Intracellular trafficking of nuclear localization signal conjugated nanoparticles for cancer therapy

, S. TAMIZHARASI, T. SIVAKUMAR Nandha College of Pharmacy and Research Institute, Erode 630052, Tamilnadu, IndiaEmail: sumoraji@gmail.comObjective: The objective of this study was to formulate and evaluate the poorly soluble drug, naringenin (NAR) into nanosuspension to increase the solubility and enhance the dissolution rate and then improve its bioavailability.Methods: Nanosuspenion of naringenin (NARNS) was prepared using high-pressure homogenization method using Soya lecithin, Polaxamer-407, Polaxamer-188, Hydroxypropyl methyl cellulose (HPMC) and Tween-80. Ten formulations were prepared to show the effect of stabilizer and its ratio. D-α-Tocopheryl polyethene glycol succinate 1000 (TPGS) was added as a co-stabilizer. All these formulations were evaluated for their particle size, PDI, zeta potential, FT-IR study, drug content, saturation solubility studies, entrapment efficiency, in vitro permeability and in vitro drug release. The formulation was further evaluated for scanning electron microscope (SEM), differential scanning calorimetry (DSC) and Powder X-ray diffraction (P-XRD) and hemocompatibility assessment.Results: All the prepared formulations were in the nano size. The optimum concentration of the stabilizer was in the formulation was found 1:1.5:1 (drug: stabilizer: co-stabilizer ratio). Dramatic effect of the particle size reduction was found by the addition of the co-stabilizer (TPGS) in formulation N2 that has P. S 80.52±0.13 nm. The solubility and dissolution of NAR in the form of NARNS were significantly higher than those of pure NAR. SEM report shows that naringenin nanosuspension revealed a smooth texture. P-XRD crystallography diffraction and DSC studies indicated that the crystalline state of NAR was converted into amorphous nature. The safety evaluation showed that NARNS provided a lower rate of erythrocyte hemolysis.Keywords: Naringenin, High-Pressure Homogenization, Nanosuspenion, Solubility, Bioavailability Conclusion:In this study, (NARNS) was successfully carried out by high-pressure homogenization technique and characterized. The physiochemical characterization shown that crystalline naringenin was converted to a polymorphic form (DSC and P-XRD Study) which evidenced by enhanced dissolution rate in comparisons of the formulation with (NAR) pure drug. The NARNS has shown 7.5±0.4 fold increased relative bioavailability when compared to the NAR. The increased drug dissolution rate may have a significant impact in absorption which in turn the improved oral bioavailability of naringenin. Thus, this delivery system may prefer to improve the dissolution of poorly soluble drugs like NAR and thus enhanced oral bioavailability. The safety evaluation showed that nanoformulation (NF2) shows a lower rate of erythrocyte hemolysis. These findings suggest that the selected formulation may represent a promising new drug formulation for intravenous administration in the treatment of certain cancers.

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“…These distinctive bands of free NAR are also present in NARNS, which indicates the chemical stability of NAR in nanosuspensions [42,43].…”

Section: Fourier Transforms Infrared Spectroscopy (Ft-ir)mentioning

confidence: 97%

Formulation and Evaluation of Polymeric Nanosuspension of Naringenin

Sumathi¹,

Sengodan²,

Sivakumar³

2017

Int J App Pharm

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“…However, its therapeutic properties are limited owing to its dependent cardio toxicity and myelosuppression (Misra and Sahoo, 2010;Acharya and Sahoo, 2011). PLGA NPs promise to be a successful system for the targeted and controlled release of doxorubicin with decreased systemic toxicity, increased therapeutic efficiency and patient compliance.…”

Section: Doxorubicinmentioning

confidence: 99%

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

Mirakabad

Nejati-Koshki²,

Akbarzadeh³

et al. 2014

Asian Pacific Journal of Cancer Prevention

389

154

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“…[18] A similar strategy has been used to enhance nuclear delivery of doxorubicin using NLS-modified PLGA nanoparticles. [178] In another example, covalent conjugation of an NLS derived from the SV40 virus on PLGA nanospheres was demonstrated to enhance the gene transfection efficiency of the encapsulated pDNA. [179] While decoration of polymers or polymer nanoparticles with NLSs provides a powerful strategy to enhance nuclear delivery, in vivo the positively charged nature of these peptides may lead to nonspecific cellular uptake in the blood stream.…”

Section: Mitochondrial Deliverymentioning

confidence: 99%

“…This can be achieved by labeling the polymer carrier with a fluorescent dye and measuring the colocalization with the nucleus, which can be stained with nuclear-specific markers such as DAPI, Hoechest 33342, and Draq 5. [79,171,177] Alternatively, the cargo can be tracked in case of fluorescent drugs such as doxorubicin [178] or when labeled pDNA are delivered. [180,183,184] Labeling both the polymer carrier and the cargo with a fluorescent dye allows to monitor release of the active compound, e.g., plasmid DNA.…”

Section: Monitoring Nuclear Deliverymentioning

confidence: 99%

“…[147] Flierl et al used another approach to overcome the size limitations. In this work, an MTS peptide-peptide nucleic acid (PNA) conjugate was annealed to an oligonucleotide with a complementary PNA sequence and the complex was Linear polymer [177] α,β-Importins Nuclear localization signals (NLSs) [167,168,174,175] CGYGPKKKRKVGG Micelles [18] DRQIKIWFQNRRM-KWKK Nanoparticles [178] PKKRKV Nanoparticles [179] CVKRKKKP Linear polymers [63,79] Cytoplasmic NFkB Linear polymers [180,181] (11 of 26) 1700022 transferred into the cytosol using a PEI carrier. While the carrier allowed endosomal escape, the MTS targeting peptide directed the oligonucleotide to the mitochondria.…”

Section: Mitochondrial Deliverymentioning

confidence: 99%

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Controlling and Monitoring Intracellular Delivery of Anticancer Polymer Nanomedicines

Battistella

Klok

2017

Macromolecular Bioscience

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Polymer nanomedicines are very attractive to improve the delivery of chemotherapeutics. Polymer conjugates and other polymer‐based nanocarriers allow to increase plasma half‐life and drug bioavailability and can also be guided toward tumors using passive and active targeting strategies. Since many chemotherapeutics act on targets that are located in well‐defined subcellular compartments, other important factors that contribute to an efficient therapy include cellular internalization and subsequent intracellular trafficking of the polymer nanomedicines and/or its payload to the appropriate organelle in the cytoplasm. This article provides an overview of the different approaches that have been developed to control intracellular delivery of polymer nanomedicines and discusses the different techniques that can be used to monitor these processes.

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Intracellular trafficking of nuclear localization signal conjugated nanoparticles for cancer therapy

Cited by 196 publications

References 44 publications

Formulation and Evaluation of Polymeric Nanosuspension of Naringenin

Formulation and Evaluation of Polymeric Nanosuspension of Naringenin

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

Controlling and Monitoring Intracellular Delivery of Anticancer Polymer Nanomedicines

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