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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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The currently available systemic chemotherapy for treating breast cancer often results in serious systemic side effects and compromises patient compliance. The distinct anatomical features of human breasts (e.g., embryological origin of breast skin, highly developed internal lymphatic and venous circulation, and the presence of mammary fat layers) help in preferential accumulation of drugs into breasts after topical application on breast region. This unique feature is termed as localized transdermal delivery which could be utilized for effectively delivering anticancer agents to treat breast cancer and reducing the systemic side effects by limiting their presence in blood. However, the clinical effectiveness of this drug delivery approach is highly limited by barrier properties of skin reducing the permeation of anticancer drugs. In the present work, we have developed high permeation vesicles (HPVs) using phospholipids and synergistic combination of permeation enhancers (SCOPE) to improve the skin permeation of drugs. Docetaxel (DTX) was used as a model drug for hypothesis testing. The optimized SCOPE mixture composed of sodium oleate/sodium lauryl ether sulfate/propylene glycol in 64:16:20% w/w ratio. DTX HPVs were prepared using phospholipid: SCOPE, 8:2% w/w ratio. DTX HPVs exhibited as a uniform deformable vesicles with size range 124.2 ± 7.6 nm, significantly improved skin permeation profile, and sustained drug release until 48 h. Superior vesicle deformability, better vesicle membrane fluidization, and SCOPE mediated enhancement in skin fluidization were the prime factors behind enhancement of DTX permeation. The improved cellular uptake, reduced IC50 values, and higher apoptotic index of DTX HPVs in MCF-7 and MDA-MB-231 cells ensured the therapeutic effectiveness of HPV based therapy. Also, HPVs were found to be predominantly internalized inside cells through clathrin and caveolae-dependent endocytic pathways. Bioimaging analysis in mice confirmed the tumor penetration potential and effective accumulation of HPVs inside tumors after topical application. In vivo studies were carried out in comparison with marketed intravenous DTX injection (Taxotere) to compare the effectiveness of topical chemotherapy. The topical application of DTX HPV gel in tumor bearing mice resulted in nearly 4-fold tumor volume reduction which was equivalent to intravenous Taxotere therapy. Toxicity analysis of DTX HPV gel in comparison with intravenous Taxotere dosing showcased remarkably lower levels of toxicity biomarkers (aspartate transaminase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), and creatinine), indicating improved safety of topical chemotherapy. Overall results warranted the effectiveness of topical DTX chemotherapy to reduce tumor burden with substantially reduced risk of systemic toxicities in breast cancer.

PEGylation (i.e., attachment of polyethylene-glycol) of carbon nanotubes (CNTs) is one of the most widely used strategies to improve its biocompatibility and aqueous dispersion stability, which are critical for their successful clinical application. However, PEGylation of nanomaterials has recently been associated with production of anti-PEG antibody, low cellular uptake, and degradation. Herein, we explore surface functionalization of CNTs using the bovine-milk-derived protein succinylated β-lactoglobuline (Sblg) as an alternative strategy to PEGylation. The aqueous dispersion stability, in vitro cell uptake and biocompatibility of Sblg-functionalized multiwalled CNTs (Sblg-f-MWCNTs) was compared to PEGylated MWCNTs (PEG-f-MWCNTs). The surface functionalization with Sblg was found to improve the IC50 values of CNTs by ∼5- to 6-fold in comparison with pristine CNTs in various cell lines. Both Sblg-f-MWCNTs and PEG-f-MWCNTs improved the aqueous colloidal stability of CNTs, which remained suspended for a period of one month. Our study concluded that the Sblg provides a cost-effective alternative to the PEG-based CNT functionalization with significant improvement in the biocompatibility and dispersion stability of CNTs.

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