Aspects of high-performance and bio-acceptable magnetic nanoparticles for biomedical application.

This review covers extensively the synthesis & surface modification, characterization, and application of magnetic nanoparticles. For biomedical applications, consideration should be given to factors such as design strategies, the synthesis process, coating, and surface passivation. The synthesis method regulates post-synthetic change and specific applications in vitro and in vivo imaging/diagnosis and pharmacotherapy/administration. Special insights have been provided on biodistribution, pharmacokinetics, and toxicity in a living system, which is imperative for their wider application in biology. These nanoparticles can be decorated with multiple contrast agents and thus can also be used as a probe for multi-mode imaging or double/triple imaging, for example, MRI-CT, MRI-PET. Similarly loading with different drug molecules/dye/fluorescent molecules and integration with other carriers have found application not only in locating these particles in vivo but simultaneously target drug delivery/hyperthermia inside the body. Studies are underway to collect the potential of these magnetically driven nanoparticles in various scientific fields such as particle interaction, heat conduction, imaging, and magnetism. Surely, this comprehensive data will help in the further development of advanced techniques for theranostics based on high-performance magnetic nanoparticles and will lead this research area in a new sustainable direction.

Amphotericin B loaded ethyl cellulose nanoparticles with magnified oral bioavailability for safe and effective treatment of fungal infection.

Amphotericin B is a gold standard drug used in various fungal and parasitic infection treatment. Most of the marketed formulations are administered intravenously, but show dose-dependent adverse effects i.e., nephrotoxicity and hemolysis. Oral route eliminates the toxic concern but exhibits poor bioavailability. Therefore, ethylcellulose nanoparticles (EC-NPs) have been used for magnified oral delivery of AmB, where EC provides gastrointestinal stability. These nanoparticles were synthesized by high-pressure emulsification solvent evaporation (HPESE) method and evaluated for in vitro and in vivo studies. This method yields small, monodisperse AmB-EC-NPs along with smooth surface morphology and improved encapsulation efficiency. The developed formulation showed a sustained release pattern following Higuchi diffusion kinetics along with gastric and storage stability. Aggregation study revealed that AmB was present in its monomeric form inside the biocompatible EC matrix. The antifungal result demonstrated that the MIC of AmB-EC-NPs was reduced ∼1/3rd than AmB and Fungizone® at 24 h whereas it was observed ∼1/8th at 48 h. in vivo pharmacokinetic analysis demonstrated 1.3-fold higher AUC than Fungizone® even at a 4.5-time lesser dose via the oral route and a ∼15-fold rise in the bioavailability in contrast to the native AmB. The hemolytic study revealed that the developed formulation exhibited 8-fold lesser hemolysis than Fungizone®. Furthermore, the biosafety profile of AmB-EC-NPs was ensured by the significantly lesser level of blood urea nitrogen and plasma creatinine along with the normal pattern of renal tubules in comparison to AmB and Fungizone®. In conclusion, the results stipulated that the AmB-EC-NPs could be effective, viable and a better alternative to currently existing iv formulations, for magnified oral delivery of AmB in the treatment of fungal infection without associated adverse effects.

Investigations of potent biocompatible metal-organic framework for efficient encapsulation and delivery of Gemcitabine: biodistribution, pharmacokinetic and cytotoxicity study.

Gemcitabine (GEM), a nucleoside analogue, is used for the treatment of various cancers. However, this drug possesses several limitations such as poor pharmacokinetics, metabolic degradation by cytidine deaminase, development of drug resistance, and schedule dependent toxicity. To circumvent these drawbacks, it can be entrapped in a suitable formulation for protection against metabolic degradation or urinary excretion. To this end, we have synthesized and investigated different iron (Fe-III)-based biocompatible metal-organic frameworks (MOFs), namely, MIL-101-NH2 (rigid), MIL-88A, and MIL-53 (flexible). All these MOFs have different topologies, connectivity, and chemical composition. MIL-53 was identified as a promising carrier for GEM delivery, with enhanced encapsulation and progressive release in relation to other candidates. The release of GEM from MIL-53 followed zero order kinetics, leading to an effective plasma concentration within the therapeutic range. Furthermore, in- vitro cytotoxicity study by using pancreatic cancer cell lines (MIAPaCa-2 and PANC1) stipulated that GEM loaded in MIL-53 (MIL53-GEM) had an increased cytotoxic effect relative to native GEM. Additionally, the slow release of GEM in a controlled manner could protect the drug from enzymatic degradation to increase its efficacy, half-life, and bioavailability without toxicity to organs as evidenced by in-vivo studies. This study demonstrates the potential of MIL53-GEM in upgrading the clinical outcome of GEM-based chemotherapy against cancer.

