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Biodegradable nanocarriers possess enormous potential for use as drug delivery systems that can accomplish controlled and targeted drug release, and a wide range of nanosystems have been reported for the treatment and/or diagnosis of various diseases and disorders. Of the various nanocarriers currently available, liposomes and polymer nanoparticles have been extensively studied and some formulations have already reached the market. However, a combination of properties to create a single hybrid system can give these carriers significant advantages, such as improvement in encapsulation efficacy, higher stability, and active targeting towards specific cells or tissues, over lipid or polymer-based platforms. To this aim, this work presents the formulation of poly(lactic-co-glycolic) acid (PLGA) nanoparticles in the presence of a hyaluronic acid (HA)-phospholipid conjugate (HA-DPPE), which was used to anchor HA onto the nanoparticle surface and therefore create an actively targeted hybrid nanosystem. Furthermore, ionic interactions have been proposed for drug encapsulation, leading us to select the free base form of pentamidine (PTM-B) as the model drug. We herein report the preparation of hybrid nanocarriers that were loaded via ion-pairing between the negatively charged PLGA and HA and the positively charged PTM-B, demonstrating an improved loading capacity compared to PLGA-based nanoparticles. The nanocarriers displayed a size of below 150 nm, a negative zeta potential of -35 mV, a core-shell internal arrangement and high encapsulation efficiency (90%). Finally, the ability to be taken up and exert preferential and receptor-mediated cytotoxicity on cancer cells that overexpress the HA specific receptor (CD44) has been evaluated. Competition assays supported the hypothesis that PLGA/HA-DPPE nanoparticles deliver their cargo within cells in a CD44-dependent manner., (© 2024. Controlled Release Society.)

Nanomedicine aims to develop smart approaches for treating cancer and other diseases to improve patient survival and quality of life. Novel nanoparticles as nanodiamonds (NDs) represent promising candidates to overcome current limitations. In this study, NDs were functionalized with a 200 kDa hyaluronic acid-phospholipid conjugate (HA/DMPE), enhancing the stability of the nanoparticles in water-based solutions and selectivity for cancer cells overexpressing specific HA cluster determinant 44 (CD44) receptors. These nanoparticles were characterized by diffuse reflectance Fourier-transform infrared spectroscopy, Raman spectroscopy, and photoluminescence spectroscopy, confirming the efficacy of the functionalization process. Scanning electron microscopy was employed to evaluate the size distribution of the dry particles, while dynamic light scattering and zeta potential measurements were utilized to evaluate ND behavior in a water-based medium. Furthermore, the ND biocompatibility and uptake mediated by CD44 receptors in three different models of human adenocarcinoma cells were assessed by performing cytofluorimetric assay and confocal microscopy. HA-functionalized nanodiamonds demonstrated the advantage of active targeting in the presence of cancer cells expressing CD44 on the surface, suggesting higher drug delivery to tumors over non-tumor tissues. Even CD44-poorly expressing cancers could be targeted by the NDs, thanks to their good passive diffusion within cancer cells.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and is characterized by poor clinical outcomes, with the majority of patients not being eligible for curative therapy and treatments only being applicable for early-stage tumors. CD44 is a receptor for hyaluronic acid (HA) and is involved in HCC progression. The aim of this work is to propose HA- and PEGylated-liposomes as promising approaches for the treatment of HCC. It has been found, in this work, that CD44 transcripts are up-regulated in HCC patients, as well as in a murine model of NAFLD/NASH-related hepatocarcinogenesis. Cell culture experiments indicate that HA-liposomes are more rapidly and significantly internalized by Huh7 cells that over-express CD44, compared with HepG2 cells that express low levels of the receptor, in which the uptake seems due to endocytic events. By contrast, human and murine macrophage cell lines (THP-1, RAW264.7) show improved and rapid uptake of PEG-modified liposomes without the involvement of the CD44. Moreover, the internalization of PEG-modified liposomes seems to induce polarization of THP1 towards the M1 phenotype. In conclusion, data reported in this study indicate that this strategy can be proposed as an alternative for drug delivery and one that dually and specifically targets liver cancer cells and infiltrating tumor macrophages in order to counteract two crucial aspect of HCC progression.

