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Combinatorial nanocarrier based drug delivery approach for amalgamation of anti-tumor agents in breast cancer cells: an improved nanomedicine strategy.

ABSTRACT: Combination therapy of multiple drugs through a single system is exhibiting high therapeutic effects. We investigate nanocarrier mediated inhibitory effects of topotecan (TPT) and quercetin (QT) on triple negative breast cancer (TNBC) (MDA-MB-231) and multi drug resistant (MDR) type breast cancer cells (MCF-7) with respect to cellular uptake efficiency and therapeutic mechanisms as in vitro and in vivo. The synthesized mesoporous silica nanoparticle (MSN) pores used for loading TPT; the outer of the nanoparticles was decorated with poly (acrylic acid) (PAA)-Chitosan (CS) as anionic inner-cationic outer layer respectively and conjugated with QT. Subsequently, grafting of arginine-glycine-aspartic acid (cRGD) peptide on the surface of nanocarrier (CPMSN) thwarted the uptake by normal cells, but facilitated their uptake in cancer cells through integrin receptor mediated endocytosis and the dissociation of nanocarriers due to the ability to degrade of CS and PAA in acidic pH, which enhance the intracellular release of drugs. Subsequently, the released drugs induce remarkable molecular activation as well as structural changes in tumor cell endoplasmic reticulum, nucleus and mitochondria that can trigger cell death. The valuable CPMSNs may open up new avenues in developing targeted therapeutic strategies to treat cancer through serving as an effective drug delivery podium.

SUBMITTER: Murugan C

PROVIDER: S-EPMC5057072 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Combinatorial nanocarrier based drug delivery approach for amalgamation of anti-tumor agents in breast cancer cells: an improved nanomedicine strategy.

Murugan Chandran C Rayappan Kathirvel K Thangam Ramar R Bhanumathi Ramasamy R Shanthi Krishnamurthy K Vivek Raju R Thirumurugan Ramasamy R Bhattacharyya Atanu A Sivasubramanian Srinivasan S Gunasekaran Palani P Kannan Soundarapandian S

Scientific reports 20161011

Combination therapy of multiple drugs through a single system is exhibiting high therapeutic effects. We investigate nanocarrier mediated inhibitory effects of topotecan (TPT) and quercetin (QT) on triple negative breast cancer (TNBC) (MDA-MB-231) and multi drug resistant (MDR) type breast cancer cells (MCF-7) with respect to cellular uptake efficiency and therapeutic mechanisms as in vitro and in vivo. The synthesized mesoporous silica nanoparticle (MSN) pores used for loading TPT; the outer of ...[more]

PMID: 27725731

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Project description:BackgroundGene therapy is a very promising technology for treatment of pancreatic ductal adenocarcinoma (PDAC). However, its application has been limited by the abundant stromal response in the tumor microenvironment. The aim of this study was to prepare a dendrimer-based gene-free loading vector with high permeability in the tumor stroma and explore an imaging-guided local gene delivery strategy for PDAC to promote the efficiency of targeted gene delivery.MethodsThe experimental protocol was approved by the animal ethics committee of Zhongshan Hospital, Fudan University. Third-generation dendrigraft poly-L-lysines was selected as the nanocarrier scaffold, which was modified by cell-penetrating peptides and gadolinium (Gd) chelates. DNA plasmids were loaded with these nanocarriers via electrostatic interaction. The cellular uptake and loaded gene expression were examined in MIA PaCa-2 cell lines in vitro. Permeability of the nanoparticles in the tumor stroma and transfected gene distribution in vivo were studied using a magnetic resonance imaging-guided delivery strategy in an orthotopic nude mouse model of PDAC.ResultsThe nanocarriers were synthesized with a dendrigraft poly-L-lysine to polyethylene glycol to DTPA ratio of 1:3.4:8.3 and a mean diameter of 110.9±7.7 nm. The luciferases were strictly expressed in the tumor, and the luminescence intensity in mice treated by Gd-DPT/plasmid luciferase (1.04×10(4)±9.75×10(2) p/s/cm(2)/sr) was significantly (P<0.05) higher than in those treated with Gd-DTPA (9.56×10(2)±6.15×10 p/s/cm(2)/sr) and Gd-DP (5.75×10(3)± 7.45×10(2) p/s/cm(2)/sr). Permeability of the nanoparticles modified by cell-penetrating peptides was superior to that of the unmodified counterpart, demonstrating the improved capability of nanoparticles for diffusion in tumor stroma on magnetic resonance imaging.ConclusionThis study demonstrated that an image-guided gene delivery system with a stroma-permeable gene vector could be a potential clinically translatable gene therapy strategy for PDAC.

Project description:BackgroundMulti-monocistronic and multi-variate vectors were designed, built, and tested for the improved production of cyanidin 3-O-glucoside (C3G) in Escherichia coli BL21 (DE3). The synthetic bio-parts were designed in such a way that multiple genes can be assembled using the bio-brick system, and expressed under different promoters in a single vector. The vectors harbor compatible cloning sites, so that the genes can be shuffled from one vector to another in a single step, and assembled into a single vector. The two required genes: anthocyanidin synthase (PhANS) from Petunia hybrida, and cyanidin 3-O-glucosyltransferase (At3GT) from Arabidopsis thaliana, were individually cloned under PT7, Ptrc, and PlacUV5 promoters. Both PhANS and At3GT were shuffled back and forth, so as to generate a combinatorial system for C3G production. The constructed systems were further coupled with the genes for UDP-D-glucose synthesis, all cloned in a multi-monocistronic fashion under PT7. Finally, the production of C3G was checked and confirmed using the modified M9 media, and analyzed through various chromatography and spectrometric analyses.ResultsThe engineered strains endowed with newly generated vectors and the genes for C3G biosynthesis and UDP-D-glucose synthesis were fed with 2 mM (+)-catechin and D-glucose for the production of cyanidin, and its subsequent conversion to C3G. One of the engineered strains harboring At3GT and PhANS under Ptrc promoter and UDP-D-glucose biosynthesis genes under PT7 promoter led to the production of ~?439 mg/L of C3G within 36 h of incubation, when the system was exogenously fed with 5% (w/v) D-glucose. This system did not require exogenous supplementation of UDP-D-glucose.ConclusionA synthetic vector system using different promoters has been developed and used for the synthesis of C3G in E. coli BL21 (DE3) by directing the metabolic flux towards the UDP-D-glucose. This system has the potential of generating better strains for the synthesis of valuable natural products.

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Combinatorial nanocarrier based drug delivery approach for amalgamation of anti-tumor agents in breast cancer cells: an improved nanomedicine strategy.

Publications

Combinatorial nanocarrier based drug delivery approach for amalgamation of anti-tumor agents in breast cancer cells: an improved nanomedicine strategy.

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