Engineering dynamic covalent bond-based nanosystems for delivery of antimicrobials against bacterial infections.

Nanodrug delivery systems (NDDS) continue to be explored as novel strategies enhance therapy outcomes and combat microbial resistance. The need for the formulation of smart drug delivery systems for targeting infection sites calls for the engineering of responsive chemical designs such as dynamic covalent bonds (DCBs). Stimuli response due to DCBs incorporated into nanosystems are emerging as an alternative way to target infection sites, thus enhancing the delivery of antibacterial agents. This leads to the eradication of bacterial infections and the reduction of antimicrobial resistance. Incorporating DCBs on the backbone of the nanoparticles endows the systems with several properties, including self-healing, controlled disassembly, and stimuli responsiveness, which are beneficial in the delivery and release of the antimicrobial at the infection site. This review provides a comprehensive and current overview of conventional DCBs-based nanosystems, stimuli-responsive DCBs-based nanosystems, and targeted DCBs-based nanosystems that have been reported in the literature for antibacterial delivery. The review emphasizes the DCBs used in their design, the nanomaterials constructed, the drug release-triggering stimuli, and the antibacterial efficacy of the reported DCBs-based nanosystems. Additionally, the review underlines future strategies that can be used to improve the potential of DCBs-based nanosystems to treat bacterial infections and overcome antibacterial resistance.

Applications of peptides in nanosystems for diagnosing and managing bacterial sepsis.

Sepsis represents a critical medical condition stemming from an imbalanced host immune response to infections, which is linked to a significant burden of disease. Despite substantial efforts in laboratory and clinical research, sepsis remains a prominent contributor to mortality worldwide. Nanotechnology presents innovative opportunities for the advancement of sepsis diagnosis and treatment. Due to their unique properties, including diversity, ease of synthesis, biocompatibility, high specificity, and excellent pharmacological efficacy, peptides hold great potential as part of nanotechnology approaches against sepsis. Herein, we present a comprehensive and up-to-date review of the applications of peptides in nanosystems for combating sepsis, with the potential to expedite diagnosis and enhance management outcomes. Firstly, sepsis pathophysiology, antisepsis drug targets, current modalities in management and diagnosis with their limitations, and the potential of peptides to advance the diagnosis and management of sepsis have been adequately addressed. The applications have been organized into diagnostic or managing applications, with the last one being further sub-organized into nano-delivered bioactive peptides with antimicrobial or anti-inflammatory activity, peptides as targeting moieties on the surface of nanosystems against sepsis, and peptides as nanocarriers for antisepsis agents. The studies have been grouped thematically and discussed, emphasizing the constructed nanosystem, physicochemical properties, and peptide-imparted enhancement in diagnostic and therapeutic efficacy. The strengths, limitations, and research gaps in each section have been elaborated. Finally, current challenges and potential future paths to enhance the use of peptides in nanosystems for combating sepsis have been deliberately spotlighted. This review reaffirms peptides' potential as promising biomaterials within nanotechnology strategies aimed at improving sepsis diagnosis and management.

Multi-functional pH-responsive and biomimetic chitosan-based nanoplexes for targeted delivery of ciprofloxacin against bacterial sepsis.

Bacterial sepsis is a mortal syndromic disease characterized by a complex pathophysiology that hinders effective targeted therapy. This study aimed to develop multifunctional, biomimetic and pH-responsive ciprofloxacin-loaded chitosan (CS)/sodium deoxycholic acid (SDC) nanoplexes (CS/SDC) nanoplexes with the ability to target and modulate the TLR4 pathway, activated during sepsis. The formulated nanoplexes were characterized in terms of physicochemical properties, in silico and in vitro potential biological activities. The optimal formulation showed good biocompatibility and stability with appropriate physicochemical parameters. The surface charge changed from negative at pH 7.4 to positive at pH 6.0 accompanied with a significantly faster release of CIP at pH 6.0 compared to 7.4. The biomimicry was elucidated by in silico tools and MST and results confirmed strong binding between the system and TLR4. Furthermore, the system revealed 4- and 2-fold antibacterial enhancement at acidic pH, and 3- and 4-fold better antibiofilm efficacy against Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (P. aeruginosa) respectively, compared to bare CIP. In addition, enhanced bacterial efflux pump inhibition was demonstrated by CS/SDC nanoplexes. Finally, the developed nanosystem showed excellent antioxidant activity against DPPH radicals. Taken together, the study confirmed the multi-functionalities of CS/SDC nanoplexes and their potential benefits in improving bacterial sepsis therapy.

