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Synergistic locoregional chemoradiotherapy using a composite liposome-in-gel system as an injectable drug depot.

ABSTRACT: The use of radiosensitizers in clinical radiotherapy is limited by systemic toxicity. The biopolymeric, biodegradable, injectable liposome-in-gel-paclitaxel (LG-PTX) system was developed for regional delivery of the radiosensitizer paclitaxel (PTX), and its efficacy was evaluated with concurrent fractionated radiation. LG-PTX is composed of nano-sized drug-loaded fluidizing liposomes, which are incorporated into a porous biodegradable gellan hydrogel. This allows enhanced drug permeation while maintaining a localization of the drug depot. LG-PTX had an IC₅₀ of 325±117 nM in B16F10 melanoma cells, and cytotoxicity with concurrent doses of fractionated radiation showed significant increase in apoptotic cells (75%) compared to radiation (39%) or LG-PTX (43%) alone. Peri-tumoral injection in tumor-bearing mice showed PTX localization in the tumor 2 hours after administration, with no drug detected in plasma or other organs. LG-PTX administration with doses of focal radiation (5×3 Gy) significantly reduced tumor volumes compared to control (6.4 times) and radiation alone (1.6 times) and improved animal survival. LG-PTX thus efficiently localizes the drug at the tumor site and synergistically enhances the effect of concurrent radiotherapy. This novel liposome-in-gel system can potentially be used as a platform technology for the delivery of radiosensitizing drugs to enhance the efficacy of chemoradiotherapy.

SUBMITTER: GuhaSarkar S

PROVIDER: S-EPMC5138055 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Synergistic locoregional chemoradiotherapy using a composite liposome-in-gel system as an injectable drug depot.

GuhaSarkar Shruti S Pathak Kamal K Sudhalkar Niyati N More Prachi P Goda Jayant Sastri JS Gota Vikram V Banerjee Rinti R

International journal of nanomedicine 20161201

The use of radiosensitizers in clinical radiotherapy is limited by systemic toxicity. The biopolymeric, biodegradable, injectable liposome-in-gel-paclitaxel (LG-PTX) system was developed for regional delivery of the radiosensitizer paclitaxel (PTX), and its efficacy was evaluated with concurrent fractionated radiation. LG-PTX is composed of nano-sized drug-loaded fluidizing liposomes, which are incorporated into a porous biodegradable gellan hydrogel. This allows enhanced drug permeation while m ...[more]

PMID: 27942215

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Project description:Drug resistance presents serious difficulties for cancer treatment. A combination of paclitaxel (PTX) and lapatinib (LAPA) shows potentials in multiple drug resistant cancers in the clinic, but it is almost impossible to deliver these two drugs to the tumor at the same time with the best proportion by simple co-administration of the respective current formualtions for their different pharmacokinetic profiles. Here composite nanocrystals of PTX and LAPA (cNC) were designed with a ratio of 2:1 (w/w), which was their intracellular ratio at the best synergistic efficacy on a drug-resistant cancer cell line (MCF-7/ADR). Such cNC were prepared using a bottom-up method to achieve a nearly spherical appearance and a narrow size distribution of 95.1 ± 2.1 nm. For nanocrystal stabilization, Polyethylene glycol (PEG) coating was introduced into the cNC via polydopamine (PDA) coating in order to get a PEGylated composite nanocrystal (cNC@PDA-PEG) with nanoscale size (170.5 ± 1.4 nm), considerable drug loading (PTX: 21.33 ± 1.48%, LAPA: 10.95 ± 1.24%) and good stability for at least 4 days in plasma-containing buffers. Differential scanning calorimeter (DSC) and XRD data both indicated the different crystalline states of the cNC as well as the cNC@PDA-PEG in comparison with bulk drugs. In vitro release data showed that PTX and LAPA were gradually and completely released from cNC@PDA-PEG in 3 days, while drug release from bulk drugs or cNC was only 30%. cNC@PDA-PEG also showed negligible hemolysis in vitro. Cellular uptake experiments in the MCF-7/ADR cell line showed that the nanocrystals entered the cells in a complete form through endocytosis and then released the drug in the cell. cNC@PDA-PEG inhibits the growth of this drug-resistant cell more effectively than the unmodified version (cNC). In summary, PEGylated PTX and LAPA composite nanocrystals showed the potential for treament of drug-resistant tumors by simultaneously delivering two drugs to tumor cells with the best proportion.

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Dataset Information

Synergistic locoregional chemoradiotherapy using a composite liposome-in-gel system as an injectable drug depot.

Publications

Synergistic locoregional chemoradiotherapy using a composite liposome-in-gel system as an injectable drug depot.

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