Imaging of doxorubicin release from theranostic macromolecular prodrugs via fluorescence resonance energy transfer

Krüger, Harald Rune; Schütz, Irene; Justies, Aileen; Licha, Kai; Welker, Pia; Haucke, Volker; Calderón, Marcelo

doi:10.1016/j.jconrel.2014.08.018

Cited by 47 publications

(42 citation statements)

References 39 publications

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“…Finally, PEGylation with PEG‐mal (2 kDa) renders the final conjugates. The two modified DOX prodrugs (DOX‐EMCH and DOX‐mal) were synthesized according to scientific literature procedures and their structures are depicted in Figure .…”

Section: Resultsmentioning

confidence: 99%

“…Maleimido‐poly(ethylene glycol) (PEG‐mal) with MW = 2 kDa was purchased from Rapp Polymer, Germany. The hydrazone derivative of DOX (DOX‐EMCH) was prepared as described previously and the noncleavable control DOX‐mal was prepared according to published procedures . Dendritic PG (average MW 10 kDa, polydispersity index (PDI) = 1.6, ≈135 OH groups) was prepared according to published procedure .…”

Section: Methodsmentioning

confidence: 99%

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PEGylated Dendritic Polyglycerol Conjugate Delivers Doxorubicin to the Parasitophorous Vacuole in Leishmania infantum Infections

Gutiérrez-Corbo

Domínguez-Asenjo

Vossen

et al. 2017

Macromolecular Bioscience

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Most drugs against visceral leishmaniasis must be administered parenterally. A controlled drug release at the target site can improve the efficacy and toxicity of antileishmanial drugs in clinical use. Amastigotes live and grow inside the parasitophorous vacuole of host resident macrophages. Therefore, antileishmanial drugs should accumulate in this compartment to kill the parasite and do not produce toxicity to the cell host. PEGylated dendritic polyglycerol conjugates (PG‐PEG) can ensure a controlled drug release and the immune activation efficiency of the host. A dendritic PG conjugate with doxorubicin (DOX) attached through a pH‐cleavable hydrazone linker (PG‐DOX(pH)‐PEG), is tested on murine macrophage cell lines and on ex vivo infected BALB/c splenocytes. As a control, a dendritic PG conjugate attached via a non‐cleavable linker (PG‐DOX(non)‐PEG) is used. DOX fluorescence is useful to monitor the fate of the drug inside the infected cells by flow cytometry and confocal microscopy. The results show that PG‐DOX(pH)‐PEG slowly releases DOX inside the targeted macrophages, protecting the host of toxic drug concentrations. In addition, unlike free DOX, PG‐DOX(pH)‐PEG is actively internalized through the acidic endocytic pathway and colocalized surrounding the amastigotes. These results prove that PG‐DOX(pH)‐PEG is a promising candidate for releasing antileishmanial drugs in a controlled manner.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

PEGylated Dendritic Polyglycerol Conjugate Delivers Doxorubicin to the Parasitophorous Vacuole in Leishmania infantum Infections

Gutiérrez-Corbo

Domínguez-Asenjo

Vossen

et al. 2017

Macromolecular Bioscience

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“…The FRET effect, a non-radiative energy transfer process between an excited donor and a proximal ground state acceptor, has recently been used in pharmaceutical science for a variety of detection purposes [37-39]. In our design, FITC was incorporated at the terminal ends of the HPMA copolymers while Dabcyl, the acceptor, was integrated into the peptidic/PEG linkers.…”

Section: Resultsmentioning

confidence: 99%

Cathepsin S-cleavable, multi-block HPMA copolymers for improved SPECT/CT imaging of pancreatic cancer