Inflammation-responsive drug delivery nanosystems for treatment of bacterial-induced sepsis.

Sepsis, a complication of dysregulated host immune systemic response to an infection, is life threatening and causes multiple organ injuries. Sepsis is recognized by WHO as a big contributor to global morbidity and mortality. The heterogeneity in sepsis pathophysiology, antimicrobial resistance threat, the slowdown in the development of antimicrobials, and limitations of conventional dosage forms jeopardize the treatment of sepsis. Drug delivery nanosystems are promising tools to overcome some of these challenges. Among the drug delivery nanosystems, inflammation-responsive nanosystems have attracted considerable interest in sepsis treatment due to their ability to respond to specific stimuli in the sepsis microenvironment to release their payload in a precise, targeted, controlled, and rapid manner compared to non-responsive nanosystems. These nanosystems posit superior therapeutic potential to enhance sepsis treatment. This review critically evaluates the recent advances in the design of drug delivery nanosystems that are inflammation responsive and their potential in enhancing sepsis treatment. The sepsis microenvironment's unique features, such as acidic pH, upregulated receptors, overexpressed enzymes, and enhanced oxidative stress, that form the basis for their design have been adequately discussed. These inflammation-responsive nanosystems have been organized into five classes namely: Receptor-targeted nanosystems, pH-responsive nanosystems, redox-responsive nanosystems, enzyme-responsive nanosystems, and multi-responsive nanosystems. Studies under each class have been thematically grouped and discussed with an emphasis on the polymers used in their design, nanocarriers, key characterization, loaded actives, and key findings on drug release and therapeutic efficacy. Further, this information is concisely summarized into tables and supplemented by inserted figures. Additionally, this review adeptly points out the strengths and limitations of the studies and identifies research avenues that need to be explored. Finally, the challenges and future perspectives on these nanosystems have been thoughtfully highlighted.

Halting aberrant DNA methylation via in silico Identification of potent inhibitors of DNMT3B enzyme: Atomistic insights.

To date, Cancer remains a global threat due to its impact on growing life expectancy. With the many efforts and methods of combating the disease, complete success remains a challenge owing to several limitations including cancer cells developing resistance through mutations, off-target effect of some cancer drugs resulting in toxicities, among many others. Aberrant DNA methylation is understood to be the primary reason for improper gene silence, which can result in neoplastic transformation, carcinogenesis, and tumour progression. DNA methyltransferase B (DNMT3B) enzyme is considered a potential target for the treatment of several cancers due to its important role in DNA methylation. However, only a few DNMT3B inhibitors have been reported to date. Herein, in silico molecular recognition techniques such as Molecular docking, Pharmacophore-based virtual screen and MD simulation were employed to identify potential inhibitors of DNMT3B that can halt aberrancy in DNA methylation. Findings initially identified 878 hit compounds based on a designed pharmacophore model from the reference compound Hypericin. Molecular docking was used to rank the hits by testing their efficiency when bound to the target enzyme and the top three (3) selected. All three (3) of the top hits showed excellent pharmacokinetic properties but two (2) (Zinc33330198 and Zinc77235130) were identified to be non-toxic. Molecular dynamic simulation of the final two hits showed good stability, flexibility, and structural rigidity of the compounds on DNMT3B. Finally, thermodynamic energy estimations show both compounds had favourable free energies comprising - 26.04 kcal/mol for Zinc77235130 and - 15.73 kcal/mol for Zinc33330198. Amongst the final two hits, Zinc77235130 showed consistency in favourable results across all the tested parameters and was thus selected as the lead compound for further experimental validation. The identification of this lead compound will form important basis for the inhibition of aberrant DNA methylation in cancer therapy.

Enzyme-responsive biomimetic solid lipid nanoparticles for antibiotic delivery against hyaluronidase-secreting bacteria.

