Peptide-targeted, stimuli-responsive polymersomes for delivering a cancer stemness inhibitor to cancer stem cell microtumors

Abstract

Often cancer relapses after an initial response to chemotherapy because of the tumor's heterogeneity and the presence of progenitor stem cells, which can renew. To overcome drug resistance, metastasis, and relapse in cancer, a promising approach is the inhibition of cancer stemness. In this study, the expression of the neuropilin-1 receptor in both pancreatic and prostate cancer stem cells was identified and targeted with a stimuli-responsive, polymeric nanocarrier to deliver a stemness inhibitor (napabucasin) to cancer stem cells. Reduction-sensitive amphiphilic block copolymers PEG-S-S-PLA and the N-PEG-PLA were synthesized. The tumor penetrating iRGD peptide-hexynoic acid conjugate was linked to the N-PEG-PLA polymer via a Cu catalyzed "Click" reaction. Subsequently, this peptide-polymer conjugate was incorporated into polymersomes for tumor targeting and tissue penetration. We prepared polymersomes containing 85% PEG-S-S-PLA, 10% iRGD-polymer conjugate, and 5% DPPE-lissamine rhodamine dye. The iRGD targeted polymersomes encapsulating the cancer stemness inhibitor napabucasin were internalized in both prostate and pancreatic cancer stem cells. The napabucasin encapsulated polymersomes significantly (p < .05) reduced the viability of both prostate and pancreatic cancer stem cells and decreased the stemness protein expression notch-1 and nanog compared to the control and vesicles without any drug. The napabucasin encapsulated polymersome formulations have the potential to lead to a new direction in prostate and pancreatic cancer therapy by penetrating deeply into the tumors, releasing the encapsulated stemness inhibitor, and killing cancer stem cells.

Biomolecule–polymer hybrid compartments: combining the best of both worlds

“…Targeting or cell penetrating peptides, less expensive and smaller than antibodies, have been widely exploited to target polymersomes to locations of interest within cells or living organisms. For example, cyclic (RGD and NGQ), [46][47][48][49] pH sensitive fusogenic (GALA) 47 and other targeting (GE11, NLS, LinTT1, ApoE, Tet-1) [50][51][52][53][54] peptides have been mainly used to deliver smart polymer vehicles to specific cells or organelles and/or to improve their tumour penetration for therapeutic or diagnostic applications. Recently, targeting of the nuclear interior has been achieved using polymersomes functionalized with nuclear localization signal (peptide NLS), which position themselves as promising nanocarriers for drug delivery to cell nuclei.…”

“…55 The most frequent approach to prepare such vesicular peptide/polymer biohybrids consists in the preparation of polymer compartments followed by the decoration of their surface via the chemical ligation of the chosen targeting peptide. 44,47,49,52,53,56 Beyond that, the peptides can also be coupled to the block copolymers prior to vesicle formation via mixing of the nonfunctionalized polymer with a peptide-functionalized counterpart that self-assemble together to form peptide-functionalized polymersomes. 46,48,50,51,54 Nevertheless, even if this approach enables the simultaneous usage of different types of polymer, e.g.…”

<p>Self-Renewal Signalling Pathway Inhibitors: Perspectives on Therapeutic Approaches for Cancer Stem Cells</p>

“…Napabucasin Napabucasin (BBI608) is an oral CSC inhibitor that targets Stat3. 104,105 In both preclinical toxicology studies and clinical trials, napabucasin was well tolerated and showed no signs of adverse effects on haematopoiesis or other normal adult stem cells. Napabucasin effectively downregulated stemness gene expression and eliminated cancer cells exhibiting high stemness marker expression, leading to inhibition of cancer cell spherogenesis.…”

Nanosensors based on polymer vesicles and planar membranes: a short review

“…Most reduction-sensitive vesicles contain disulfide bonds in the polymer membrane to achieve structure loss in the presence of reducing agents, like glutathione [ 13 , 14 ]. Those vesicles can be applied for drug delivery since redox potentials vary highly between tumor and normal tissue.…”