Selective N-Alkylation of β-Alanine Facilitates the Synthesis of a Poly(amino acid)-Based Theranostic Nanoagent

Abstract

The development of functional amino acid based polymeric materials is emerging as a platform to create biodegradable and non-toxic nanomaterials for medical and biotechnology applications. In particular, facile synthetic routes for these polymers and their corresponding polymeric nanomaterials would have a positive impact in the development of novel biomaterials and nanoparticles. However, progress has been hampered by the need to use complex protection-deprotection methods and toxic phase transfer catalyst. In this study, we report a facile, single-step approach for the synthesis of an N-alkylated amino acid as an AB-type functional monomer to generate a novel pseudopolyamino acid, without using the laborious multi-step, protection-deprotection steps. This synthetic strategy is reproducible, easy to scale up and produces no toxic byproducts. In addition, the synthesized amino acid-based polymer is different from conventional linear polymers as the butyl pendants enhance its solubility in common organic solvents and facilitate the creation of hydrophobic nanocavities for the effective encapsulation of hydrophobic cargos upon nanoparticle formation. Within the nanoparticles, we have encapsulated a hydrophobic DiI dye and a therapeutic drug, Taxol. In addition, we have conjugated folic acid as a folate receptor-targeting ligand for the targeted delivery of the nanoparticles to cancer cells expressing the folate receptor. Cell cytotoxicity studies confirm the low toxicity of the polymeric nanoparticles and drug-release experiments with the Taxol-encapsulated nanoparticles only exhibit cytotoxicity upon internalization into cancer cells expressing the folate receptor. Taken together, these results suggested that our synthetic strategy can be useful for the one-step synthesis of amino acid-based small molecules, biopolymers and theranostic polymeric nanoagents for the targeted detection and treatment of cancer.

A Dual‐Targeting Octaguanidine–Doxorubicin Conjugate Transporter for Inducing Caspase‐Mediated Apoptosis on Folate‐Expressing Cancer Cells

“…Out of the eight cell lines examined, HeLa and SKOV3 cells showed significantly higherF Re xpression, whereas A549 and 3T3L1 showedm inimum FR expression ( Figure 2A,B). The resultsc orrelated well with similar studies [24][25][26] and enabled us to select HeLaa nd SKOV3 as FR-positive and A549 as FR-negative cells for in vitro assays.F urthermore, Ehrlich ascites carcinoma( EAC) and Daltons lymphoma ascites (DLA) cells showed moderate levels of FR expression, and would therefore be suitable for in vivo assaysw ith FR-targeting systems.…”

Characteristics of novel polymer based on pseudo-polyamino acids GluLa-DPG-PEG600: binding of albumin, biocompatibility, biodistribution and potential crossing the blood-brain barrier in rats

“…The nontoxicity and biocom patibility of this class of polymers are confirmed by several studies [17]. In addition, amino acidbased polymers, such as polyglutamic acid, polyaspartic acid are widely used in biomedical application due to their biocompatibility, enhanced solubility and low profile cytotoxicity [18].…”

Optical Imaging and Chemotherapy

“…Encapsulation of hydrophobic dyes and drug molecules into aminoacid-based NPs was also reported. 17,18 Formulation of nanotheranostics using chemically modified materials was chosen by other groups in order to avoid any possible misinterpretation of the imaging results as consequence of fluorescent dye desorption and/or release. For example, dye-labelled lipids were introduced in the liposomal formulation when fluorescent RGDfunctionalized Dox-loaded liposomes were prepared by the thin film hydration method, mixing DSPC, cholesterol, DOPE, DSPEmPEG2000, DSPE-cRGDfK and BODIPY-modified DOPE.…”