Inhalable bioresponsive chitosan microspheres of doxorubicin and soluble curcumin augmented drug delivery in lung cancer cells.

In present investigation, doxorubicin (Dox) and soluble curcumin (Cur-2-HP-ß-CD-complex) combination was simultaneously loaded in inhalable bioresponsive chitosan microspheres (Dox/Cur-2-HP-ß-CD-complex-elastin-CMs) bearing a substrate-stimuli, elastin. The mean particle size and mean aerodynamic diameter of inhalable bioresponsive microspheres displayed noteworthy differences after incorporation of elastin. Moreover, combination of Dox and soluble curcumin was molecularly dispersed in microspheres matrix as substantiated by a range of spectral techniques. Inhalable bioresponsive microspheres released astonishingly higher amount of Dox in presence of elastase enzyme at pH∼5.5 in comparison to pH∼7.4. However, the release of soluble curcumin from tailored bioresponsive microspheres in presence of elastase enzyme was independent of pH. Consistently, inhalable bioresponsive microspheres exhibited outstandingly lower IC50 of 3.4-µM in comparison to 6.5-µM of inhalable drug loaded microspheres (Dox/Cur-2-HP-ß-CD-complex-CMs) bearing no elastin, against A549, non-small cell lung cancer cells. The superior therapeutic profile of inhalable bioresponsive microspheres may be attributed to enhanced drug release and consequently augmented drug exposure to A549 cells expressing elastase enzyme. In this way, stimuli triggered drug release from tailored inhalable bioresponsive microspheres boosted the phenomena of apoptosis in A549 cells. In conclusion, Dox/Cur-2-HP-ß-CD-complex-elastin-CMs warrant further in-vivo tumor regression study to prove its therapeutic efficacy.

Vincristine sulfate loaded dextran microspheres amalgamated with thermosensitive gel offered sustained release and enhanced cytotoxicity in THP-1, human leukemia cells: In vitro and in vivo study.

Vincristine sulfate (VCS) is a drug of choice for the treatment of childhood and adult acute lymphocytic leukemia, Hodgkin's, non-Hodgkin's lymphoma as well as solid tumors including sarcomas. However, poor biopharmaceutical and pharmacokinetic traits of VCS like short serum half-life (12 min), high dosing frequency (1.4 mg/m(2) per week for 4 weeks) and extensive protein binding (75%) limit the clinical potential of VCS in cancer therapy. In present investigation, injectable vincristine sulfate loaded dextran microspheres (VCS-Dextran-MSs) were prepared and amalgamated with chitosan-ß-glycerophosphate gel (VCS-Dextran-MSs-Gel) to surmount the biopharmaceutical and pharmacokinetic limitations of VCS that consequently induced synergistic sustained release pattern of the drug. Particle size and zeta-potential of VCS-Dextran-MSs were measured to be 6.8 ± 2.4 µm and -18.3 ± 0.11 mV along with the encapsulation efficiency of about 60.4 ± 4.5%. Furthermore, VCS-Dextran-MSs and VCS-Dextran-MSs-Gel exhibited slow release pattern and 94.7% and 95.8% of the drug was released in 72 h and 720 h, respectively. Results from cell viability assay and pharmacokinetic as well as histopathological analysis in mice indicated that VCS-Dextran-MSs-Gel offers superior therapeutic potential and higher AUClast than VCS-Dextran-MSs and drug solution. In conclusion, VCS-Dextran-MSs-Gel warrants further preclinical tumor growth study to scale up the technology.

Fabrication, characterization and cytotoxicity studies of ionically cross-linked docetaxel loaded chitosan nanoparticles.

The present investigation aimed at the fabrication and characterization of ionically cross-linked docetaxel (DTX) loaded chitosan nanoparticles (DTX-CH-NP) using ionic gelation technique with sodium tripolyphosphate (TPP) as the cross-linking agent. The formulated nanoparticles were characterized in terms of particle size, drug entrapment efficiency (EE), scanning electron microscopy (SEM), in vitro release and cytotoxicity studies. Formulation factors (chitosan, TPP and drug concentration) were examined systematically for their effects on size of the nanoparticles. The average size of the nanoparticles was observed to be in the range of 159.2 ± 3.31 to 220.7 ± 2.23 nm with 78-92% encapsulation efficiency (EE). The in vitro cytotoxicity studies on breast cancer cell lines (MDA-MB-231) revealed the advantages of DTX-CH-NP over pure DTX with approximately 85% cell viability reduction. The results indicate that systematic modulation of the surface charge and particle size of ionically cross-linked nanoparticles can be readily achieved with the right control of critical processing parameters. Thus, DTX-CH-NP presents a promising delivery alternative for breast cancer treatment.

