AB2-type amphiphilic block copolymer containing a pH-cleavable hydrazone linkage for targeted antibiotic delivery.

A novel AB2-type amphiphilic block copolymer [OA-CN-NH-(PEG)2] with hydrazone linkage was synthesized and explored for pH-triggered antibiotic delivery. Vancomycin (VCM) loaded micelles of the polymer [OA-CN-NH-(PEG)2-VCM] were spherical in shape with size, polydispersity index, zeta potential and entrapment efficiency of 130.33 ± 7.36 nm, 0.163 ± 0.009, -4.33 ± 0.55 mV and 39.61 ± 4.01% respectively. The dilution stability study exhibited no significant change in the size distribution of OA-CN-NH-(PEG)2-VCM micelles up to 320-fold dilution. An in vitro drug release assay confirmed greater release of VCM from OA-CN-NH-(PEG)2-VCM at pH 6, compared to pH 7.4. An in vitro antibacterial activity evaluation of OA-CN-NH-(PEG)2-VCM showed 2-fold enhancement in antibacterial activity of VCM after 54 h of incubation against Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA) at acidic pH compared to physiological pH. An in vivo antibacterial activity of OA-CN-NH-(PEG)2-VCM further proved the enhanced activity of OA-CN-NH-(PEG)2-VCM against MRSA. In conclusion, micelles from pH-responsive OA-CN-NH-(PEG)2 could be utilized for site-specific delivery of VCM at the infection site.

Preparation and Optimization of Meropenem-Loaded Solid Lipid Nanoparticles: In Vitro Evaluation and Molecular Modeling.

Encapsulation of antibiotics into nanocarriers has the potential to overcome resistance and disadvantages associated with conventional dosage forms as well as increase half-life of an antibiotic. Encapsulation of meropenem (MRPN) into solid lipid nanoparticles (SLNs) remains unexplored among the limited work reported on nanoformulation incorporating MRPN. The study aimed to use an experimental design, to optimize MRPN-loaded SLNs, and to undertake in vitro and in silico evaluations. A Box-Behnken design (BBD) was used to optimize manufacturing conditions of glycerol monostearate (GMS) SLNs loaded with MRPN. The SLNs were prepared using hot homogenization and ultrasonication method. Optimized MRPN-SLNs showed particle size, zeta potential, and entrapment efficiency of 112.61 ± 0.66 nm, -20.43 ± 0.99 mV, and 89.94 ± 1.26%, respectively. The morphology of the SLNs revealed nearly spherical shaped particles. Differential scanning calorimetry and X-ray diffraction analysis showed that meropenem was present in amorphous form in the SLNs. Controlled in vitro MRPN release from SLNs was achieved and followed the Korsmeyer-Peppas model (R 2 = 0.9679). Prolonged in vitro antibacterial activity against Escherichia coli was also observed. The molecular modeling showed that both hydrophobic interactions and hydrogen bonding led to a stable MRPN-GMS complex formation, which was confirmed by its low heat of formation (-5536.13 kcal/mol). This stable complex could have contributed to the controlled release of MRPN from the SLNs and subsequent sustained antibacterial activity.

Hydrazone linkages in pH responsive drug delivery systems.

Stimuli-responsive polymeric drug delivery systems using various triggers to release the drug at the sites have become a major focus area. Among various stimuli-responsive materials, pH-responsiveness has been studied extensively. The materials used for fabricating pH-responsive drug delivery systems include a specific chemical functionality in their structure that can respond to changes in the pH of the surrounding environment. Various chemical functionalities, for example, acetal, amine, ortho ester, amine and hydrazone, have been used to design materials that are capable of releasing their payload at the acidic pH conditions of the tumor or infection sites. Hydrazone linkages are significant synthons for numerous transformations and have gained importance in pharmaceutical sciences due to their various biological and clinical applications. These linkages have been employed in various drug delivery vehicles, such as linear polymers, star shaped polymers, dendrimers, micelles, liposomes and inorganic nanoparticles, for pH-responsive drug delivery. This review paper focuses on the synthesis and characterization methods of hydrazone bond containing materials and their applications in pH-responsive drug delivery systems. It provides detailed suggestions as guidelines to materials and formulation scientists for designing biocompatible pH-responsive materials with hydrazone linkages and identifying future studies.

Ultra-small lipid-dendrimer hybrid nanoparticles as a promising strategy for antibiotic delivery: In vitro and in silico studies.

