An Oral 3D Printed PLGA-Tocopherol PEG Succinate Nanocomposite Hydrogel for High-Dose Methotrexate Delivery in Maintenance Chemotherapy.

High-dose methotrexate (HDMTX) is one of the chemotherapeutic agents used to treat a variety of cancers in both adults and children. However, the toxicity associated with HDMTX has resulted in the spread of infections and treatment interruption. Further, poor bioavailability due to efflux pump activities mediated by P-glycoprotein has also been linked to poor therapeutic effects of methotrexate following oral administrations. D-α-Tocopheryl poly-ethylene glycol 1000 succinate (TPGS) is known to improve the bioavailability of poorly soluble drugs by inhibiting P-gp efflux activities, thus enhancing cellular uptake. Therefore, to achieve improved bioavailability for MTX, this study aimed to design and develop a novel drug delivery system employing TPGS and a biodegradable polymer, i.e., PLGA, to construct methotrexate-loaded nanoparticles fixated in alginate-gelatine 3D printable hydrogel ink to form a solid 3D printed tablet for oral delivery. The results indicated that high accuracy (>95%) of the 3D printed tablets was achieved using a 25 G needle. In vitro, drug release profiles were investigated at pH 1.2 and pH 7.4 to simulate the gastrointestinal environment. The in vitro release profile displayed a controlled and prolonged release of methotrexate over 24 h. The in silico modeling study displayed P-gp ATPase inhibition, suggesting enhanced MTX absorption from the gastrointestinal site. The 3D-printed hydrogel-based tablet has the potential to overcome the chemotherapeutic challenges that are experienced with conventional therapies.

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.

Biomedicine Innovations and Its Nanohydrogel Classifications.

As one of the most cutting-edge and promising polymer crosslinked network nanoparticle systems. Polymer nano-sized hydrogels (nanogels) have been a hot topic in the biomedical field over the last few decades. Due to their unique characteristics, which include their relatively high drug encapsulation efficiency, ease of preparation, high tunability, low toxicity, high stability in serum and responsive behavior to a range of stimuli to facilitate drug release. Nanogels are thought to be the next generation of drug delivery systems that can completely change the way that drug delivery systems have an impact on patients' lives. Nanogels have demonstrated significant potential in a variety of fields, including chemotherapy, diagnosis, organ targeting, and delivery of bioactive molecules of different dimensions. However, the lack of substantial clinical data from nanogels becomes one of the major barriers to translating the nanogel concept into a practical therapeutic application for many disease conditions. In addition, nanogel safety profiles have been the major concern that hinders it advancement to the clinical trial phase. This review aims to emphasize the unique properties of nanogels as delivery systems for a variety of bioactive molecules over other nano-delivery systems. Also, this review attempts to give insight into the recent progress in nanogels as a carrier in the field of nanomedicine to overcome complex biological barriers. Relevant scientific data and clinical rationale for the development and the potential use of nanogel as a carrier for targeted therapeutic interventions are discussed. Finally, the concluding points of this review highlight the importance of understanding the long-term toxicity profile of nanogel within the biological system to fully understand their biocompatibility.

pH-Responsive Micelles From an Oleic Acid Tail and Propionic Acid Heads Dendritic Amphiphile for the Delivery of Antibiotics.

The aim of this study was to synthesize a novel biocompatible pH-responsive oleic acid-based dendritic lipid amphiphile (OLA-SPDA) which self-assembled into stable micelles (OLA-SPDA -micelles) with a relatively low critical micelle concentration (CMC) of 5.6 × 10-6 M. The formulated micelles had particle size, polydispersity index (PDI) and zeta potential (ZP) of 84.16 ± 0.184 nm, 0.199 ± 0.011 and -42.6 ± 1.98 mV, respectively, at pH 7.4. The vancomycin (VCM) encapsulation efficiency was 78.80 ± 3.26%. The micelles demonstrated pH-responsiveness with an increase in particle size to 141.1 ± 0.0707 nm and a much faster release profile at pH 6.0, as compared to pH 7.4. The minimum inhibitory concentration (MIC) of VCM-OLA-SPDA-micelle against methicillin-resistant staphylococcus aureus (MRSA) was 8-fold lower compared to bare VCM, and the formulation had a 4-fold lower MIC at pH 6.0 when compared to the formulation's MIC at pH 7.4. MRSA viability assay showed the micelles had a percentage killing of 93.39% when compared bare-VCM (58.21%) at the same MIC (0.98 µg/mL). In vivo mice (BALB/c) skin infection models showed an 8-fold reduction in MRSA burden after treatment with VCM-OLA-SPDA-micelles when compared with bare VCM. The above results suggest that pH-responsive VCM-OLA-SPDA-micelles has the potential to be an effective carrier to enhance therapeutic outcomes against infections characterised by low pH.

Novel two-chain fatty acid-based lipids for development of vancomycin pH-responsive liposomes against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA).

The development of bacterial resistance against antibiotics is attributed to poor localisation of lethal antibiotic dose at the infection site. This study reports on the synthesis and use of novel two-chain fatty acid-based lipids (FAL) containing amino acid head groups in the formulation of pH-responsive liposomes for the targeted delivery of vancomycin (VAN). The formulated liposomes were characterised for their size, polydispersity index (PDI), surface charge and morphology. The drug-loading capacity, drug release, cell viability, and in vitro and in vivo efficacy of the formulations were investigated. A sustained VAN release profile was observed and in vitro antibacterial studies against S. aureus and MRSA showed superior and prolonged activity over 72 h at both pH 7.4 and 6.0. Enhanced antibacterial activity at pH 6.0 was observed for the DOAPA-VAN-Lipo and DLAPA-VAN-Lipo formulations. Flow cytometry studies indicated a high killing rate of MRSA cells using DOAPA-VN-Lipo (71.98%) and DLAPA-VN-Lipo (73.32%). In vivo studies showed reduced MRSA recovered from mice treated with formulations by four- and two-folds lower than bare VN treated mice, respectively. The targeted delivery of VAN can be improved by novel pH-responsive liposomes from the two-chain (FAL) designed in this study.