Stealth lipid coated aquasomes bearing recombinant human interferon-α-2b offered prolonged release and enhanced cytotoxicity in ovarian cancer cells.

PURPOSE: In present investigation, recombinant human interferon-α-2b (rhINF-α-2b) loaded aquasomes were prepared, optimized and overlaid with PEGylated phospholipid to offer prolong release and high therapeutic index against ovarian cancer, SKOV3 cells. METHODS AND RESULTS: Central Composite Design (CCD) and Response Surface Methodology (RSM) were employed to calculate the optimized conditions, 1:3 core to coat ratio, sonication power of 12.5W and time of about 55min for preparation of aquasomes. Consequently, rhINF-α-2b-Py-5-P-Aq.somes exhibited higher protein loading capacity and retained structural conformations of rhINF-α-2b, as compared to rhINF-α-2b-Cellob-Aq.somes, rhINF-α-2b-Tre-Aq.somes and rhINF-α-2b-Core (CaHPO4). Further, optimized rhINF-α-2b-Py-5-P-Aq.somes was superimposed with phospholipid-PEG2000 to prolong the release pattern of rhINF-α-2b from aquasomes. The rhINF-α-2b-core (CaHPO4) released 97.3% of protein in 1h, while 95.3% of rhINF-α-2b was released by rhINF-α-2b-Tre-Aq.somes in 4h. Concurrently, rhINF-α-2b-Cellob-Aq.somes and rhINF-α-2b-Py-5-P-Aq.somes released 96.2% and 97.8% of rhINF-α-2b respectively in 6 and 8h. Ultimately, rhINF-α-2b-Py-5-P-Aq.somes-P-PEG2000 displayed evidence of its prolonged release pattern and released 98.1% of rhINF-α-2b in 336h. FT-IR and XRD substantiated the involvement of vigorous intermolecular hydrogen bonding and amorphous geometry in rhINF-α-2b-Py-5-P-Aq.somes. In last, rhINF-α-2b-Py-5-P-Aq.somes-P-PEG2000 exhibited the∼4.55, 1.92, 2.3, 2.8, and 3.84 fold reductions in IC50 as compared to free rhINF-α-2b, rhINF-α-2b-Py-5-P-Aq.somes, rhINF-α-2b-Cellob-Aq.somes, rhINF-α-2b-Tre-Aq.somes and rhINF-α-2b-Core (CaHPO4), respectively. CONCLUSION: Therefore, rhINF-α-2b-Py-5-P-Aq.somes-P-PEG2000 warrant further in depth in vitro and in vivo antitumor study to scale up the technology for clinical intervention.

Docetaxel loaded chitosan nanoparticles: formulation, characterization and cytotoxicity studies.

The primary objective of the present investigation was to explore biodegradable chitosan as a polymeric material for formulating docetaxel nanoparticles (DTX-NPs) to be used as a delivery system for breast cancer treatment. Docetaxel loaded chitosan nanoparticles were formulated by water-in-oil nanoemulsion system and characterized in terms of particle size, zeta potential, polydispersity index, drug entrapment efficiency (EE), loading capacity (LC), scanning electron microscopy (SEM), in vitro release study and drug release kinetics. Further, to evaluate the potential anticancer efficacy of docetaxel loaded chitosan nanoparticulate system, in vitro cytotoxicity studies on human breast cancer cell line (MDA-MB-231) were carried out. The morphological studies revealed the spherical shape of docetaxel loaded chitosan nanoparticles having an average size of 170.1±5.42-227.6±7.87nm, polydispersity index in the range of 0.215±0.041-0.378±0.059 and zeta potential between 28.3 and 31.4mV. Nanoparticles exhibited 65-76% of drug entrapment and 8-12% loading capacity releasing about 68-83% of the drug within 12h following Higuchi's square-root kinetics. An increase of 20% MDA-MB-231 cell line growth inhibition was determined by docetaxel loaded chitosan nanoparticles with respect to the free drug after 72h incubation.