Direct radiolabeling of methotrexate and methotrexate micelles with Tc-99m using QbD approach.

The aim of the work presented in this manuscript was to radiolabel methotrexate and prepare radiolabeled methotrexate micelles, an antifolate drug with Tc-99m using QbD approach. The radiolabeling was executed using the experimental design and the radiolabeled drug was further encapsulated in micelles. The authors are of the view that the radiolabeled MTX could be used to target the folate receptor overexpressing cancers such as the kidney, colorectal, breast, brain etc thereby opening newer possibilities to the theranostic applications of the formed conjugate.

Radiolabelled folate micellar carriers as proposed diagnostic aid for CNS tumors by nasal route.

Glioma refers to the most atypical variant of the malignant central nervous system tumors posturing massive challenge to the research fraternity owing to the flimsy improvement in the patient survival rate over the past years. The aim of the proposed work was developing a diagnostic aid for brain tumors, which could be administered via the non-invasive intranasal route. Since overexpression of folate receptors in the central nervous system tumors is 500 times more than the normal healthy cells, we aimed at fabricating a radiolabeled folate encapsulated micellar delivery system to be given via the nasal route. Folate conjugated bifunctional chelating agent was synthesized, radiolabeled with 99mTc, and encapsulated in a micellar carrier. The fabricated micelles were further evaluated for in vivo nasal toxicity in rats and the same were found safe for intranasal administration. The fabricated micelles owing to their nano size, mucoadhesive nature, and enhanced permeation were observed to have a higher uptake into the brain (around 16% in 4 h) than as compared to the radiolabeled conjugated folate solution when studied for in vivo biodistribution in mice. Single-photon emission computerized tomography imaging performed in higher animals upon intranasal administration of the micellar formulation revealed enhanced uptake of the micelles into the animal brain. It is believed that the aforementioned formulation can be of a great diagnostic value in the detection of not only brain tumors but also other folate expressing cancers such as cervical, breast, and lungs as the system is fast, non-toxic, accurate, non-invasive, and simple.

Nose-to-brain delivery: exploring newer domains for glioblastoma multiforme management.

Glioblastoma multiforme (GBM) is the most common and aggressive form of the primary brain tumors in humans. The intricate pathophysiology, the development of resistance by tumor cells, and the inability of the drugs to effectively cross the blood-brain and blood-tumor barriers result in poor prognosis for GBM patients, with a median survival time of only 1 to 2 years. Nose-to-brain delivery offers an attractive, noninvasive strategy to enhance drug penetration or transport novel drug/gene carriers into the brain. Although the exact mechanism of intranasal delivery remains elusive, the olfactory and trigeminal nerve pathways have been found to play a vital role in circumventing the traditional barriers of brain targeting. This review discusses the intranasal pathway as a novel domain for delivering drugs and nanocarriers encapsulating drugs/genes, as well as stem cell carriers specifically to the glioma cells. Considering the fact that most of these studies are still in preclinical stage, translating such intranasal delivery strategies from bench to bedside would be a critical step for better management and prognosis of GBM. Graphical abstract.

Preparation and Characterization of Micelles.

Nanoformulations in the past few decades have gained tremendous attention owing to their affirmative applications in increasing the bioavailability of poorly soluble drugs. Micelles in particular are favored due to their varied advantages which include thermodynamic stability, simple formulating steps, Newtonian flow, and enhanced biological barrier penetration. Owing to these advantages micellar nanosystems find extensive applications in oral, transdermal, and parenteral administration, and are now being explored for ocular and other noninvasive novel pathways of drug delivery such as nose to brain. In this chapter, we have discussed the protocol for the preparation of sumatriptan loaded micelles for the therapy of migraine. The inner core of these micelles comprises hydrophobic region of diblock polymer which holds the drug, while the hydrophilic region of the same provides conformational stability in the aqueous environment.

Fabrication and efficacy evaluation of chloroquine nanoparticles in CFA-induced arthritic rats using TNF-α ELISA.

Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, stimulates various immune cells especially macrophages, causing release of various proinflammatory cytokines such as TNF-α leading to persistent synovitis. Chloroquine, an anti-malarial drug inhibits the production of TNF-α, thus, halting the disease progression. The aim of the present study was fabrication, characterization and demonstration of kinetic and dynamic efficacy of chloroquine loaded solid lipid nanoparticles (CQ-SLNs) in arthritic rats and in lowering TNF-α levels. CQ-SLNs were prepared using melt homogenization method and subjected to lyophilization. The particle size, zeta potential, PDI and entrapment efficiency were found to be 113.6±0.15nm, -27.8±1.21mV, 0.125±0.03 and 93.45±0.43% respectively. Ex vivo endocytic uptake studies revealed engrossment of endocytic pathways in the uptake of SLN from intestine. Plasma drug profile upon pharmacokinetic evaluation demonstrated increased AUC, half-life and decreased elimination rate of the drug. Pharmacodynamic studies revealed reduction in the paw volume, bone erosion and cartilage destruction, the same was also reflected in histopathological studies. The TNF-α ELISA concluded that the TNF-α level was significantly reduced in the synovial fluid upon treatment with CQ-SLN, thus, leading to the conclusion that CQ-SLN could be used as a potential in reducing inflammatory TNF-α at the arthritic site and halting the disease progression.

Formulation of mucoadhesive gastric retentive drug delivery using thiolated xyloglucan.

Tamarind seed xyloglucan is a polymer reported to possess mucoadhesive property. In the present work, role of cysteine derivative of tamarind seed polysaccharide (thiomer) to enhance the mucoadhesion and its influence on drug permeation has been studied. The xyloglucan was first chemically modified to carboxymethyl derivative which was further converted to thiomer by conjugation with cysteine in presence of a coupling agent, EDAC. The matrix tablets of simvastatin prepared using thiomer demonstrated drug release retardation, increased mucoadhesion force and increased ex vivo permeation, the same were proportional to the increase in the amount of thiomer. The in vivo residence of thiomer placebo was more than 7h in rabbit. Pharmacokinetic evaluation in rabbits indicated higher AUC for the formulation with highest content of thiomer and level 'A' correlation could be established from the generated dissolution and bioavailability data.

In-vivo bioavailability and lymphatic uptake evaluation of lipid nanoparticulates of darunavir.

Darunavir is effective against wild-type and PI-resistant HIV, and has an oral bioavailability of 37%. It needs to be combined with ritonavir, which increases the bioavailability to 82%. The aim of this study was to evaluate the in-vivo efficacy of the darunavir-SLN and demonstrate lymphatic transport as a contributing pathway in increasing the drug bioavailability. The SLN was prepared by hot-homogenization technique using GMS as lipid. In-vitro drug release from SLN at the 12th hour was retarded (80.6%) compared to marketed tablet (92.6%). Ex-vivo apparent permeability of the freeze-dried SLN across everted rat intestine was 24 × 10-6 at 37 °C and 5.6 × 10-6 at 4 °C. The presence of endocytic process inhibitors like chlorpromazine and nystatin reduced it to 18.8 × 10-6 and 20.2 × 10-6, respectively, which established involvement of endocytic mechanism in the uptake of SLN. In-vivo pharmacokinetic studies on rats demonstrated increase in the AUC of SLN (26) as compared to that of marketed tablet (13.22), while the presence of lymphatic uptake inhibitor cycloheximide lowered the AUC of SLN to 17.19 which further led credence to the involvement of lymphatic uptake behind improved bioavailability. The detection of darunavir in the lymphatic fluid of the rats administered with darunavir-SLN further reinforced the conclusion of SLN being taken up by the lymphatic system.

Formulation and evaluation of Adapalene-loaded nanoparticulates for epidermal localization.

Adapalene (ADP), a topically administered antiacne drug, finds limitation due to poor penetration, limited localization, and associated incompatibility of photosensitization and skin irritation. To explicate an innovative and safe method for ADP administration and alleviating the associated limitations, solid lipid nanoparticles (SLN) of ADP have been fabricated and evaluated for efficacy in the present work. The SLN were prepared using pre-emulsion sonication method and incorporated into convenient topical dosage form, hydrogels. In vitro permeation studies of the hydrogels through HCS indicated gel containing ADP-SLN showed 2-fold more accumulation in skin layers as compared to conventional ADP gel. Rheological studies demonstrated ADP-SLN gel to possess pseudoplastic behavior, occlusion and hydration studies revealed permeation effectiveness of ADP-SLN gel over conventional ADP gel while primary skin irritation studies established safety of the ADP-SLN gel upon topical application. Hence, it was concluded that the studied ADP-SLN formulation with skin localizing ability may be a promising carrier for topical delivery of ADP.