Investigation of Targeting Mechanism of New Dextran-Peptide-Methotrexate Conjugates Using Biodistribution Study in Matrix-Metalloproteinase-Overexpressing Tumor Xenograft Model

Chau, Ying; Dang, Natalie M.; Tan, Frederick E.; Langer, Robert

doi:10.1002/jps.20548

Cited by 85 publications

(70 citation statements)

References 17 publications

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“…Under in vitro (cell cultures) and in vivo conditions, this feature may account for unspecific OGP release from both peptides. Similar observations have been previously reported by Chau et al [36][37][38], who designed two dextran-peptide-methotrexate (MTX) conjugates for tumor targeting, where the peptide linkers corresponded to the same sequences used in this study (PVGLIG and GIVGPL) [36][37][38]. In vitro, GIVGPL-dextran conjugates were only minimally hydrolyzed by MMP-2, and PVGLIG-dextran conjugates released the drug in the presence of MMP-2, but remained intact in all the serum-containing conditions [38].…”

Section: Enzymatic Cleavage Of Free and Alginate-conjugated Ogp Analogssupporting

confidence: 93%

Hydrogel depots for local co-delivery of osteoinductive peptides and mesenchymal stem cells

Maia

Barbosa²,

Gomes

et al. 2014

Journal of Controlled Release

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The outcome of cell-based therapies can benefit from carefully designed cell carriers. A multifunctional injectable vehicle for the co-delivery of human mesenchymal stem cells (hMSCs) and osteoinductive peptides is proposed, to specifically direct hMSCs osteogenic differentiation. The osteogenic growth peptide (OGP) inspired the design of two peptides, where the bioactive portion of OGP was flanked by a protease-sensitive linker, or its scrambled sequence, to provide faster and slower release rates, respectively. Peptides were fully characterized and chemically grafted to alginate. Both OGP analogs released bioactive fragments in vitro, at different kinetics, which stimulated hMSCs proliferation and osteogenesis. hMSCs-laden OGP-alginate hydrogels were tested at an ectopic site in a xenograft mouse model. After 4 weeks, OGP-alginate hydrogels were more degraded and colonized by vascularized connective tissue than the control (without OGP). hMSCs were able to proliferate, migrate outward the hydrogels, produce endogenous extracellular matrix and mineralize it. Moreover, OGP-groups stimulated hMSCs osteogenesis, as compared with the control. Overall, the ability of the proposed platform to direct the fate of transplanted hMSCs in loco was demonstrated, and OGP-releasing hydrogels emerged as a potentially useful system to promote bone regeneration.

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Section: Enzymatic Cleavage Of Free and Alginate-conjugated Ogp Analogssupporting

confidence: 93%

Hydrogel depots for local co-delivery of osteoinductive peptides and mesenchymal stem cells

Maia

Barbosa²,

Gomes

et al. 2014

Journal of Controlled Release

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“…Nonionic natural polysaccharides dextran and peptide dendrons, which are major building blocks in organisms [17], should have excellent biocompatibility. The cytotoxicity of the blank FPD-HZN-Dex nanoparticles was evaluated after 24 h of treatment in HEK293 and HepG2 cells, respectively.…”

Section: In Vitro Cytotoxicitymentioning

confidence: 99%

“…Many polysaccharides have been used because of their high biodegrability, biocompatibility and low immunogenicity. Dextran is a neutral hydrophilic polymer that has been approved by the FDA to be a plasma expander with excellent biodistribution profile [17]. Considering the activity sequence of hydroxyl groups in dextran, it's hard to functionalize for biomedical applications.…”

Section: Introductionmentioning

confidence: 99%

Self-assembly of pH-sensitive fluorinated peptide dendron functionalized dextran nanoparticles for on-demand intracellular drug delivery

