Amphotericin
B (AmB) is one of the most effective drugs used in the treatment of
leishmaniasis and systemic fungal infections. Considering the global
burden of leishmaniasis, ∼90% of disease cases occur in developing
countries, suggestive of the need for an affordable AmB therapy. However,
owing to the physicochemical properties of AmB, all the clinically
available formulations must be administered by intravenous route,
thereby creating a significant hurdle in patients’ access to
AmB due to pharmacoeconomic considerations. We have previously demonstrated
that lipid conjugation (e.g., fatty acids) to AmB significantly decreases
the toxicity of resulting prodrug by a favorable alteration in the
aggregation pattern. The hypothesis of the present work was to investigate
the potential of the previously established AmB-lipid conjugate [AmB-oleyl
conjugate (AmB-OA)] in improving the physicochemical properties such
as gastric instability and lower intestinal permeability that otherwise
limits the oral delivery of AmB. The synthesized AmB-OA conjugate
was remarkably stable at gastric pH in contrast to AmB and exhibited
significantly higher permeation across the Caco-2 monolayer (indicative
of intestinal permeability). Mechanistic studies revealed that AmB-OA
retained an equivalent antifungal activity. Also, AmB-OA was found
to interact preferentially with intracellular membranes of Saccharomyces cerevisiae, while AmB interacted with
the plasma membrane. The results of Caco-2 monolayer permeation experiments
were further confirmed by in vivo pharmacokinetics, which showed that
AmB-OA exhibited a 3.13-fold increase in the C
max and a 4.88-fold increase in AUCTot as compared
to AmB. In conclusion, the lipid conjugation approach may provide
an effective solution for current challenges in designing drug delivery
systems intended for oral AmB therapy.
miR-34a is a master tumor suppressor playing a key role in the several signaling mechanisms involved in cancer. However, its delivery to the cancer cells is the bottleneck in its clinical translation. Herein we report cationic amphiphilic copolymers grafted with cholesterol (chol), N, N-dimethyldipropylenetriamine (cation chain) and 4-(2-aminoethyl)morpholine (morph) for miR-34a delivery. The copolymer interacts with miR-34a at low N/P ratios (∼2/1) to form nanoplexes of size ∼108 nm and a zeta potential ∼ +39 mV. In vitro studies in 4T1 and MCF-7 cells indicated efficient transfection efficiency. The intracellular colocalization suggested that the copolymer effectively transported the FAM labeled siRNA into the cytoplasm within 2 h and escaped from the endo-/lysosomal environment. The developed miR-34a nanoplexes inhibited the breast cancer cell growth as confirmed by MTT assay wherein 28% and 34% cancer cell viability was observed in 4T1 and MCF-7 cells, respectively. Further, miR-34a nanoplexes possess immense potential to induce apoptosis in both cell lines.
Aim: To design a nanocarrier platform for enhanced transdermal drug permeation. Materials & methods: Gel-based high permeation vesicles (HPVs) were developed and their performance in terms of transdermal flux improvement, in vitro release and skin irritancy was assessed. The mechanistic insights of permeation enhancement were explored using confocal laser scanning microscopy, ATR-FTIR, DSC and P31 NMR. Results: HPVs exhibited as vesicles with uniform size (∼150 nm), extended drug-release profile (∼48 h) and improved transdermal flux. HPVs were also nontoxic and nonirritant to skin. Enhanced vesicle deformability, improved vesicle membrane fluidity and synergistic permeation enhancement action of synergistic combination of permeation enhancer components was found to be responsible for HPV-mediated permeation enhancement. Conclusion: Overall, the study established that HPVs demonstrate a promising therapeutic advantage over conventional transdermal drug carriers.
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