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Purpose: Nanoparticles (NPs) exhibiting responsiveness towards pH variations in organs, tissue microenvironments and cellular compartments can significantly add on to the drug delivery potential. Here, we have developed NPs from an amphipathic dipeptide, Arginine-α, β-dehydrophenylalanine (RΔF), and tried to explore their pH responsive drug delivery potential in various cancer cells., Methods: RΔF-NPs were architectured by harnessing the process of molecular self-assembly followed by the assessment of effect of pH on NPs morphology using zetasizer, SEM and CD. FTIR and PXRD analysis of the dipeptide and doxorubicin (Dox) were carried out for compatibility assessment followed by encapsulation of Dox in RΔF-NPs. RΔF-Dox-NPs were evaluated for pH dependent release as well as for in-vitro cellular internalization and efficacy in cancer cells., Results: RΔF self-assembled to form monodispersed particles at pH 7. SEM analysis revealed a loss of overall particle morphology along with particle aggregation at highly acidic and basic pH respectively. The NPs demonstrated a slow and sustained release behaviour at pH 7 (97.64 ± 4.71% after 36 h) in comparison to pH 2 (90.27 ± 1.45% after 8 h) and pH 10 (96.39 ± 3.87% after 12 h). In-vitro efficacy studies carried-out in various cancer cells revealed that RΔF-Dox-NPs exhibited higher efficacy with 1.65, 1.95 and 13.34 fold lower IC 50 values in comparison to Dox in C6, HCT-116 and AGS cell lines., Conclusions: RΔF-Dox-NPs with higher drug release at acidic pH, enhanced internalization in cancer cells along with higher cytotoxic potential can act as effective pH responsive drug delivery systems.

Surging reports of peptide-based nanosystems and their growing potency in terms of biological utility demand for the search of newer and simpler peptide-based systems that could serve as smart templates for the development of self-assembled nanostructures. Use of simple amino acids as monomeric building blocks for synthesizing ensembles of nanostructures have gained momentum in this direction with some reports focusing on the development of nanosystems from single or modified single amino acids. In this work, we have demonstrated self-assembly and nanoparticle formation ability of a single amino acid derivative, N-alpha-(9-fluorenylmethyloxycarbonyl)-N(in)-tert-butyloxycarbonyl-L-tryptophan [Fmoc-Trp(Boc)-OH]. The nanoparticles formed by the amino acid were found to be stable to various environmental perturbations like temperature, salts and showed responsiveness to pH change. These were capable of loading and releasing different bioactive molecules and were biocompatible. These systems demonstrated high cellular uptake and doxorubicin-loaded nanoparticles were found to be more efficient in killing glioma cells as compared to the drug alone. Thus, their simple amino acid-based origin along with the ability to ferry bioactive molecules to various cells, endows them the suitability for future applications in the field of drug delivery.

Aim: Different nanoparticles have been investigated to deliver chemotherapeutic agents, but complex synthesis procedures and biocompatibility issues raise concerns in developing them for safe human usage. The aim of this work is to develop α,β-dehydrophenylalanine-containing, self-assembled, amphipathic dipeptide nanoparticles for tumor-targeted drug delivery and therapy., Material & Methods: Solution-phase peptide synthesis was used to synthesize dipeptides. Nanoparticles were prepared by molecular self-assembly. A tumor distribution study was carried out using a radiolabeling method. Tumor regression studies were carried out in murine ascitic tumors in BALB/c mice and breast tumor xenografts in in nonobese diabetic/severe combined immunodeficiency mice., Results: Arg-α,β-dehydrophenylalanine formed self-assembled nanoparticles that could be easily derivatized with folic acid. Folic acid-derivatized nanoparticles showed enhanced cellular uptake and, when loaded with doxorubicin, showed enhanced tumor regression compared with underivatized nanoparticles or native drug, without any adverse side effects, both in vitro and in vivo.