Anti-Glioma Activity Achieved by Dual Blood-Brain Barrier/Glioma Targeting Naive Chimeric Peptides-Based Co-Assembled Nanophototheranostics.

Peptide monomers can either self-assemble with themselves enacting a solo-component assembly or they can co-assemble by interacting with other suitable partners to mediate peptide co-assembly. Peptide co-assemblies represent an innovative class of naive, multifunctional, bio-inspired supramolecular constructs that result in the production of nanostructures with widespread functional, structural, and chemical multiplicity. Herein, the co-assembly of novel chimeric peptides (conjugates of T7 (HAIYPRH)/t-Lyp-1 (CGNKRTR) peptides and aurein 1.2 (GLFDIIKKIAESF)) has been explored as a means to produce glioma theranostics exhibiting combinatorial chemo-phototherapy. Briefly, we have reported here the design and solid phase synthesis of a naive generation of twin-functional peptide drugs incorporating the blood-brain barrier (BBB) and glioma dual-targeting functionalities along with anti-glioma activity (G-Anti G and B-Anti G). Additionally, we have addressed their multicomponent co-assembly and explored their potential application as glioma drug delivery vehicles. Our naive peptide drug-based nanoparticles (NPs) successfully demonstrated a heightened glioma-specific delivery and anti-glioma activity. Multicomponent indocyanine green (ICG)-loaded peptide co-assembled NPs (PINPs: with a hydrodynamic size of 348 nm and a zeta-potential of 5 mV) showed enhanced anti-glioma responses in several cellular assays involving C6 cells. These included a mass demolition with no wound closure (i.e., a 100% cell destruction) and around 63% collaborative chemo-phototoxicity (with both a photothermal and photodynamic effect) after near infrared (NIR) 808 laser irradiation. The dual targeting ability of peptide bioconjugates towards both the BBB and glioma cells, presents new opportunities for designing tailored and better peptide-based nanostructures or nanophototheranostics for glioma.

Near infrared triggered chemo-PTT-PDT effect mediated by glioma directed twin functional-chimeric peptide-decorated gold nanoroses.

The successful application of nanomedicine against glioma is basically hooked on to the fabrication of specific and efficient glioma targeted multifunctional theranostics. Herein, through an easy synthetic methodology, we fabricated a type of novel multifunctional theranostic nanoplatform comprising of anisotropic gold nanoroses (AuNs) co-loaded with doxorubicin (DOX) and the near-infrared (NIR) active/responsive dye, indocyanine green (ICG). The tailored nanotheranostics upon being exposed to NIR laser helped in achieving combinatorial chemo-phototherapy along with optical cell imaging. BBB/glioma-targeting ability was realized by amalgamating the AuNs with a naive peptide drug with BBB-glioma targeting and anti-glioma twin functionality. Efficacy studies carried out in C6 cells and spheroids demonstrated heightened synergistic glioma chemo-PDT-PTT effect (~85% ablation in C6 cells and ~88% in C6 spheroids) by the AuNDIPs as compared to the individual therapeutic entities. Here, the AuNs derived nanophototheranostics with in force targeting and on-demand drug release nature will further aid in abolishing chemotherapy associated adverse events by adopting a combinatorial approach for synergistic glioma eradication.

Dual Blood-Brain Barrier-Glioma Targeting Peptide-Poly(levodopamine) Hybrid Nanoplatforms as Potential Near Infrared Phototheranostic Agents in Glioblastoma.

Combined chemo-phototherapy for boosting the efficacy of individual modalities by synergism for antiglioma treatments is in its embryonic stage and far away from effective clinical translation. Herein, moving a step closer, we recommend a facile stratagem to fabricate smart biocompatible and biodegradable multifunctional nanoplatforms comprising inherently fluorescent poly(levodopamine) nanoparticles (FLs) co-loaded with doxorubicin (DOX) and indocyanine green (ICG). The designed near-infrared (NIR) phototheranostic agents upon NIR laser irradiation helped precipitate combined chemo-phototherapy [both photothermal therapy (PTT) and photodynamic therapy (PDT)] and optical imaging under one roof. Excellent glioma-targeting ability was allocated to the nanoplatforms by conjugating them with a novel chimeric therapeutic peptide with glioma homing and antiglioma dual functionality. Further, DOX/ICG/peptide co-loaded nanoplatforms (FLDIPs) exhibited triggered drug release in response to multiple stimuli. Studies performed in 2D C6 glioma cells and 3D spheroids exhibited superior combined chemo-PDT/PTT effects (∼94% killing in cells and ∼87% in spheroids) of the designed FL based nanoplatforms compared to individual therapeutic components. Herein, the FL based multifunctional nanoplatforms with active targeting ability and stimuli responsive drug release behavior will further help in nullifying chemotherapy based adverse effects and mitigate chemo-resistance by adopting a combinatorial approach.

Comprehensive evaluation of chitosan nanoparticle based phage lysin delivery system; a novel approach to counter S. pneumoniae infections.

Cpl-1, an endolysin derived from Cp-1 phage has been found to be effective in a number of in-vitro and in-vivo pneumococcal infection models. However its lower bioavailability under in-vivo conditions limits its applicability as therapeutic agent. In this study, Cpl-1 loaded chitosan nanoparticles were set up in order to develop a novel therapeutic delivery system to counter antibiotic resistant S. pneumoniae infections. Interactions of chitosan and Cpl-1 were studied by in-silico docking analysis. Chitosan nanoparticles and Cpl-1 loaded chitosan nanoparticles were prepared by using ionic gelation method and the process was optimized by varying chitosan:TPP ratio, pH, stirring time, stirring rate and Cpl-1 concentration. Chitosan nanoparticles and Cpl-1 loaded chitosan nanoparticles were characterized to ascertain successful formation of nanoparticles and entrapment of Cpl-1 into nanoparticles. Chitosan nanoparticles and Cpl-1 loaded nanoparticles were also evaluated for nanoparticle yield, entrapment efficiency, in-vitro release, stability, structural integrity of Cpl-1, in-vitro bioassay, swelling studies, in-vitro biodegradation and heamolysis studies. Mucoadhesion behavior of chitosan nanoparticles and Cpl-1 loaded nanoparticles was explored using mucous glycoprotein assay and ex-vivo mucoadhesion assay, both preparations exhibited their mucoadhesive nature. Cellular cytotoxicity and immune stimulation studies revealed biocompatible nature of nanoparticles. The results of this study confirm that chitosan nanoparticles are a promising biocompatible candidate for Cpl-1 delivery with a significant potential to increase bioavailability of enzyme that in turn can increase its in-vivo half life to treat S. pneumoniae infections.