In this work, a potent hyaluronidase inhibitor (ascorbyl stearate (AS)) was successfully employed to design vancomycin-loaded solid lipid nanoparticles (VCM-AS-SLNs) with biomimetic and enzyme-responsive features, to enhance the antibacterial efficacy of vancomycin against bacterial-induced sepsis. The VCM-AS-SLNs prepared were biocompatible and had appropriate physicochemical parameters. The VCM-AS-SLNs showed an excellent binding affinity to the bacterial lipase. The in vitro drug release study showed that the release of the loaded vancomycin was significantly accelerated by the bacterial lipase. The in silico simulations and MST studies confirmed the strong binding affinity of AS and VCM-AS-SLNs to bacterial hyaluronidase compared to its natural substrate. This binding superiority indicates that AS and VCM-AS-SLNs could competitively inhibit the effect of hyaluronidase enzyme, and thus block its virulence action. This hypothesis was further confirmed using the hyaluronidase inhibition assay. The in vitro antibacterial studies against sensitive and resistant Staphylococcus aureus revealed that the VCM-AS-SLNs had a 2-fold lower minimum inhibitory concentration, and a 5-fold MRSA biofilm elimination compared to the free vancomycin. Furthermore, the bactericidal-kinetic showed a 100% bacterial clearance rate within 12 h of treatment with VCM-AS-SLNs, and <50 % eradication after 24 h for the bare VCM. Therefore, the VCM-AS-SLN shows potential as an innovative multi-functional nanosystem for effective and targeted delivery of antibiotics.

Stimuli-responsive and biomimetic delivery systems for sepsis and related complications.

Sepsis, a consequence of an imbalanced immune response to infection, is currently one of the leading causes of death globally. Despite advances in the discoveries of potential targets and nanotechnology, sepsis still lacks effective drug delivery systems for optimal treatment. Stimuli-responsive and biomimetic nano delivery systems, specifically, are emerging as advanced bio-inspired nanocarriers for enhancing the treatment of sepsis. Herein, we present a critical review of different stimuli-responsive systems, including pH-; enzyme-; ROS- and toxin-responsive nanocarriers, reported in the delivery of therapeutics for sepsis. Biomimetic nanocarriers, utilizing natural pathways in the inflammatory cascade to optimize sepsis therapy, are also reviewed, in addition to smart, multifunctional vehicles. The review highlights the nanomaterials designed for constructing these systems; their physicochemical properties; the mechanisms of drug release; and their potential for enhancing the therapeutic efficacy of their cargo. Current challenges are identified and future avenues for research into the optimization of bio-inspired nano delivery systems for sepsis are also proposed. This review confirms the potential of stimuli-responsive and biomimetic nanocarriers for enhanced therapy against sepsis and related complications.

Engineering hybrid nanosystems for efficient and targeted delivery against bacterial infections.

Hybrid nanoparticles (NPs) are emerging as superior alternatives to conventional nanocarriers for enhancing the delivery of antibiotics and improving their targeting at the infection site, resulting in the eradication of bacterial infections and overcoming antimicrobial resistance. They can specifically control the release of antibiotics when reaching the targeted site of infection, thus enhancing and prolonging their antimicrobial efficacy. In this review, we provide a comprehensive and an up-to-date overview of the recent advances and contributions of lipid-polymer hybrid NPs; organic-inorganic hybrid NPs; metal-organic frameworks; cell membrane-coated hybrid NPs; hybrid NP-hydrogels; and various others, that have been reported in the literature for antibacterial delivery, with emphasis on their design approaches; the nanomaterials constructed; the mechanisms of drug release; and the enhanced antibacterial efficacy of the reported hybrid nanocarriers. This review also highlights future strategies that can be used to improve the potential of hybrid nanosystems to treat bacterial infections and overcome antibiotic resistance.

Synthesis of pH-responsive dimethylglycine surface-modified branched lipids for targeted delivery of antibiotics.

The rampant antimicrobial resistance crisis calls for efficient and targeted drug delivery of antibiotics at the infectious site. Hence, this study aimed to synthesize a pH-responsive dimethylglycine surface-modified branched lipid (DMGSAD-lipid). The structure of the synthesized lipid was fully confirmed. The lipid polymer hybrid nanoparticles (LPHNPs) were formulated using the solvent evaporation method and characterised. Two LPHNPs (VCM_HS15_LPHNPs and VCM_RH40_LPHNPs) were formulated and characterised for size, polydispersity index (PDI), and zeta potential (ZP). Atomistic molecular dynamics simulations revealed that both the systems self-assembled to form energetically stable aggregates. The ZP of RH40_VCM_LPHNPs changed from 0.55 ± 0.14-9.44 ± 0.33 Vm, whereas for SH15_VCM_LPHNPs, ZP changed from - 1.55 ± 0.184 Vm to 9.83 ± 0.52 Vm at pH 7.4 and 6.0, respectively. The encapsulation efficiencies of VCM were above 40% while the drug release was faster at acidic pH when compared to pH 7.4. The antibacterial activity of LPHNPs against MRSA was eight-fold better in MICs at pH 6.0, compared to 7.4, when compared to bare VCM-treated specimens. The study confirms that pH-responsive LPHNPs have the potential for enhancing the treatment of bacterial infections and other diseases characterised by acidic conditions at the target site.

