Evaluation of polycaprolactone matrices for sustained intravaginal delivery of a natural macromolecular microbicide, lactoferrin

Polycaprolactone (PCL) matrices incorporating lactoferrin as a natural macromolecular microbicide, were prepared by rapidly cooling a suspension of lactoferrin particulates in PCL solution to induce crystallisation and hardening of the polymer. Thermal analysis revealed a 7% decrease in crystallinity of the PCL phase for 10% lactoferrin-loaded matrices compared with lactoferrin-free matrices and a 41% decrease in hardness of lactoferrin -loaded matrices, indicating a major influence of lactoferrin through inhibition of PCL crystal nucleation and growth. Exposure of the matrices to simulated vaginal fluid (SVF) at 37 °C resulted in rapid release of 13–14% of the lactoferrin content on day 1 and sustained delivery of the glycoprotein with high efficiency (90–95% of the content) over 14 days. SDS-PAGE analysis confirmed molecular weight preservation of the lactoferrin released from PCL matrices into SVF, indicating that it was not degraded during formulation and release. These findings recommend further investigations of PCL matrices as vaginal delivery systems for controlled release of macromolecular microbicides in the treatment and prevention of sexually transmitted infections

Pristine mesoporous carbon hollow spheres as safe adjuvants induce excellent Th2-biased immune response

The development of a safe and effective adjuvant that amplifies the immune response to an antigen is important for vaccine delivery. In this study, we developed pristine mesoporous carbon hollow spheres as high-capacity vaccine protein nanocarriers and safe adjuvants for boosting the immune response. Mono-dispersed invaginated mesostructured hollow carbon spheres (IMHCSs) have an average particle size of ∼200 nm, large pore size of 15 nm, and high pore volume of 2.85 cm·g. IMHCSs exhibited a very high loading capacity (1,040 μg·mg) towards ovalbumin (OVA, a model antigen), controlled OVA release behavior, excellent safety profile to normal cells, and high antigen delivery efficacy towards macrophages. In vivo immunization studies in mice demonstrated that OVA-loaded IMHCSs induced a 3-fold higher IgG response compared to a traditional adjuvant QuilA used in veterinary vaccine research. OVA delivered by IMHCSs induced a higher IgG1 concentration than IgG2a, indicating a T-helper 2 (Th2)-polarized response. Interferon-γ and interleukin-4 concentration analysis revealed both T-helper 1 (Th1) and Th2 immune responses induced by OVA-loaded IMHCSs. IMHCSs are safer adjuvants than QuilA. Our study revealed that pure IMHCSs without further functionalization can be used as a safe adjuvant for promoting Th2-biased immune responses for vaccine delivery

Understanding the effect of surface chemistry of mesoporous silica nanorods on their vaccine adjuvant potency

Mesoporous silica nanoparticles are reported as adjuvants in nanovaccines in generating robust antigen-specific immunity. However, the effect of surface chemistry in initiating and modulating the immune response remains largely unexplored. In this study, mesoporous silica nanorods (MSNRs) are modified with -NH2 and -C-18 groups to investigate the influence of surface functional groups (-OH, -NH2, and -C-18) on their adjuvant efficacy. It is found that compared to -OH and -NH2 groups, the hydrophobic -C-18 modification significantly enhances antigen uptake by antigen presenting cells and endosomal-lysosomal escape in vitro, dendritic cells, and macrophages maturation ex vivo, and elicits secretion of interferon-gamma level and antibody response in immunized mice. Moreover, bare MSNR and MSNR -NH2 exhibit T-helper 2 biased immune response, while MSNR -C-18 shows a T-helper 1 biased immune response. These findings suggest that the surface chemistry of nanostructured adjuvants has profound impact on the immune response, which provides useful guidance for the design of effective nanomaterial based vaccines

Asymmetric mesoporous silica nanoparticles as potent and safe immunoadjuvants provoke high immune responses

Asymmetric mesoporous silica nanoparticles with a head-tail structure are potent immunoadjuvants for delivering a peptide antigen, generating a higher antibody immune response in mice compared to their symmetric counterparts

Designed synthesis of organosilica nanoparticles for enzymatic biodiesel production

Porous nanomaterials are of great significance in enzyme immobilization by addressing the intrinsic issues of the native form of enzymes, such as low enzymatic activity and reusability. In this work, we report the successful fabrication of benzene-bridged dendritic mesoporous organosilica nanoparticles (BDMONs) with highly enriched benzene groups in the pore channel wall by a delayed addition method. The developed BDMONs were explored as nano-carriers for lipase immobilization. This platform exhibited a specific activity 6.5 times higher than that of the free enzyme with an excellent reusability, and enhanced thermal and pH stability. It is demonstrated that both the hydrophobic benzene groups and dendritic large-pores are responsible for the superior performance of the immobilized lipase in comparison with dendritic mesoporous silica nanoparticles, ethane-bridged dendritic mesoporous organosilica nanoparticles, and benzene-bridged MONs without large-pores. In particular, the designed nanobiocatalyst functions better than the free enzyme in the transesterification of corn oil to produce biodiesel, showing 93% conversion in the first cycle while retaining 94% of the initial catalytic activity after 5 cycles

