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Design of 5-fluorouracil (5-FU) loaded, folate conjugated peptide linked nanoparticles, a potential new drug carrier for selective targeting of tumor cells.

ABSTRACT: In the present investigation folate peptide (FA-Pep) conjugated 5-fluorouracil (5-FU) loaded nanoparticles were synthesized and their tumor targeting potentiality was monitored by different in vitro and in vivo techniques. FA-Pep-1 and FA-Pep-2 were synthesized and radiolabeled with ^99mTc(CO)₃(H₂O)₃. ^99mTc(CO)₃-FA-Pep-1 exhibited promising tumor uptake in an in vivo model (nude mice bearing HeLa cell xenograft and Balb/c mice bearing B16F10 melanoma tumor) as compared to ^99mTc(CO)₃-FA-Pep-2. FA-Pep-1 was then conjugated with 5-FU-NPs (118 ± 4.3), as confirmed by the XPS study. These showed promising cytotoxic and apoptotic potential in B16F10 cell lines as compared to free 5-FU and unconjugated 5-FU-NPs. In vivo biodistribution and gamma-scintigraphy showed good accumulation of peptide conjugated NPs in the tumor region. Therapeutic efficacy studies in B16F10 tumor xenografts also exhibited substantial tumor growth inhibition. The above studies reveal that folate peptide conjugation may facilitate the tumor-targeting approach of 5-FU-NPs.

SUBMITTER: Kazi J

PROVIDER: S-EPMC6482664 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Design of 5-fluorouracil (5-FU) loaded, folate conjugated peptide linked nanoparticles, a potential new drug carrier for selective targeting of tumor cells.

Kazi Julekha J Mukhopadhyay Ria R Sen Ramkrishna R Jha Tarun T Ganguly Shantanu S Debnath Mita Chatterjee MC

MedChemComm 20190312 4

In the present investigation folate peptide (FA-Pep) conjugated 5-fluorouracil (5-FU) loaded nanoparticles were synthesized and their tumor targeting potentiality was monitored by different in vitro and in vivo techniques. FA-Pep-1 and FA-Pep-2 were synthesized and radiolabeled with 99mTc(CO)3(H2O)3. 99mTc(CO)3-FA-Pep-1 exhibited promising tumor uptake in an in vivo model (nude mice bearing HeLa cell xenograft ...[more]

PMID: 31057736

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Project description:Purpose: Nanoparticles (NPs) of the polydopamine (PDA)-based,loaded with temozolomide (TMZ) and conjugated with Pep-1 (Peptide-1) as a feasible nano-drug delivery system were constructed and utilized for chemotherapy (CT) and photothermal therapy (PTT) of glioblastoma (GBM). Method: PDA NPs were synthesized from dopamine (DA) hydrochloride and reacted with TMZ to obtain the PDA-TMZ NPs and then the PDA NPs and the PDA-TMZ NPs were conjugated and modified by Pep-1 to obtain the Pep-1@PDA NPs and Pep-1@PDA-TMZ NPs via the Schiff base reaction (SBR), respectively.Their dimensions, charge, and shape were characterized by dynamic light scattering (DLS) and scanning electron microscope (SEM). The assembly of TMZ was verified by Fourier-transform infrared spectroscopy (FT-IR) and ultraviolet and visible spectroscopy (UV-Vis). The biostability of both the nanocarrier and the synthetic NPs were validated using water and fetal bovine serum (FBS). The antitumor activities of the PDA-TMZ NPs and Pep-1@PDA-TMZ NPs were verified in U87 cells and tumor-bearing nude mice. Results: The prepared PDA NPs, PDA-TMZ NPs, Pep-1@PDA NPs, and Pep-1@PDA-TMZ NPs were regular and spherical, with dimension of approximately 122, 131, 136, and 140 nm, respectively. The synthetic nanoparticles possessed good dispersity, stability,solubility, and biocompatibility. No obvious toxic side effects were observed, and the loading rate of TMZ was approximately 50%.In vitro research indicated that the inhibition ratio of the Pep-1@PDA-TMZ NPs combined with 808 nm laser was approximately 94% for U87 cells and in vivo research was approximately 77.13%, which was higher than the ratio of the other groups (p < 0.05). Conclusion: Pep-1 was conjugated and modified to PDA-TMZ NPs, which can serve as a new targeted drug nano-delivery system and can offer a CT and PTT integration therapy against GBM. Thus, Pep-1@PDA-TMZ NPs could be a feasible approach for efficient GBM therapy, and further provide some evidence and data for clinical transformation so that gradually conquer GBM.

Project description:In the past few decades, the successful theranostic application of nanomaterials in drug delivery systems has significantly improved the antineoplastic potency of conventional anticancer therapy. Several mechanistic advantages of nanomaterials, such as enhanced permeability, retention, and low toxicity, as well as surface engineering with targeting moieties, can be used as a tool in enhancing the therapeutic efficacy of current approaches. Inorganic calcium phosphate nanoparticles have the potential to increase the therapeutic potential of antiproliferative drugs due to their excellent loading efficiency, biodegradable nature and controlled-release behaviour. Herein, we report a novel system of 5-fluorouracil (5-FU)-loaded calcium phosphate nanoparticles (CaP@5-FU NPs) synthesized via a reverse micelle method. The formation of monodispersed, spherical, crystalline nanoparticles with an approximate diameter of 160-180 nm was confirmed by different methods. The physicochemical characterization of the synthesized CaP@5-FU NPs was done with transmission electron microscopy (TEM), dynamic light scattering (DLS), field emission scanning electron microscopy (FE-SEM), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). The antineoplastic potential of the CaP@5-FU NPs against colorectal and lung cancer cells was reported. The CaP@5-FU NPs were found to inhibit half the population (IC50) of lung adenocarcinoma (A549) cells at 32 ?g/mL and colorectal (HCT-15) cancer cells at 48.5 ?g/mL treatment. The apoptotic induction of CaP@5-FU NPs was confirmed with acridine orange/ethidium bromide (AO/EB) staining and by examining the morphological changes with Hoechst and rhodamine B staining in a time-dependent manner. The apparent membrane bleb formation was observed in FE-SEM micrographs. The up-regulated proapoptotic and down-regulated antiapoptotic gene expressions were further confirmed with semiquantitative reverse transcriptase polymerase chain reaction (PCR). The increased intracellular reactive oxygen species (ROS) were quantified via flow cytometry upon CaP@5-FU NP treatment. Likewise, the cell cycle analysis was performed to confirm the enhanced apoptotic induction. Our study concludes that the calcium phosphate nanocarriers system, i.e. CaP@5-FU NPs, has higher antineoplastic potential as compared to 5-FU alone and can be used as an improved alternative to the antimitotic drug, which causes severe side effects when administrated alone.

Dataset Information

Design of 5-fluorouracil (5-FU) loaded, folate conjugated peptide linked nanoparticles, a potential new drug carrier for selective targeting of tumor cells.

Publications

Design of 5-fluorouracil (5-FU) loaded, folate conjugated peptide linked nanoparticles, a potential new drug carrier for selective targeting of tumor cells.

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