Dual acting acid-cleavable self-assembling prodrug from hyaluronic acid and ciprofloxacin: A potential system for simultaneously targeting bacterial infections and cancer.

The incidence and of bacterial infections, and resulting mortality, among cancer patients is growing dramatically, worldwide. Several therapeutics have been reported to have dual anticancer and antibacterial activity. However, there is still an urgent need to develop new drug delivery strategies to improve their clinical efficacy. Therefore, this study aimed to develop a novel acid cleavable prodrug (HA-Cip) from ciprofloxacin and hyaluronic acid to simultaneously enhance the anticancer and antibacterial properties of Cip as a superior drug delivery system. HA-Cip was synthesised and characterised (FT-IR, HR-MS, and H1 NMR). HA-Cip generated stable micelles with an average particle size, poly dispersion index (PDI) and zeta potential (ZP) of 237.89 ± 25.74 nm, 0.265 ± 0.013, and -17.82 ± 1.53 mV, respectively. HA-Cip showed ≥80 % cell viability against human embryonic kidney 293 cells (non-cancerous cells), ˂0.3 % haemolysis; and a faster pH-responsive ciprofloxacin release at pH 6.0. HA-Cip showed a 5.4-fold improvement in ciprofloxacin in vitro anticancer activity against hepatocellular cancer (HepG2) cells; and enhanced in vitro antibacterial activity against Escherichia coli and Klebsiella pneumoniae at pH 6.0. Our findings show HA-Cip as a promising prodrug for targeted delivery of ciprofloxacin to efficiently treat bacterial infections associated, and/or co-existing, with cancer.

Nano delivery systems to the rescue of ciprofloxacin against resistant bacteria "E. coli; P. aeruginosa; Saureus; and MRSA" and their infections.

Ciprofloxacin (CIP) a broad-spectrum antibiotic, is used extensively for the treatment of diverse infections and diseases of bacteria origin, and this includes infections caused by E. coli; P. aeruginosa; S. aureus; and MRSA. This extensive use of CIP has therefore led to an increase in resistance by these infection causing organisms. Nano delivery systems has recently proven to be a possible solution to resistance to these organisms. They have been applied as a strategy to improve the target specificity of CIP against infections and diseases caused by these organisms, thereby maximising the efficacy of CIP to overcome the resistance. Herein, we proffer a brief overview of the mechanisms of resistance; the causes of resistance; and the various approaches employed to overcome this resistance. The review then proceeds to critically evaluate various nano delivery systems including inorganic based nanoparticles; lipid-based nanoparticles; capsules, dendrimers, hydrogels, micelles, and polymeric nanoparticles; and others; that have been applied for the delivery of CIP against E. coli; P. aeruginosa; S. aureus; and MRSA infections. Finally, the review highlights future areas of research, for the optimisation of various nano delivery systems, to maximise the therapeutic efficacy of CIP against these organisms. This review confirms the potential of nano delivery systems, for addressing the challenges of resistance to caused by E. coli; P. aeruginosa; S. aureus; and MRSA to CIP.

A hyaluronic acid-based nanogel for the co-delivery of nitric oxide (NO) and a novel antimicrobial peptide (AMP) against bacterial biofilms.

Biofilms are a global health concern because they are associated with chronic and recurrent infections as well as resistance to conventional antibiotics. The aim of this study was to prepare a nanogel for the co-delivery of NO and AMPs against bacteria and biofilms. The NO-releasing nanogel was prepared by crosslinking HA solution with divinyl sulfone and extensively characterized. The nanogel was found to be biocompatible, injectable and NO release from the gel was sustained over a period of 24 h. In vitro antibacterial studies showed that the NO-AMP-loaded nanogel exhibited a broad spectrum antibacterial/antibiofilm activity. The NO-releasing nanogel had a greater antibacterial effect when compared to NO alone with MIC values of 1.56, 0.78 and 0.39 µg/ml against Escherichia coli, Methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa bacteria respectively. The antibiofilm results showed there was a 12.5 and 24-folds reduction in biofilms of MRSA, and P. aeruginosa respectively for catheters exposed to nanogel loaded with AMP/NO when compared to only NO, while a 7 and 9.4-folds reduction in biofilms of MRSA, and P. aeruginosa respectively was displayed by the nanogel loaded with only NO compared to only NO. The AMP/NO-releasing nanogel showed the potential to combat both biofilms and bacterial infections.