This work provides information on the features of low molecular weight hyaluronic acid (HA)-decorated liposomes to target resveratrol (RSV) in the skin. Deformable liposomes were made of soy-phosphatidylcholine with Tween 80 as the fluidizing agent. For HA conjugation, three different phosphoethanolamines were tested: 1,2-dipalmitoyl- sn -glycero-3-phosphoethanolamine (DPPE), 1,2-dimyristoyl- sn -glycero-3-phosphoethanolamine (DMPE), and 1,2-dioleoyl- sn -glycero-3-phosphoethanolamine (DOPE). The different phosphoethanolamine-HA conjugates were inserted into the liposome bilayer by hydration (HA on both faces of the bilayer) or by the postinsertion method (HA only on the external face of the bilayer). The effect of these variables on deformability was experimentally assessed by an in-house method ( K value, the lower the value, the higher the deformability) and molecular dynamics (MD) simulations. The results showed that the K values of HA-liposomes obtained by hydration were higher than the K values of HA-liposomes prepared by postinsertion, and both were at least 10-fold higher than the K values of the corresponding plain liposomes. The nature of the lipid anchor played a key role in deformability (DMPE > DOPE > DPPE) with high variability in the case of DOPE formulations. These data were justified by the trends found in silico for the bilayer bending modulus and the HA end-to-end distance. In addition to liposome flexibility, the HA extent seems to be the key factor governing the skin penetration of RSV. When the extent is higher, the amount of the drug retained in the skin is larger. Regarding skin permeation, a parabolic trend was recorded, and the optimal amount to favor skin permeation was an approximately 30 HA/phospholipid (μg/mmol) ratio. This study reports the first piece of evidence that it is possible to control drug delivery in the skin by tuning the amount of HA on the vesicle surface.

Chronic lung allograft dysfunction (CLAD) and interstitial lung disease associated with collagen tissue diseases (CTD-ILD) are two end-stage lung disorders in which different chronic triggers induce activation of myo-/fibroblasts (LFs). Everolimus, an mTOR inhibitor, can be adopted as a potential strategy for CLAD and CTD-ILD, however it exerts important side effects. This study aims to exploit nanomedicine to reduce everolimus side effects encapsulating it inside liposomes targeted against LFs, expressing a high rate of CD44. PEGylated liposomes were modified with high molecular weight hyaluronic acid and loaded with everolimus (PEG-LIP(ev)-HA400kDa). Liposomes were tested by in vitro experiments using LFs derived from broncholveolar lavage (BAL) of patients affected by CLAD and CTD-ILD, and on alveolar macrophages (AM) and lymphocytes isolated, respectively, from BAL and peripheral blood. PEG-LIP-HA400kDa demonstrated to be specific for LFs, but not for CD44-negative cells, and after loading everolimus, PEG-LIP(ev)-HA400kDa were able to arrest cell cycle arrest and to decrease phospho-mTOR level. PEG-LIP(ev)-HA400kDa showed anti-inflammatory effect on immune cells. This study opens the possibility to use everolimus in lung fibrotic diseases, demonstrating that our lipids-based vehicles can vehicle everolimus inside cells exerting the same drug molecular effect, not only in LFs, but also in immune cells.

In this work hyaluronic acid (HA) oligosaccharides with degree of polymerization (DP) 4, 6 and 8, obtained by enzymatic depolymerization of HA, were conjugated to a PEG-phospholipid moiety. The products (HA-DP4, HA-DP6 and HA-DP8) were used to prepare decorated liposomes. The cellular uptake of HA-DP4, HA-DP6 and HA-DP8-decorated fluorescently labelled liposomes was significantly higher (12 to 14-fold) in lung cancer cell lines with high CD44 expression than in those with low CD44 expression, suggesting a receptor-mediated entry of HA-conjugated formulations. Competition assays showed that the uptake followed this rank order: HA-DP8>HA-DP6>HA-DP4 liposomes. Moreover, they are capable of a faster interaction with CD44, followed by phagocytosis, than HA liposomes obtained from HA of higher molecular weight (4800 and 14800 Da). HA-DP4, HA-DP6 and HA-DP8-liposomes did not show cytotoxicity or inflammatory effects. Overall, we propose our new HA-DP oligosaccharides as biocompatible and effective tools for a potential drug delivery to CD44-positive cells., (Copyright © 2020 Elsevier Ltd. All rights reserved.)