Polymeric nanoparticles for targeted radiosensitization of prostate cancer cells

Abstract

One of the many issues of using radiosensitizers in a clinical setting is timing daily radiation treatments to coincide with peak drug concentration in target tissue. To overcome this deficit, we have synthesized a novel nanoparticle system consisting of poly (lactic-co-glycolic acid) (PLGA) nanoparticles conjugated with prostate cancer cell penetrating peptide-R11 and encapsulated with a potent radio-sensitizer 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441) to allow prostate cancer-specific targeting and sustained delivery over 3 weeks. Preliminary characterization studies showed that the R11-conjugated nanoparticles (R11-NU7441 NPs) had an average size of about 274 ± 80 nm and were stable for up to 5 days in de-ionized water and serum. The nanoparticles were cytocompatible with immortalized prostate cells (PZ-HPV-7). Further, the particles showed a bi-phasic release of encapsulated NU7441 and were taken up by PC3 prostate cancer cells in a dose- and magnetic field-dependent manner while not being taken up in non-prostate cancer cell lines. In addition, R11-NU7441 NPs were effective radiation sensitizers of prostate cancer cell lines in vitro. These results thus demonstrate the potential of R11-conjugated PLGA NPs as novel platforms for targeted radiosensitization of prostate cancer cells.

NU7441 Enhances the Radiosensitivity of Liver Cancer Cells

“…NU7441, a derivative from LY294002, is a synthetic and specific DNA-PK inhibitor. In in vitro experiments, NU7441 exerted radiosensitizing activity in breast cancer, leukemia, and prostate cancer [15][16][17]. However, no studies have been performed to examine the effect of NU7441 on liver cancer cells.…”

“…Data Analysis SPSS Statistical software 17.0 was used to analyze the experimental data. The results were expressed as mean ± standard deviation.…”

The role of recent nanotechnology in enhancing the efficacy of radiation therapy

“…To overcome the deficit of timing daily radiation fractions to coincide with peak drug concentration, NP systems with sustained drug delivery would be advantageous [27]. For this purpose, Menon et al [27] developed PLGA NPs conjugated with prostate cancer cell penetrating peptide R11 targeting the laminin receptor encapsulating the radiation sensitizer 8-dibenzothiophen-4-yl-2-morpholin-4yl-chromen-4-one (NU7441).…”

“…For this purpose, Menon et al [27] developed PLGA NPs conjugated with prostate cancer cell penetrating peptide R11 targeting the laminin receptor encapsulating the radiation sensitizer 8-dibenzothiophen-4-yl-2-morpholin-4yl-chromen-4-one (NU7441). NU7441 is an inhibitor of the DNA-dependent protein kinase (DNA-PK), which is involved in non-homologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs) [61].…”

“…A variety of natural and synthetic polymeric NP formulations have been designed to enhance the effect and/or tumor delivery of radiation sensitizing agents, such as chemotherapeutic drugs, small molecule cancer drugs [26][27][28][29] or nucleic acids [30][31][32]. In general, two different strategies have been applied to develop polymeric NPs.…”