et al. 2016

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This work continues our efforts to improve the diagnostic and radiotherapeutic effectiveness of nanomedicine platforms by developing approaches to reduce the non-target accumulation of these agents. Herein, we developed multi-block HPMA copolymers with backbones that are susceptible to cleavage by cathepsin S, a protease that is abundantly expressed in tissues of the mononuclear phagocyte system (MPS). Specifically, a bis-thiol terminated HPMA telechelic copolymer containing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was synthesized by reversible addition−fragmentation chain transfer (RAFT) polymerization. Three maleimide modified linkers with different sequences, including cathepsin S degradable oligopeptide, scramble oligopeptide and oligo ethylene glycol, were subsequently synthesized and used for the extension of the HPMA copolymers by thiol–maleimide click chemistry. All multi-block HPMA copolymers could be labeled by 177Lu with high labeling efficiency and exhibited high serum stability. In vitro cleavage studies demonstrated highly selective and efficient cathepsin S mediated cleavage of the cathepsin S-susceptible multi-block HPMA copolymer. A modified multi-block HPMA copolymer series capable of Förster Resonance Energy Transfer (FRET) was utilized to investigate the rate of cleavage of the multi-block HPMA copolymers in monocyte-derived macrophages. Confocal imaging and flow cytometry studies revealed substantially higher rates of cleavage for the multi-block HPMA copolymers containing the cathepsin S-susceptible linker. The efficacy of the cathepsin S-cleavable multi-block HPMA copolymer was further examined using an in vivo model of pancreatic ductal adenocarcinoma. Based on the biodistribution and SPECT/CT studies, the copolymer extended with the cathepsin S susceptible linker exhibited significantly faster clearance and lower non-target retention without compromising tumor targeting. Overall, these results indicate that exploitation of the cathepsin S activity in MPS tissues can be utilized to substantially lower non-target accumulation, suggesting this is a promising approach for the development of diagnostic and radiotherapeutic nanomedicine platforms.

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“…Further, incorporation of the CD12 ligand NGR tripeptide and α V β 3 ligand RGD into the N-terminus of diblock ELP copolymers [V 1 A 8 G 7 ] 64 /ELP[V] 90 stimulates self-assembly into monodisperse spherical micelles presenting targeting ligands on theirs coronas and enhances binding activity as well as tumor vasculature-specific localization 23-24. Unique features in cancer cells, such as overexpression of several receptors 25-26, up-regulation of certain enzymes, and lower pH 27-28, can be used in the development of several targeted drug carriers. Likewise, Interleukin-4 receptor (IL-4R) is highly expressed in a wide variety of solid tumors and confers resistance against drug-induced cancer cell death 29-30.…”

Section: Introductionmentioning

confidence: 99%

Multivalent Targeting Based Delivery of Therapeutic Peptide using AP1-ELP Carrier for Effective Cancer Therapy

Sarangthem¹,

Kim²,

Singh³

et al. 2016

Theranostics

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Elastin-like polypeptide (ELP)-based drug delivery has been utilized for various applications including cancer therapies for many years. Genetic incorporation of internalization ligands and cell-targeting peptides along with ELP polymer enhanced tumor accumulation and retention time as well as stability and activities of the drug conjugates. Herein, we described a unique delivery system comprised of genetically engineered ELP incorporated with multiple copies of IL-4 receptor targeting peptide (AP1) periodically and proapoptotic peptide (KLAKLAK)2 referred to as AP1-ELP-KLAK. It triggered thermal-responsive self-assembly into a nanoparticle-like structure at physiological body temperature and stabilized its helical conformation, which is critical for its membrane-disrupting activities. Increased IL-4 receptor specific cellular internalization was associated with the enhanced cytotoxic effect of (KLAKLAK)2 peptide. Additionally, multivalent presentation of targeting ligands by AP1-ELP-KLAK significantly enhanced intratumoral localization and prolonged the retention time compared to ELP-KLAK, non-targeted control. Systemic administration of AP1-ELP-KLAK significantly inhibited tumor growth by provoking cell apoptosis in various tumor xenograft models without any specific organ toxicity. Thus, our newly designed AP1-ELP-KLAK polymer nanoparticle is a promising candidate for effective cancer therapy and due to the simple preparative procedures of ELPs, this platform can be used as a good carrier for tumor-specific delivery of other therapeutics.

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Imaging of doxorubicin release from theranostic macromolecular prodrugs via fluorescence resonance energy transfer

Cited by 47 publications

References 39 publications

PEGylated Dendritic Polyglycerol Conjugate Delivers Doxorubicin to the Parasitophorous Vacuole in Leishmania infantum Infections

PEGylated Dendritic Polyglycerol Conjugate Delivers Doxorubicin to the Parasitophorous Vacuole in Leishmania infantum Infections

Cathepsin S-cleavable, multi-block HPMA copolymers for improved SPECT/CT imaging of pancreatic cancer

Multivalent Targeting Based Delivery of Therapeutic Peptide using AP1-ELP Carrier for Effective Cancer Therapy

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