Synthesis of doxorubicin-loaded peptosomes hybridized with gold nanorod for targeted drug delivery and CT imaging of metastatic breast cancer

Abstract

Background Cancer nanomedicines based on synthetic polypeptides have attracted much attention due to their superior biocompatibility and biodegradability, stimuli responsive capability through secondary conformation change, adjustable functionalities for various cargos such as peptides, proteins, nucleic acids and small therapeutic molecules. Recently, a few nanoformulations based on polypeptides comprising NK105, NC6004, NK911, CT2103, have entered phase I-III clinical trials for advanced solid tumors therapy. In the current study, we prepared polypeptide-based vesicles called peptosome via self-assembly of amphiphilic polypeptide-based PEG-PBLG diblock copolymer. Results In this regard, poly(γ-benzyl L-glutamate (PBLG) was synthesized via ring opening polymerization (ROP) of γ-benzyl L-glutamate-N-carboxyanhydride (BLG-NCA) using N-hexylamine as initiator. Then amine-terminated PBLG was covalently conjugated to heterofuctional maleimide PEG-carboxylic acid or methyl-PEG-carboxylic acid. The PEG-PBLG peptosomes were prepared through double emulsion method for the co-delivery of doxorubicin.HCl and gold nanorods as hydrophilic and hydrophobic agents in interior compartment and membrane of peptosomes, respectively (Pep@MUA.GNR-DOX) that DOX encapsulation efficiency and loading capacity were determined 42 ± 3.6 and 1.68 ± 3.6. Then, theranostic peptosomes were decorated with thiol-functionalized EpCAM aptamer throught thiol-maleimide reaction producing Apt-Pep@MUA.GNR-DOX for targeted delivery. The non-targeted and targeted peptosomes showed 165.5 ± 1.1 and 185 ± 4.7 nm diameters, respectively while providing sustained, controlled release of DOX. Furthermore, non-targeted and targeted peptosomes showed considerable serum stability. In vitro study on MCF-7 and 4T1 cells showed significantly higher cytotoxicity for Apt-Pep@MUA.GNR-DOX in comparison with Pep@MUA.GNR-DOX while both system did not show any difference in cytotoxicity against CHO cell line. Furthermore, Apt-Pep@MUA.GNR-DOX illustrated higher cellular uptake toward EpCAM-overexpressing 4T1 cells compared to Pep@MUA.GNR-DOX. In preclinical stage, therapeutic and diagnostic capability of the prepared Pep@MUA.GNR-DOX and Apt-Pep@MUA.GNR-DOX were investigated implementing subcutaneous 4T1 tumor model in BALB/c mice. The obtained data indicated highest therapeutic index for Apt-Pep@MUA.GNR-DOX compared to Pep@MUA.GNR-DOX and free DOX. Moreover, the prepared system showed capability of CT imaging of tumor tissue in 4T1 tumorized mice through tumor accumulation even 24 h post-administration. Conclusion In this regard, the synthesized theranostic peptosomes offer innovative hybrid multipurpose platform for fighting against breast cancer. Graphical Abstract

Targeted Co-Delivery of FOXM1 Aptamer and DOX By Nucleolin Aptamer-Functionalized pH-Responsive Biocompatible Nanodelivery System to Enhance Therapeutic Efficacy Against Breast Cancer: In Vitro and In Vivo

“…These ndings suggested high targeting activity and prolonged accumulation time of AF-PDA-DOX@TNP in cancer cells. The results were in good agreement with other studies on development of AS1411 aptamer-functionalized nanodelivery system using peptosomes hybridized with gold nanorod [53].…”

Nanomaterial-based CT contrast agents and their applications in image-guided therapy

“…AuNPs also allow facile surface modifications to increase their biocompatibility and durability due to their high affinity for thiol derivatives [13]. Furthermore, AuNPs with controllable shapes have been synthesized as nanospheres [14,15], nanorods [16][17][18][19], nanostars [20][21][22], nanoplates [23], nanocages [24], nanoshells [25], nanoprisms [26], and nanodisks [27]. These AuNPs with unique chemical, electrical, and optical properties have been widely used in the biomedical field.…”

“…Although the CT contrast effect in vitro is not substantially affected by the shape of NPs, the gold nanorods (AuNRs) exhibit a stronger in vivo CT contrast due to better performance in evading clearance by phagocytes and attaining a longer circulation time and higher intratumoral enrichment than AuNSp [16][17][18][19]. Liang et al developed Arg-Gly-Asp (RGD)-modified AuNR nanoprobes with no toxicity, high contrast, and long imaging time as promising contrast agents for in vivo CT imaging (Figure 2B) [32].…”

Targeting anti-inflammatory immunonanocarriers to human and murine neutrophils via the Ly6 antigen for psoriasiform dermatitis alleviation

“…24 The melting points of PVA and PEG-maleimide were 324 and 34 °C, respectively, which were similar to the previous studies showing the endothermic peak at 320 and 40-50 °C for PVA and PEG-maleimide, respectively. 25,26 The DSC curve exhibited a sharp melting peak at 154 °C for RFL. NPs and NPs-RFL showed the peaks at about 320 and 345 °C.…”