Zhou

Wali

et al. 2015

J Mater Sci: Mater Med

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In this study, the amphiphilic fluorinated peptide dendrons functionalized dextran (FPD-HZN-Dex) via an acid-sensitive hydrazone linkage was successfully designed and prepared for the first time. We demonstrated a spontaneous self-assembly of amphiphilic FPD-HZN-Dex into the well-defined nanoparticles with the core-shell architecture in aqueous media, which is attributed to the efficient amphiphilic functionalization of dextran by the hydrophobic fluorinated peptide dendrons. The spherical morphology, uniform particle size and good storage stability of the prepared FPD-HZN-Dex nanoparticles were characterized by dynamic light scattering and transmission electron microscopy, respectively. In vitro drug release studies showed a controlled and pH dependent hydrophobic drug release profile. The cell viability assays show excellent biocompatibility of the FPD-HZN-Dex nanoparticles for both normal cells and tumor cells. Moreover, the FPD-HZN-Dex self-assembled systems based on pH-sensitive hydrazone linkage also can serve as stimulus bioresponsive carriers for on-demand intracellular drug delivery. These self-assembled nanoparticles exhibit a stimulus-induced response to endo/lysosome pH (pH 5.0) that causes their disassembly over time, enabling controlled release of encapsulated DOX. This work has unveiled a unique non-covalent interaction useful for engineering amphiphilic dendrons or dendrimers self-assembled systems.

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“…For targeted delivery into sensitive and/or resistant tumor cells MTX or pemetrexed [20] has been conjugated to protein [21], peptides including CPP [22][23][24][25], polymeric polypeptides [26], dendrimers [27,28] and oligosaccharides [29]. In spite of the potency of polyglutamylated MTX as effective drug against resistant tumors only few studies were reported on conjugates with this molecule.…”

Section: Introductionmentioning

confidence: 99%

Cell-penetrating conjugates of pentaglutamylated methotrexate as potential anticancer drugs against resistant tumor cells

Szabó

Orbán

Schlosser

et al. 2016

European Journal of Medicinal Chemistry

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The emerging resistance of tumor cells against methotrexate (MTX) is one of the major limitations of the MTX treatment of tumorous diseases. The disturbance in the polyglutamation which is a main step in the mechanism of methotrexate action is often the reason of the resistance. Delivery of polyglutamylated MTX into cells may evade the mechanisms that are responsible for drug resistance. In this study conjugates of methotrexate and its pentaglutamylated derivatives with cell-penetrating peptides -penetratin and octaarginine -were investigated. The cellular-uptake and in vitro cytostatic activity of conjugates were examined on breast cancer cell cultures (MDA-MB-231 as resistant and MCF-7 as sensitive cell culture). These cell cultures showed very different behaviour towards the conjugates. Although the presence of pentaglutamyl moiety significantly decreased the internalisation of conjugates, some of them were significantly active in vitro. All of the conjugates were able to penetrate in some extent into both cell types, but only the conjugates of penetratin showed in vitro cytostatic activity. The most effective conjugates were the MTX-Glu 5 -Penetratin(desMet) and MTX-Glu 5 -GFLG-Penetratin(desMet). The latter was effective on both cell cultures while the former was active only on the resistant tumor cells. Our results suggest that the translocation of polyglutamylated MTX may be a new way to treat sensitive and more importantly resistant tumors. While both penetratin and octaarginine peptides were successfully used to deliver several kinds of cargos earlier in our case the activity of penetratin conjugates was more pronounced.

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Investigation of Targeting Mechanism of New Dextran-Peptide-Methotrexate Conjugates Using Biodistribution Study in Matrix-Metalloproteinase-Overexpressing Tumor Xenograft Model

Cited by 85 publications

References 17 publications

Hydrogel depots for local co-delivery of osteoinductive peptides and mesenchymal stem cells

Hydrogel depots for local co-delivery of osteoinductive peptides and mesenchymal stem cells

Self-assembly of pH-sensitive fluorinated peptide dendron functionalized dextran nanoparticles for on-demand intracellular drug delivery

Cell-penetrating conjugates of pentaglutamylated methotrexate as potential anticancer drugs against resistant tumor cells

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