IKBKE is an oncogene in triple-negative breast cancer (TNBC), and we demonstrate that IKBKE small interfering RNA (siRNA) inhibits the proliferation, migration, and invasion of TNBC cells. Despite the recent success of siRNA therapeutics targeting to the liver, there still remains a great challenge to deliver siRNAs to solid tumors. Here, we report a hybrid nanocomplex to co-deliver the IKBKE siRNA and cabazitaxel to TNBC to achieve an optimal antitumor effect. The nanocomplex is modified with hyaluronic acid to target CD44 on TNBC cells. The nanocomplex shows higher cellular uptake and better tumor penetration of the encapsulated cargos. The nanocomplex also exhibits high tumor accumulation and antitumor activity in an orthotopic TNBC mouse model. Encapsulation of cabazitaxel in the nanocomplex enhances the activity of the IKBKE siRNA. The hybrid nanocomplex provides a novel and versatile platform for combination therapies using siRNAs and chemotherapy.
Blockade of the interaction between programmed cell death
ligand-1
(PD-L1) and its receptor PD-1 has shown great success in cancer immunotherapy.
Peptides possess unique characteristics that give them significant
advantages as immune checkpoint inhibitors. However, unfavorable physicochemical
properties and proteolytic stability profiles limit the translation
of bioactive peptides as therapeutic agents. Studies have revealed
that cyclization improves the biological activity and stability of
linear peptides. In this study, we report the use of macrocyclization
scanning for the discovery of cyclic anti-PD-L1 peptides with improved
bioactivity. The cyclic peptides demonstrated up to a 34-fold improvement
in the PD-1/PD-L1 blocking activity and significant in vivo anti-tumor
activity. Our results demonstrate that macrocyclization scanning is
an effective way to improve the serum stability and bioactivity of
the anti-PD-L1 linear peptide. This strategy can be employed in the
optimization of other bioactive peptides, particularly those for protein–protein
interaction modulation.
Despite the great potential of peptides as therapeutics, there is an unmet challenge in sustaining delivery of sufficient amounts in their native forms. This manuscript describes a novel nanocarrier capable of delivering functional small peptides in its native form. Self-assembling multi-layered nanomicelles composed of two polymers, polyoxyethylene hydrogenated castor oil 40 (HCO-40) and octoxynol 40 (OC-40), were designed to combine hydrophilic interaction and solvent-induced encapsulation of peptides and proteins. The polymers are employed to encapsulate peptide or protein in the core of the organo-nanomicelles which are further encapsulated with another layer of the same polymers to form an aqueous stable nanomicellar solution. The size of the multi-layered nanomicelles ranges from ~16 to 20 nm with zeta potential close to neutral (~− 2.44 to 0.39 mV). In vitro release studies revealed that octreotide-loaded multi-layered nanomicelles released octreotide at much slower rate in simulated tear fluid (STF) (~27 days) compared to PBST (~11 days) in its native form. MTT assay demonstrated negligible toxicity of the multilayered nanomicelles at lower concentrations in human retinal pigment epithelial (HRPE, D407), human conjunctival epithelial (CCL 20.2), and rhesus choroid-retinal endothelial (RF/ 6A) cells. This work demonstrates an efficient small peptide delivery platform with significant advantages over existing approaches, as it does not require modification of the peptide, is biodegradable, and has a small size and high loading capacity.
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