Development of Novel Bisphosphonate Prodrugs of Doxorubicin for Targeting Bone Metastases That Are Cleaved pH Dependently or by Cathepsin B: Synthesis, Cleavage Properties, and Binding Properties to Hydroxyapatite As Well As Bone Matrix

Hochdörffer, Katrin; Ajaj, Khalid Abu; Schäfer-Obodozie, Cynthia; Kratz, Felix

doi:10.1021/jm300493m

Cited by 93 publications

(73 citation statements)

References 53 publications

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“…cyclo[DKP-RGD]-CH 2 NH 2 (2), [19] Fmoc-Val-Ala-N-[4-(hydroxymethyl)-phenyl] (10 a), [30] and N-(Boc)-N,N'-dimethylethylenediamine (17) [25] were prepared according to the literature procedures, and their analytical data were in agreement with those already published. The synthetic procedures for the preparation of compounds 7 and 8 are included in the Supporting Information, along with the 1 H NMR and 13 C NMR spectra, the HPLC traces of the final RGD-PTX conjugates, and the procedures for the evaluation of the cellular expression of a v b 3 integrin.…”

Section: Methodsmentioning

confidence: 71%

Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers

Corso

Caruso

Belvisi

et al. 2015

Chemistry A European J

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Two small-molecule-drug conjugates (SMDCs, 6 and 7) featuring lysosomally cleavable linkers (namely the Val-Ala and Phe-Lys peptide sequences) were synthesized by conjugation of the αvβ3-integrin ligand cyclo[DKP-RGD]-CH2NH2 (2) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP-RGD]-PTX conjugate with a nonpeptide "uncleavable" linker (8) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified αVβ3-integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8, which possesses a nonpeptide "uncleavable" linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF-CEM (αVβ3-) and its subclone CCRF-CEM αVβ3 (αVβ3+). Fairly effective integrin targeting was displayed by the cyclo[DKP-RGD]-Val-Ala-PTX conjugate (6), which was found to differentially inhibit proliferation in antigen-positive CCRF-CEM αVβ3 versus antigen-negative isogenic CCRF-CEM cells. The total lack of activity displayed by the "uncleavable" cyclo[DKP-RGD]-PTX conjugate (8) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload.

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Section: Methodsmentioning

confidence: 71%

Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers

Corso

Caruso

Belvisi

et al. 2015

Chemistry A European J

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“…Thus, linkers sensitive to enzymes or low pH could be introduced to enable selective release at resorption surfaces. For example, the peptide sequences GGGMGPSGPWGGK [75], HPGGPQ [76,77], and GGP-Nle [78], which are substrates for cathepsin K, or polyketals [79,80], acetals [80], and hydrazones [81,82 • ,83], which are acid-labile bonds, could be incorporated. By using linkers dependent on osteoclast bone catabolism, rate of release may be matched to the required regenerative response because osteoclasts appear early in the repair process, increase in number during soft and hard callus formation, and decrease during resolution [84–86].…”

Section: Controlled Drug Delivery To Bonementioning

confidence: 99%

Local and targeted drug delivery for bone regeneration

Newman

Benoit

2016

Current Opinion in Biotechnology

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While experimental bone regeneration approaches commonly employ cells, technological hurdles prevent translation of these therapies. Alternatively, emulating the spatiotemporal cascade of endogenous factors through controlled drug delivery may provide superior bone regenerative approaches. Surgically placed drug depots have clinical indications. Additionally, noninvasive systemic delivery can be used as needed for poorly healing bone injuries. However, a major hurdle for systemic delivery is poor bone biodistribution of drugs. Thus, peptides, aptamers, and phosphate-rich compounds with specificity toward proteins, cells, and molecules within the regenerative bone microenvironment may enable the design of targeted carriers with bone biodistribution greater than that achieved by drug alone. These carriers, combined with osteoregenerative drugs and/or stimuli-sensitive linkers, may enhance bone regeneration while minimizing off-target tissue effects.

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“…23, and they were shown to be viable materials for tissue regeneration and other biomedical applications. [41][42][43][44][45][46][47][48] Mineralization of polymeric hydrogel scaffolds, with the aim of mimicking bone structure for tissue engineering applications, is another interesting field in which phosphorus containing moieties can be used. 24,25 Electrospun fibrous scaffolds 26,27 and thermosets based on a dual curing process 28 are reported.…”

Section: Introductionmentioning

confidence: 99%

Phosphonate‐functionalized poly(β‐amino ester) macromers as potential biomaterials

Akyol

Tatliyuz

Duman

et al. 2018

J Biomedical Materials Res

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Biodegradability, hemocompatibility, resistance to protein adsorption, and strong interactions with hydroxyapatite (HAP)-based tissues such as dentin, enamel, and bone are important properties of phosphorus-containing biomaterials. Here, novel phosphonate-functionalized poly(β-amino ester) (PBAE) macromers are synthesized through aza-Michael addition of various diacrylates [1,6-hexanediol diacrylate (HDDA), poly(ethylene glycol) diacrylate (PEGDA, M = 575), 1,4-butanediol diacrylate (BDDA), 1,6-hexanediol ethoxylate diacrylate (HDEDA) and triethylene glycol diacrylate (TEGDA)] and a phosphonate-containing primary amine (diethyl 2-aminoethylphosphonate, A1) efficiently without any catalyst; where replacement of A1 with propyl amine (PA) served as control. The macromers, whose molecular weight is ca. 1000-4000 Da as confirmed by both GPC and H-NMR spectroscopy, are photopolymerized to give biodegradable gels. The degradation behavior and cell interaction of these gels are studied. The degradation rates of the gels can be varied by choice of starting acrylates and the acrylate:amine ratio. Furthermore, the gels showed slightly higher degradability than PA-based analogs (controls). Except TEGDA and PEGDA-based ones, all phosphonate-functionalized PBAE gels supported the attachment of larger number of SaOS-2 cells than nonphosphonated ones and the best film was found to be the one based on HDEDA-A1 with balanced hydrophilicity. Degradation products of these films have no significant cytotoxicity except HDDA-PA. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1390-1399, 2018.

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Development of Novel Bisphosphonate Prodrugs of Doxorubicin for Targeting Bone Metastases That Are Cleaved pH Dependently or by Cathepsin B: Synthesis, Cleavage Properties, and Binding Properties to Hydroxyapatite As Well As Bone Matrix

Cited by 93 publications

References 53 publications

Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers

Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers

Local and targeted drug delivery for bone regeneration

Phosphonate‐functionalized poly(β‐amino ester) macromers as potential biomaterials

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