The purpose of this study was to explore the preparation of a new lipid-dendrimer hybrid nanoparticle (LDHN) system to effectively deliver vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) infections. Spherical LDHNs with particle size, polydispersity index and zeta potential of 52.21±0.22 nm, 0.105±0.01, and -14.2±1.49 mV respectively were prepared by hot stirring and ultrasonication using Compritol 888 ATO, G4 PAMAM- succinamic acid dendrimer, and Kolliphor RH-40. Vancomycin encapsulation efficiency (%) in LDHNs was almost 4.5-fold greater than in lipid-polymer hybrid nanoparticles formulated using Eudragit RS 100. Differential scanning calorimetry and Fourier transform-infrared studies confirmed the formation of LDHNs. The interactions between the drug-dendrimer complex and lipid molecules using in silico modeling revealed the molecular mechanism behind the enhanced encapsulation and stability. Vancomycin was released from LDHNs over the period of 72 h with zero order kinetics and super case II transport mechanism. The minimum inhibitory concentration (MIC) against S. aureus and MRSA were 15.62 µg/ml and 7.81 µg/ml respectively. Formulation showed sustained activity with MIC of 62.5 µg/ml against S. aureus and 500 µg/ml against MRSA at the end of 72 and 54 h period respectively. The results suggest that the LDHN system can be an effective strategy to combat resistant infections.

Solid lipid nanoparticles of clotrimazole silver complex: An efficient nano antibacterial against Staphylococcus aureus and MRSA.

New and effective strategies to transform current antimicrobials are required to address the increasing issue of microbial resistance and declining introduction of new antibiotic drugs. In this context, metal complexes of known drugs and nano delivery systems for antibiotics are proving to be promising strategies. The aim of the study was therefore to synthesize a silver complex of clotrimazole and formulate it into a nano delivery system for enhanced and sustained antibacterial activity against susceptible and resistant Staphylococcus aureus. A silver complex of clotrimazole was synthesized, characterized and further encapsulated into solid lipid nanoparticles to evaluate its antibacterial activity against S. aureus and methicillin-resistant S. aureus (MRSA). An in vitro cytotoxicity study was performed on HepG2 cell lines to assess the overall biosafety of the synthesized clotrimazole silver complex to mammalian cells, and was found to be non-toxic to mammalian cells (cell viability >80%). The minimum inhibitory concentrations (MIC) of clotrimazole and clotrimazole-silver were 31.25 and 9.76 µg/mL against S. aureus, and 31.25 and 15.62 against MRSA, respectively. Clotrimazole SLNs exhibited MIC values of 104 and 208 µg/mL against both MSSA and MRSA at the end of 18 and 36 h, respectively, but thereafter completely lost its antibacterial activity. Clotrimazole-silver SLNs had an MIC value of 52 µg/mL up to 54 h, after which the MIC value was 104 µg/mL against both strains at the end of 72 h. Thus, clotrimazole-silver SLNs was found to be an efficient nanoantibiotic.

Ion pairing with linoleic acid simultaneously enhances encapsulation efficiency and antibacterial activity of vancomycin in solid lipid nanoparticles.

Ion pairing of a fatty acid with an antibiotic may be an effective strategy for formulation optimization of a nanoantibiotic system. The aim of this study was therefore to explore the potential of linoleic acid (LA) as an ion pairing agent to simultaneously enhance encapsulation efficiency and antibacterial activity of triethylamine neutralized vancomycin (VCM) in solid lipid nanoparticles (SLNs). The prepared VCM-LA2 conjugate was characterized by Fourier transform-infrared (FT-IR) spectroscopy, logP and binding energy calculations. The shifts in the FT-IR frequencies of COOH, NH2 and CO functionalities, an increase in logP value (1.37) and a lower interaction energy between LA and VCM (-125.54 kcal/mol) confirmed the formation of the conjugate. SLNs were prepared by a hot homogenization and ultrasonication method, and characterized for size, polydispersity index (PI), zeta potential (ZP), entrapment efficiency (%EE), surface morphology and physical stability. In vitro antibacterial activity studies against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) were conducted. Size, PI and ZP for VCM-LA2_SLNs were 102.7±1.01, 0.225±0.02 and -38.8±2.1 (mV) respectively. SLNs were also stable at 4 °C for 3 months. %EE for VCM-HCl_SLNs and VCM-LA2_SLNs were 16.81±3.64 and 70.73±5.96 respectively, indicating a significant improvement in encapsulation of the drug through ion pairing with LA. Transmission electron microscopy images showed spherical nanoparticles with sizes in the range of 95-100 nm. After 36 h, VCM-HCl showed no activity against MRSA. However, the minimum inhibitory concentration for VCM-HCl_SLNs and VCM-LA2_SLNs were 250 and 31.25 µg/ml respectively against S. aureus, while against MRSA it was 500 and 15.62 µg/ml respectively. This confirms the enhanced antibacterial activity of VCM-LA2_SLNs over VCM-HCl_SLNs. These findings therefore suggest that VCM-LA2_SLNs is a promising nanoantibiotic system for effective treatment against both sensitive and resistant S. aureus infections.