Surface modification of nano-drug delivery systems for enhancing antibiotic delivery and activity.

Rampant antimicrobial resistance calls for innovative strategies to effectively control bacterial infections, enhance antibacterial efficacy, minimize side effects, and protect existing antibiotics in the market. Therefore, to enhance the delivery of antibiotics and increase their bioavailability and accumulation at the site of infection, the surfaces of nano-drug delivery systems have been diversely modified. This strategy applies various covalent and non-covalent techniques to introduce specific coating materials that have been found to be effective against various sensitive and resistant microorganisms. In this review, we discuss the techniques of surface modification of nanocarriers loaded with antibacterial agents. Furthermore, saccharides, polymers, peptides, antibiotics, enzymes and cell membranes coatings that have been used for surface functionalization of nano-drug delivery systems are described, emphasizing current approaches for enhancing delivery, bioavailability, and efficacy of surface-modified antibacterial nanocarriers at infection sites. This article offers a critical overview of the potential of surface-modified antibacterial nanocarriers to overcome the limitations of conventional antibiotics in the treatment of bacterial infections. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Development of niosomes for encapsulating captopril-quercetin prodrug to combat hypertension.

Novel and effective anti-hypertensive agents are required to manage hypertension; therefore, we synthesised a novel antihypertensive drug from captopril and quercetin (cap-que) and explored its antihypertensive potential in a niosomal formulation via molecular hybridisation. The cap-que hybrid was synthesised, and its structure was characterised via NMR, FTIR, and HRMS. Niosomes were then loaded with cap-que using the thin-film hydration method. The particle size, polydispersity index, surface charge and drug entrapment efficiency (EE%) of the formulation were 418.8 ± 4.21 nm, 0.393 ± 0.063, 16.25 ± 0.21 mV, and 87.74 ± 2.82%, respectively. The drug release profile showed a sustained release of the active compound (43 ± 0.09%) from the niosomal formulation, compared to the parent drug (80.7 ± 4.68%), over 24 h. The cell viability study confirmed the biosafety of the formulation. The in vivo study in a rat model showed enhanced antihypertensive activity of the hybrid molecule and niosomal formulation which reduced systolic and diastolic pressure when compared to the individual, bare drugs. The findings of this study concluded that the antihypertensive potential of captopril can be enhanced by its hybridisation with quercetin, followed by niosomal nano drug delivery.

Chitosan-Based Hydrogel for the Dual Delivery of Antimicrobial Agents Against Bacterial Methicillin-Resistant Staphylococcus aureus Biofilm-Infected Wounds.

Chronic wound infections caused by antibiotic-resistant bacteria have become a global health concern. This is attributed to the biofilm-forming ability of bacteria on wound surfaces, thus enabling their persistent growth. In most cases, it leads to morbidity and in severe cases mortality. Current conventional approaches used in the treatment of biofilm wounds are proving to be ineffective due to limitations such as the inability to penetrate the biofilm matrix; hence, biofilm-related wounds remain a challenge. Therefore, there is a need for more efficient alternate therapeutic interventions. Hydrogen peroxide (HP) is a known antibacterial/antibiofilm agent; however, prolonged delivery has been challenging due to its short half-life. In this study, we developed a hydrogel for the codelivery of HP and antimicrobial peptides (Ps) against bacteria, biofilms, and wound infection associated with biofilms. The hydrogel was prepared via the Michael addition technique, and the physiochemical properties were characterized. The safety, in vitro, and in vivo antibacterial/antibiofilm activity of the hydrogel was also investigated. Results showed that the hydrogel is biosafe. A greater antibacterial effect was observed with HP-loaded hydrogels (CS-HP; hydrogel loaded with HP and CS-HP-P; hydrogel loaded with HP and peptide) when compared to HP as seen in an approximately twofold and threefold decrease in minimum inhibitory concentration values against methicillin-resistant Staphylococcus aureus (MRSA) bacteria, respectively. Similarly, both the HP-releasing hydrogels showed enhanced antibiofilm activity in the in vivo study in mice models as seen in greater wound closure and enhanced wound healing in histomorphological analysis. Interestingly, the results revealed a synergistic antibacterial/antibiofilm effect between HP and P in both in vitro and in vivo studies. The successfully prepared HP-releasing hydrogels showed the potential to combat bacterial biofilm-related infections and enhance wound healing in mice models. These results suggest that the HP-releasing hydrogels may be a superior platform for eliminating bacterial biofilms without using antibiotics in the treatment of chronic MRSA wound infections, thus improving the quality of human health.