Mesoporous Organosilica Nanoparticles to Fight Intracellular Staphylococcal Aureus Infections in Macrophages

Intracellular bacteria are inaccessible and highly tolerant to antibiotics, hence are a major contributor to the global challenge of antibiotic resistance and recalcitrant clinical infections. This, in tandem with stagnant antibacterial discovery, highlights an unmet need for new delivery technologies to treat intracellular infections more effectively. Here, we compare the uptake, delivery, and efficacy of rifampicin (Rif)-loaded mesoporous silica nanoparticles (MSN) and organo-modified (ethylene-bridged) MSN (MON) as an antibiotic treatment against small colony variants (SCV) Staphylococcus aureus (SA) in murine macrophages (RAW 264.7). Macrophage uptake of MON was five-fold that of equivalent sized MSN and without significant cytotoxicity on human embryonic kidney cells (HEK 293T) or RAW 264.7 cells. MON also facilitated increased Rif loading with sustained release, and seven-fold increased Rif delivery to infected macrophages. The combined effects of increased uptake and intracellular delivery of Rif by MON reduced the colony forming units of intracellular SCV-SA 28 times and 65 times compared to MSN-Rif and non-encapsulated Rif, respectively (at a dose of 5 µg/mL). Conclusively, the organic framework of MON offers significant advantages and opportunities over MSN for the treatment of intracellular infections

Rifampicin-Loaded Mesoporous Silica Nanoparticles for the Treatment of Intracellular Infections

Infectious diseases remain a major burden in today’s world, causing high mortality rates and significant economic losses, with >9 million deaths per year predicted by 2030. Invasion of host cells by intracellular bacteria poses treatment challenges due to the poor permeation of antimicrobials into the infected cells. To overcome these limitations, mesoporous silica nanoparticles (MSNP) loaded with the antibiotic rifampicin were investigated as a nanocarrier system for the treatment of intracellular bacterial infection with specific interest in the influence of particle size on treatment efficiency. An intracellular infection model was established using small colony variants (SCV) of S. aureus in macrophages to systemically evaluate the efficacy of rifampicin-loaded MSNP against the pathogen as compared to a rifampicin solution. As hypothesized, the superior uptake of MSNP by macrophages resulted in an enhanced treatment efficacy of the encapsulated rifampicin as compared to free antibiotic. This study provides a potential platform to improve the performance of currently available antibiotics against intracellular infections

Combating Acute Myeloid Leukemia via Sphingosine Kinase 1 Inhibitor-Nanomedicine Combination Therapy with Cytarabine or Venetoclax

MP-A08 is a novel sphingosine kinase 1 (SPHK1) inhibitor with activity against acute myeloid leukemia (AML). A rationally designed liposome-based encapsulation and delivery system has been shown to overcome the physicochemical challenges of MP-A08 and enable its effective delivery for improved efficacy and survival of mice engrafted with human AML in preclinical models. To establish therapies that overcome AML’s heterogeneous nature, here we explored the combination of MP-A08-loaded liposomes with both the standard chemotherapy, cytarabine, and the targeted therapy, venetoclax, against human AML cell lines. Cytarabine (over the dose range of 0.1–0.5 µM) in combination with MP-A08 liposomes showed significant synergistic effects (as confirmed by the Chou–Talalay Combination Index) against the chemosensitised human AML cell lines MV4-11 and OCI-AML3. Venetoclax (over the dose range of 0.5–250 nM) in combination with MP-A08 liposomes showed significant synergistic effects against the chemosensitised human AML cell lines, particularly in venetoclax-resistant human AML cells. This strong synergistic effect is due to multiple mechanisms of action, i.e., inhibiting MCL-1 through SPHK1 inhibition, leading to ceramide accumulation, activation of protein kinase R, ATF4 upregulation, and NOXA activation, ultimately resulting in MCL-1 degradation. These combination therapies warrant further consideration and investigation in the search for a more comprehensive treatment strategy for AML

Asymmetric silica nanoparticles with tunable head-tail structures enhance hemocompatibility and maturation of immune cells

Asymmetric mesoporous silica nanoparticles (MSNs) with controllable head tail structures have been successfully synthesized. The head particle type is tunable (solid or porous), and the tail has dendritic large pores. The tail length and tail coverage on head particles are adjustable. Compared to spherical silica nanoparticles with a solid structure (Stober spheres) or large-pore symmetrical MSNs with fully covered tails, asymmetrical head tail MSNs (HTMSNs) show superior hemocompatibility due to reduced membrane deformation of red blood cells and decreased level of reactive oxygen species. Moreover, compared to Stober spheres, asymmetrical HTMSNs exhibit a higher level of uptake and in vitro maturation of immune cells including dendritic cells and macrophage. This study has provided a new family of nanocarriers with potential applications in vaccine development and immunotherapy