Ranjita Misra

Nanoparticles: a boon to drug delivery, therapeutics, diagnostics and imaging

UNLABELLED Drug delivery is an interdisciplinary and independent field of research and is gaining the attention of pharmaceutical researchers, medical doctors and industry. A safe and targeted drug delivery could improve the performance of some classic medicines already on the market, and moreover, will have implications for the development and success of new therapeutic strategies such as anticancer drug delivery, peptide and protein delivery and gene therapy. In the last decade, several drug-delivery technologies have emerged and a fascinating part of this field is the development of nanoscale drug delivery devices. Nanoparticles (NPs) have been developed as an important strategy to deliver conventional drugs, recombinant proteins, vaccines and more recently, nucleotides. NPs and other colloidal drug-delivery systems modify the kinetics, body distribution and drug release of an associated drug. This review article focuses on the potential of nanotechnology in medicine and discusses different nanoparticulate drug-delivery systems including polymeric NPs, ceramic NPs, magnetic NPs, polymeric micelles and dendrimers as well as their applications in therapeutics, diagnostics and imaging. FROM THE CLINICAL EDITOR This comprehensive review focuses on different nanoparticulate drug-delivery systems including polymeric NPs, ceramic NPs, magnetic NPs, polymeric micelles and dendrimers as well as their applications in therapeutics, diagnostics and imaging.

Cancer nanotechnology: application of nanotechnology in cancer therapy

The application of nanotechnology for cancer therapy has received considerable attention in recent years. Cancer nanotechnology (an interdisciplinary area of research in science, engineering and medicine) is an upcoming field with extensive applications. It provides a unique approach and comprehensive technology against cancer through early diagnosis, prediction, prevention, personalized therapy and medicine. Target-specific drug therapy and methods for early diagnosis of pathologies are the priority research areas in which nanotechnology would play a vital part. This review focuses on the approaches of cancer nanotechnology in the advancement of cancer therapy.

Intracellular trafficking of nuclear localization signal conjugated nanoparticles for cancer therapy

Doxorubicin (DOX) is an anticancer drug with an intracellular site of action in the nucleus. For high antitumour activity, it should be effectively internalized into the cancer cells and accumulate in the nucleus. In this study, we have prepared a nuclear localization signal conjugated doxorubicin loaded Poly (D,L-lactide-co-glycolide) nanoparticles (NPs), to deliver doxorubicin to the nucleus efficiently. Physico-chemical characterization of these NPs showed that the drug is molecularly dispersed in spherical and smooth surfaced nanoparticles. NPs (approximately 226 nm in diameter, 46% encapsulation efficiency) under in vitro conditions exhibited sustained release of the encapsulated drug (63% release in 60 days). Cell cytotoxicity results showed that NLS conjugated NPs exhibited comparatively lower IC(50) value (2.3 microM/ml) than drug in solution (17.6 microM/ml) and unconjugated NPs (7.9 microM/ml) in breast cancer cell line MCF-7 as studied by MTT assay. Cellular uptake studies by confocal laser scanning microscopy (CLSM) and fluorescence spectrophotometer showed that greater amount of drug is targeted to the nucleus with NLS conjugated NPs as compared to drug in solution or unconjugated NPs. Flow cytometry experiments results showed that NLS conjugated NPs are showing greater cell cycle (G2/M phase) blocking and apoptosis than native DOX and unconjugated NPs. In conclusion, these results suggested that NLS conjugated doxorubicin loaded NPs could be potentially useful as novel drug delivery system for breast cancer therapy.

Coformulation of Doxorubicin and Curcumin in Poly(d,l-lactide-co-glycolide) Nanoparticles Suppresses the Development of Multidrug Resistance in K562 Cells

Doxorubicin (DOX) is a broad-spectrum anthracycline antibiotic used to treat a variety of cancers including leukemia. Chronic myeloid leukemia (CML) blasts like K562 cells are resistant to apoptosis induced by DOX due to several reasons, the primary being the sequestration of drug into cytoplasmic vesicles and induction of multidrug resistance (MDR) gene expression with DOX treatment resulting in intracellular resistance to this drug. Moreover, expression of antiapoptotic protein BCL-2 and the hybrid gene bcr/abl in K562 cells contributes resistance to DOX. Studies have shown that curcumin (CUR) has a pleiotropic therapeutic effect in cancer treatment, as it is an inhibitor of nuclear factor kappa B (NFκB) as well as a potent downregulator of MDR transporters. In this study, we investigated the potential benefit of using DOX and CUR in a single nanoparticle (NP) formulation to inhibit the development of drug resistance for the enhancement of antiproliferative activity of DOX in K562 cells. Results illustrate that the dual (DOX+CUR) drug loaded NPs were effectively delivered into K562 cells. CUR not only facilitates the retention of DOX in nucleus for a longer period of time but also inhibits the gradual expression of MDR1 and BCL-2 at the mRNA level in K562 cells. Moreover, Western blot results confirm that in combination both of the drugs were capable of inducing apoptosis even if in a lower concentration compared to either single drug in both solution or in formulation. Combinational therapy by using DOX and CUR, especially when administered in the NP formulation, has enhanced the cytotoxicity in K562 cells by promoting the apoptotic response. Overall, this combinational strategy has significant promise in the clinical management of intractable diseases, especially leukemia.

