Biotin receptors are overexpressed by various types of solid cancer cells and play a significant role in tumor metabolism, growth, and metastasis. Thus, targeting the biotin receptors on tumor cells may enhance the efficiency and reduce the side-effects of chemotherapy. The aim of this study was to develop a biotin-coupled poly(amido)amine (PAMAM) (PG4.5) dendrimer nanoparticle to enhance the tumor-specific delivery and intracellular uptake of anticancer drugs via receptor-mediated endocytosis. We modified PG4.5 with diethylenetriamine (DETA) followed by biotin via an amide bond and characterized the resulting PG4.5-DETA-biotin nanoparticles by 1H NMR, FTIR, and Raman spectroscopy. Loading and releasing of gemcitabine (GEM) from PG4.5-DETA-biotin were evaluated by UV–Visible spectrophotometry. Cell viability and cellular uptake were examined by MTT assay and flow cytometry to assess the biocompatibility, cellular internalization efficiency and antiproliferative activity of PG4.5-DETA-biotin/GEM. Gemcitabine-loaded PG4.5-DETA-biotin nanoparticles were spherical with a particle size of 81.6 ± 6.08 nm and zeta potential of 0.47 ± 1.25 mV. Maximum drug-loading content and encapsulation efficiency were 10.84 ± 0.16% and 47.01 ± 0.71%, respectively. Nearly 60.54 ± 1.99% and 73.96 ± 1.14% of gemcitabine was released from PG4.5-DETA-biotin/GEM nanoparticles after 48 h at the acidic pH values of 6.5 and 5, respectively. Flow cytometry and fluorescence microscopy of cellular uptake results revealed PG4.5-DETA-biotin/GEM nanoparticles selectively targeted cancer cells in vitro. Cytotoxicity assays demonstrated gemcitabine-loaded PG4.5-DETA-biotin significantly reduced cell viability and induced apoptosis in HeLa cells. Thus, biotin-coupled PG4.5-DETA nanocarrier could provide an effective, targeted drug delivery system and selectively convey gemcitabine into tumor cells.
Purpose
In this study, the
188
Re-labeled PEGylated nanoliposome (
188
Re-liposome) was prepared and evaluated as a therapeutic agent for glioma.
Materials and methods
The reporter cell line, F98
luc
was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of
188
Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered
188
Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the
188
Re-liposome-treated rats.
Results
By using bioluminescent imaging, the well-established reporter cell line (F98
luc
) showed a high relationship between cell number and its bioluminescent intensity (
R
2
=0.99) in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of
188
Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the
188
Re-liposome-treated group than the control group (
P
<0.05). As a result, the lifespan of glioma-bearing rats treated with
188
Re-liposome was prolonged 10.67% compared to the control group.
Conclusion
The radiotherapeutic evaluation by dosimetry and survival studies have demonstrated that passive targeting
188
Re-liposome via systemic administration can significantly prolong the lifespan of orthotopic glioma-bearing rats while maintaining reasonable systemic radiation safety. Therefore,
188
Re-liposome could be a potential therapeutic agent for glioblastoma multiforme treatment.
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