Biomimetic pH/lipase dual responsive vitamin-based solid lipid nanoparticles for on-demand delivery of vancomycin.

In this study, ascorbyl tocopherol succinate (ATS) was designed, synthesized and characterized via FT-IR, HR-MS, H1 NMR and C13 NMR, to simultaneously confer biomimetic and dual responsive properties of an antibiotic nanosystem to enhance their antibacterial efficacy and reduce antimicrobial resistance. Therefore, an in silico-aided design (to mimic the natural substrate of bacterial lipase) was employed to demonstrate the binding potential of ATS to lipase (-32.93 kcal/mol binding free energy (ΔGbind) and bacterial efflux pumps blocking potential (NorA ΔGbind: -37.10 kcal/mol, NorB ΔGbind: -34.46 kcal/mol). ATS bound stronger to lipase than the natural substrate (35 times lower Kd value). The vancomycin loaded solid lipid nanoparticles (VM-ATS-SLN) had a hydrodynamic diameter, zeta potential, polydispersity index and entrapment efficiency of 106.9 ± 1.4 nm, -16.5 ± 0.93 mV, 0.11 ± 0.012 and 61.9 ± 1.31%, respectively. In vitro biocompatibility studies revealed VM-ATS-SLN biosafety and non-haemolytic activity. Significant enhancement in VM release was achieved in response to acidified pH and lipase enzyme, compared to controls. VM-ATS-SLN showed enhanced sustained in vitro antibacterial activity for 5 days, 2-fold greater MRSA biofilm growth inhibition and 3.44-fold reduction in bacterial burden in skin infected mice model compared to bare VM. Therefore, ATS shows potential as a novel multifunctional adjuvant for effective and targeted delivery of antibiotics.

Formulation of pH responsive multilamellar vesicles for targeted delivery of hydrophilic antibiotics.

Fight against antimicrobial resistance calls for innovative strategies that can target infection sites and enhance activity of antibiotics. Herein is a pH responsive multilamellar vesicles (MLVs) for targeting bacterial infection sites. The vancomycin (VCM) loaded MLVs had 62.25 ± 8.7 nm, 0.15 ± 0.01 and -5.55 ± 2.76 mV size, PDI and zeta potential, respectively at pH 7.4. The MLVs had a negative ZP at pH 7.4 that switched to a positive charge and faster release of the drug at acidic pH. The encapsulation efficiency was found to be 46.34 ± 3.88 %. In silico studies of the lipids, interaction suggested an energetically stable system. Studies to determine the minimum inhibitory concentration studies (MIC) showed the MLVs had 2-times and 8-times MIC against Staphylococcus aureus (SA) and Methicillin resistance SA respectively at physiological pH. While at pH 6.0 there was 8 times reduction in MICs for the formulation against SA and MRSA in comparison to the bare drug. Fluorescence-activated Cell Sorting (FACS) studies demonstrated that even with 8-times lower MIC, MLVs had a similar elimination ability of MRSA cells when compared to the bare drug. Fluorescence microscopy showed MLVs had the ability to clear biofilms while the bare drug could not. Mice skin infection models studies showed that the colony finding units (CFUs) of MRSA recovered from groups treated with MLVs was 4,050 and 525-fold lower than the untreated and bare VCM treated groups, respectively. This study demonstrated pH-responsive multilamellar vesicles as effective system for targeting and enhancing antibacterial agents.

A transferosome-loaded bigel for enhanced transdermal delivery and antibacterial activity of vancomycin hydrochloride.

