Novel Polymeric Nanoparticles for Intracellular Delivery of Peptide Cargos: Antitumor Efficacy of the BCL-2 Conversion Peptide NuBCP-9

Abstract

The preclinical development of peptidyl drugs for cancer treatment is hampered by their poor pharmacological properties and cell penetrative capabilities in vivo. In this study, we report a nanoparticle-based formulation that overcomes these limitations, illustrating their utility in studies of the anti-cancer peptide NuBCP-9 which converts BCL-2 from a cell protector to a cell killer. NuBCP-9 was encapsulated in polymeric nanoparticles (NPs) comprised of a polyethylene glycol (PEG)-modified polylactic acid diblock copolymer (NuBCP-9/PLA-PEG), or PEG-polypropylene glycol-PEG-modified PLA - tetrablock copolymer (NuBCP-9/PLA-PEG-PPG-PEG). We found that peptide encapsulation was enhanced by increasing the PEG chain length in the block copolymers. NuBCP-9 release from the NPs was controlled by both PEG chain length and the PLA molecular weight, permitting time-release over sustained periods. Treatment of human cancer cells with these NPs in vitro triggered apoptosis by NuBCP-9-mediated mechanism, with a potency similar to NuBCP-9 linked to a cell-penetrating poly-Arg peptide. Strikingly, in vivo administration of NuBCP-9/NPs triggered complete regressions in the Ehrlich syngeneic mouse model of solid tumor. Our results illustrate an effective method for sustained delivery of anticancer peptides, highlighting the superior qualities of the novel PLA-PEG-PPG-PEG tetrablock copolymer formulation as a tool to target intracellular proteins.

Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation

“…Polylactic acid (PLA)-polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG tetrablock copolymers were synthesized as described (25). The NPs were loaded with GO-203 (15) and filtered through an Amikon 10-kDa ultrafilter (Millipore).…”

“…In addition, the polymeric PLA-PEG NPs have been administered clinically for the delivery of small molecule anti-cancer agents (24). By contrast and to our knowledge, polymeric NPs have not been explored for the delivery of anti-cancer peptides, other than in a recent preclinical study (25). In this regard, anti-cancer peptides have been incorporated into cationic liposomes (26), perfluorocarbon nanoemulsion vehicles (27), cyclodextrin polymerized NPs (28), and liposome-protamine-heparin NPs (29).…”

Intelligent nanoparticles for advanced drug delivery in cancer treatment

“…By loading dioleoylphosphatidic acid-cisplatin (DOPA-cisplatin) cores into PLGA nanoparticles, they increased the core hydrophobicity of PLGA, further facilitating improved loading of the hydrophobic anti-angiogenic drug rapamycin, a VEGF and tumor associated fibroblasts inhibitor. Co-encapsulation within the same nanoparticle is crucial as it can help maintain the desired dose ratio, giving better control over the release and synergistic therapeutic effect, while ensuring a lower IC 50 value than co-treatment of rapamycin and cisplatin as a result of distinct in vivo pharmacokinetics and biodistribution [46,47]. In another study, albumin-manganese dioxide nanoparticles have been used to regulate the tumor microenvironment with the aim of improving prognosis with radiation therapy [48].…”

New Generation Nanomedicines Constructed from Self-Assembling Small-Molecule Prodrugs Alleviate Cancer Drug Toxicity

“…Supramolecular chemistry enables noncovalent assembly of individual molecular building blocks (e.g., small-molecule prodrug entities, sensing molecules), thus providing innovative approaches to the creation of fascinating nanostructures for biomedical application (7)(8)(9)(10)(11)(12)(13)(14). For example, Hamachi and colleagues developed a novel sensing mechanism for selective protein detection based on the self-assembly of small amphiphilic probes (9,10,15).…”