Among respiratory infections, tuberculosis was the second deadliest infectious disease in 2020 behind COVID-19. Inhalable nanocarriers offer the possibility of actively targeting anti-tuberculosis drugs to the lungs, especially to alveolar macrophages (cellular reservoirs of the Mycobacterium tuberculosis). Our strategy was based on the development of a mannose-decorated micellar nanoformulation based in Soluplus^® to co-encapsulate rifampicin and curcumin. The former is one of the most effective anti-tuberculosis first-line drugs, while curcumin has demonstrated potential anti-mycobacterial properties. Mannose-coated rifampicin (10 mg/mL)–curcumin (5 mg/mL)-loaded polymeric micelles (10% w/v) demonstrated excellent colloidal properties with micellar size ~108 ± 1 nm after freeze-drying, and they remain stable under dilution in simulated interstitial lung fluid. Drug-loaded polymeric micelles were suitable for drug delivery to the deep lung with lung accumulation, according to the in vitro nebulization studies and the in vivo biodistribution assays of radiolabeled (99mTc) polymeric micelles, respectively. Hence, the nanoformulation did not exhibit hemolytic potential. Interestingly, the addition of mannose significantly improved (5.2-fold) the microbicidal efficacy against Mycobacterium tuberculosis H37Rv of the drug-co-loaded systems in comparison with their counterpart mannose-free polymeric micelles. Thus, this novel inhaled nanoformulation has demonstrated its potential for active drug delivery in pulmonary tuberculosis therapy.

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Currently, paclitaxel (PTX) represents the first-line therapy for TNBC; however it presents a hydrophobic behavior and produces severe adverse effects. The aim of this work is to improve the therapeutic index of PTX through the design and characterization of novel nanomicellar polymeric formulations composed of a biocompatible copolymer Soluplus^® (S), surface-decorated with glucose (GS), and co-loaded either with histamine (HA, 5 mg/mL) and/or PTX (4 mg/mL). Their micellar size, evaluated by dynamic light scattering, showed a hydrodynamic diameter between 70 and 90 nm for loaded nanoformulations with a unimodal size distribution. Cytotoxicity and apoptosis assays were performed to assess their efficacy in vitro in human MDA-MB-231 and murine 4T1 TNBC cells rendering optimal antitumor efficacy in both cell lines for the nanoformulations with both drugs. In a model of TNBC developed in BALB/c mice with 4T1 cells, we found that all loaded micellar systems reduced tumor volume and that both HA and HA-PTX-loaded SG micelles reduced tumor weight and neovascularization compared with the empty micelles. We conclude that HA-PTX co-loaded micelles in addition to HA-loaded formulations present promising potential as nano-drug delivery systems for cancer chemotherapy.

Vismodegib is a first-in-class inhibitor for advanced basal cell carcinoma treatment. Its daily oral doses present a high distribution volume and several side effects. We evaluated its skin penetration loaded in diverse nanosystems as potential strategies to reduce side effects and drug quantities. Ultradeformable liposomes, ethosomes, colloidal liquid crystals, and dendrimers were able to transport Vismodegib to deep skin layers, while polymeric micelles failed at this. As lipidic systems were the most effective, we assessed the in vitro and in vivo toxicity of Vismodegib-loaded ultradeformable liposomes, apoptosis, and cellular uptake. Vismodegib emerges as a versatile drug that can be loaded in several delivery systems for topical application. These findings may be also useful for the consideration of topical delivery of other drugs with a low water solubility.

Background: Latent tuberculosis infection (LTBI) remains a global health challenge, in part due to the ability of Mycobacterium tuberculosis (Mtb) to persist within granulomatous lesions where drug exposure may be limited. Because granulomas are heterogeneous structures composed of different macrophage populations, targeting disease-relevant intracellular niches may improve antimicrobial treatment. Here, we developed mannose-functionalized polymeric micelles loaded with isoniazid (INH) to target mannose receptor (CD206)-expressing macrophages within a human tuberculosis granuloma model. Methods: Mannose-functionalized Soluplus^® micelles loaded with INH (ManPM-INH) and non-functionalized micelles (PM-INH) were characterized for particle size, polydispersity, and colloidal stability. Antimycobacterial activity against MtbH37Rv was evaluated by CFU assays. A human peripheral blood mononuclear cell (PBMC) three-dimensional in vitro granuloma model was used to assess micelle accumulation and antimycobacterial activity. Cellular uptake was evaluated in M0, M1, and M2 macrophages using rhodamine-labeled micelles. CD206-associated and clathrin-mediated uptake were investigated using D-mannose and chlorpromazine, respectively. Results: ManPM-INH exhibited suitable physicochemical properties and maintained colloidal stability after mannose functionalization. In the granuloma model, ManPM showed significantly greater intracellular accumulation than PM. M2-like macrophages predominated within granulomas, and ManPM displayed preferential uptake by M2 macrophages. Furthermore, D-mannose competitively reduced ManPM uptake in macrophages with significantly greater inhibition in M2 cells. Chlorpromazine reduced ManPM internalization, supporting involvement of a clathrin-dependent pathway. ManPM-INH achieved the greatest reduction in intracellular MtbH37Rv burden compared with INH and PM-INH, particularly at low drug concentrations. Conclusions: Mannose-functionalized micelles enhance intracellular INH delivery by targeting CD206-expressing macrophages within tuberculosis granuloma, supporting macrophage-targeted nanotherapeutic strategies against persistent intracellular Mtb.