Sustained antibacterial activity of doxycycline- loaded poly(d,l-lactide-co-glycolide) and poly(e-caprolactone) nanoparticles

AIM To increase the entrapment efficiency of doxycycline (DXY)-loaded poly(D,L-lactide-co-glycolide) (PLGA):poly(epsilon-caprolactone) (PCL) nanoparticles by up to 70% by varying the different formulation parameters such as polymer ratio, amount of drug loading (w/w), solvent selection, electrolyte addition and pH in the formulation. METHOD Biodegradable polymers PLGA and PCL are used in various ratios for nanoparticle preparation using the water-in-oil-in-water double emulsion technique for water-soluble DXY. The physicochemical characterization of nanoparticles included size and surface charge measurement, study of surface morphology using scanning-electron microscopy, Fourier transform infrared spectroscopy study, differential scanning calorimetry analysis and in vitro release kinetics study. RESULTS The mean particle size ranged from 230 to 360 nm, as measured by dynamic laser light scattering, and scanning-electron microscopy confirmed the spherical nature and smooth surface of the nanoparticles. Fourier transform infrared spectroscopy analysis of void nanoparticles, drug-loaded nanoparticles and native DXY indicated no interaction between the drug and polymer in the nanoparticle. Differential scanning calorimetry analysis of drug-loaded nanoparticles indicated a molecular level dispersion of DXY in the formulation. The antibacterial activity of native DXY and DXY-loaded nanoparticles were tested using a strain of Escherichia coli (DH5alpha) through growth inhibition and colony-counting method. The results indicated that DXY-loaded nanoparticles are more effective than native DXY due to the sustained release of DXY from nanoparticles in the E. coli strain.

Reversal of multidrug resistance in vitro by co-delivery of MDR1 targeting siRNA and doxorubicin using a novel cationic poly(lactide-co-glycolide) nanoformulation

Over expression of drug efflux transporters such as P-glycoprotein (P-gp) cumulatively leading to multidrug resistance (MDR) embodies a major hindrance for successful cancer therapy. A paradigm nanomedicinal approach involving an anticancer drug and modulators of drug resistance within one multifunctional nanocarrier-based delivery system represent an ideal modality for the treatment of MDR. In this regards, we have developed a cationic polymeric nanoparticulate system loaded with MDR1-siRNA and doxorubicin. Results indicated augmented synergistic effect of combinational nanoformulation in overcoming MDR in MCF-7/ADR cells. Therefore, the above regime could be a promising co-delivery system for effective therapy of drug resistant breast cancer.

Antibacterial Activity of Doxycycline-Loaded Nanoparticles

Doxycycline is a tetracycline antibiotic with a potent antibacterial activity against a wide variety of bacteria. However, poor cellular penetration limits its use for the treatment of infectious disease caused by intracellular pathogens. One potential strategy to overcome this problem is the use of nanotechnology that can help to easily target the intracellular sites of infection. The antibacterial activity of these antibiotics is enhanced by encapsulating it in polymeric nanoparticles. In this study, we describe the improvement of the entrapment efficiency of doxycycline hydrochloride (doxycycline)-loaded PLGA:PCL nanoparticles up to 70% with variation of different formulation parameters such as polymer ratio, amount of drug loading (w/w), solvent selection, electrolyte addition, and pH alteration in the formulation. We have evaluated the efficacy of these nanoparticles over native doxycycline against a strain of Escherichia coli (DH5α) through growth inhibition and colony counting. The results indicate that doxycycline-loaded nanoparticles have superior effectiveness compared to native doxycycline against the above bacterial strain, resulting from the sustained release of doxycycline from nanoparticles. These results are encouraging for the use of these doxycycline-loaded nanoparticles for the treatment of infections caused by doxycycline-sensitive bacteria.