HP tumors, large vessels and less hypoxic/acidic microenvironments were associated with a pattern resulting from consistent tissue distribution and cellular uptake as whole conjugate followed by intracellular drug release. In A2780cis tumors, an inconsistent pattern of distribution partly resulting from premature drug release was associated with a more hypoxic/acidic microenvironment, compacted tumor tissue with compressed vessels and specific pre-damaged tissue structures. A completely different distribution pattern was observed in HT29 tumors, resulting from high accumulation of polymer in abundant fibrotic structures, with small embedded vessels featuring this tumor type together with pronounced premature drug release due to the strongly hypoxic/acidic microenvironment. In conclusion, the pattern of intratumoral distribution and drug release strongly depends on the tumor substructure and microenvironment and may result in different degrees of therapeutic efficacy. This reflects the pronounced heterogeneity observed in the clinical application of nanomedicines and can be exploited for the future design of such conjugates.

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Section: Methodsmentioning

confidence: 99%

Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment

Noack

Lucas

Chytil

et al. 2020

IJMS

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“…Polymer-drug conjugates can induce this stability transition using intracellularly cleavable linkages, including acid-labile bonds (e.g., hydrazone and b-carboxylic amides), redox-sensitive bonds, and enzyme-sensitive linkers. [358][359][360][361][362][363][364][365][366][367][368][369][370][371] For noncovalently encapsulated drugs, a transition can be realized by the swelling or dissociation of the hydrophobic cores in response to low pH, ROS, enzymes, or adenosine-5 0triphosphate (ATP). [372][373][374][375][376][377][378] For instance, in the ATP-triggered stability transition, ATP-binding moieties (such as aptamers, chaperonin, phenylboronic acid, or metal ions) were integrated into the cores of the nanomedicines.…”

Section: Stimulus-responsive Polymers For Anticancer Drug and Gene Dementioning

confidence: 99%

Advanced functional polymer materials

Wang¹,

Amin²,

An³

et al. 2020

Mater. Chem. Front.

135

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“…This can be at least partially overcome by new formulations of old cytostatic agents, e.g., by encapsulation of small molecule chemotherapy agents in liposomes. The enhanced permeability and retention (EPR) effect results in passive trapping of large liposomes within the chaotic lymphoma vasculature with prolonged exposure of tumor cells to the toxic payloads, while (relatively) sparing healthy tissues [72]. However, in contrast to other hematologic malignancies including acute myelogeneous leukemia or multiple myeloma, liposomal formulations of anthracyclines or cytarabine have not yet been approved for the therapy of NHLs [73].…”

Section: Compartmentalization Of Lymphoma Cells and Survival Of Anti-mentioning

confidence: 99%

Drug Resistance in Non-Hodgkin Lymphomas

Klener

Klánová

2020

IJMS

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Non-Hodgkin lymphomas (NHL) are lymphoid tumors that arise by a complex process of malignant transformation of mature lymphocytes during various stages of differentiation. The WHO classification of NHL recognizes more than 90 nosological units with peculiar pathophysiology and prognosis. Since the end of the 20th century, our increasing knowledge of the molecular biology of lymphoma subtypes led to the identification of novel druggable targets and subsequent testing and clinical approval of novel anti-lymphoma agents, which translated into significant improvement of patients’ outcome. Despite immense progress, our effort to control or even eradicate malignant lymphoma clones has been frequently hampered by the development of drug resistance with ensuing unmet medical need to cope with relapsed or treatment-refractory disease. A better understanding of the molecular mechanisms that underlie inherent or acquired drug resistance might lead to the design of more effective front-line treatment algorithms based on reliable predictive markers or personalized salvage therapy, tailored to overcome resistant clones, by targeting weak spots of lymphoma cells resistant to previous line(s) of therapy. This review focuses on the history and recent advances in our understanding of molecular mechanisms of resistance to genotoxic and targeted agents used in clinical practice for the therapy of NHL.

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Effective doxorubicin-based nano-therapeutics for simultaneous malignant lymphoma treatment and lymphoma growth imaging

Cited by 33 publications

References 25 publications

Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment

Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment

Advanced functional polymer materials

Drug Resistance in Non-Hodgkin Lymphomas

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