Transdermal drug delivery is an attractive route of administration relative to other routes as it offers enhanced therapeutic efficacy. However, due to poor skin permeability of certain drugs, their application in transdermal delivery is limited. The ultra-deformable nature of transferosomes makes them suitable vehicles for transdermal delivery of drugs that have high molecular weights and hydrophilicity. However, their low viscosity, which leads to low contact time on the surface of the skin, has restricted their application in transdermal delivery. Therefore, this study aimed to deliver transferosomes loaded with a highly water-soluble and high molecular weight vancomycin hydrochloride (VCM-HCl) via a bigel for systemic delivery and treatment of microbial infections. VCM-HCl-loaded transferosomal formulations (TNFs) were prepared using a reverse-phase evaporation method and then loaded into a bigel. Both the TNFs and TNFs-loaded bigel (TNF-L-B) were characterized by a range of in vitro and ex vivo techniques. TNFs and TNF-L-B were tested for biosafety via the MTT assay and found to be biosafe. Prepared TNFs had sizes, zeta potential and entrapment efficiency of 63.02 ± 5.34 nm, -20.93 ± 6.13 mV and 84.48 ± 1.22% respectively. VCM-HCl release from TNF-L-B showed a prolonged release profile with 39.76 ± 1.6% after 24hrs when compared to bare VCM-HCl loaded in the bigel (74.81 ± 8.84%). Ex-vivo permeation of prepared TNF-L-B showed a higher permeation flux of 0.56 µg/cm2/h compared to the bare VCM-HCl-loaded bigel of 0.23 µg/cm2/h, indicating superior permeation and bioavailability of the drug. Additionally, the prepared TNF-L-B demonstrated improved antimicrobial activity. The TNF-L-B showed minimum inhibitory concentrations (MIC) of 0.97 µg/ml against Staphylococcus aureus (SA) and 1.95 µg/ml against methicillin-resistant SA (MRSA), which were 2-fold lower MIC values than the bare drug. The time-kill assay showed that both TNFs and TNF-L-B systems caused a 5.6-log reduction (100%) in MRSA compared to bare VCM-HCl after 24 hrs of incubation. Furthermore, as opposed to the bare VCM-HCl solution, the degree of biofilm reduction caused by TNFs (55.72%) and TNF-L-B (34.58%) suggests their dominance in eradicating MRSA biofilm. These findings indicate that TNF-L-B is a promising system for transdermal delivery of hydrophilic and high molecular weight drugs.

Photodynamic Antimicrobial Chemotherapy: Advancements in Porphyrin-Based Photosensitize Development.

The reduction of available drugs with effectiveness against microbes is worsening with the current global crisis of antimicrobial resistance. This calls for innovative strategies for combating antimicrobial resistance. Photodynamic Antimicrobial Chemotherapy (PACT) is a relatively new method that utilizes the combined action of light, oxygen, and a photosensitizer to bring about the destruction of microorganisms. This technique has been found to be effective against a wide spectrum of microorganisms, including bacteria, viruses, and fungi. Of greater interest is their ability to destroy resistant strains of microorganisms and in effect help in combating the emergence of antimicrobial resistance. This manuscript reviews porphyrins and porphyrin-type photosensitizers that have been studied in the recent past with a focus on their structure-activity relationship.

Liposomes with pH responsive 'on and off' switches for targeted and intracellular delivery of antibiotics.

pH responsive drug delivery systems are one of the new strategies to address the spread of bacterial resistance to currently used antibiotics. The aim of this study was to formulate liposomes with 'On' and 'Off'' pH responsive switches for infection site targeting. The vancomycin (VCM) loaded liposomes had sizes below 100 nm, at pH 7.4. The QL-liposomes had a negative zeta potential at pH 7.4 that switched to a positive charge at acidic pH. VCM release from the liposome was quicker at pH 6 than pH 7.4. The OA-QL-liposome showed 4-fold lower MIC at pH 7.4 and 8- and 16-fold lower at pH 6.0 against both MSSA and MRSA compared to the bare drug. OA-QL liposome had a 1266.67- and 704.33-fold reduction in the intracellular infection for TPH-1 macrophage and HEK293 cells respectively. In vivo studies showed that the amount of MRSA recovered from mice treated with formulations was 189.67 and 6.33-fold lower than the untreated and bare VCM treated mice respectively. MD simulation of the QL lipid with the phosphatidylcholine membrane (POPC) showed spontaneous binding of the lipid to the bilayer membrane both electrostatic and Van der Waals interactions contributed to the binding. These studies demonstrated that the 'On' and 'Off' pH responsive liposomes enhanced the activity targeted and intracellular delivery VCM.