Nano Today
Self-assembly of pentapeptides into morphology-adaptable nanomedicines for enhanced combinatorial chemo-photodynamic therapy
Graphical abstract
Introduction
Nanomedicines have showed extraordinary advantages in targeting drug delivery and pharmokinetics to optimize the therapeutic efficacy compared to conventional approaches [[1], [2], [3], [4], [5], [6], [7]]. The efficient delivery of nanomedicines has been accomplished by either utilizing delivering platforms or self-delivering strategies [[8], [9], [10], [11], [12], [13], [14]]. In the former strategies, various platforms consisting of polymers, lipids, peptides, nucleotide acids, inorganic nanoparticles, and among others, have been established during the past few decades [[15], [16], [17], [18], [19]]. The latter strategies focus on the formation of nanostructures directly by drugs or by drugs with removable small assistant moieties, referred to as pro-drugs [[20], [21], [22]]. In both of the platform- or self-delivering strategies, the formed nanostructures usually exhibit a persistent morphology and release drugs at tumor sites driven by internal or external stimuli. However, a considerable number of preclinical studies demonstrate that the clinical translation of nanomedicines requires further improvement of pharmokinetics and drug delivering efficiency. In principle, while the pharmokinetics benefits from prolonged blood circulation and cell retention, the efficient drug delivery could be facilitated by high tumor penetration and cellular internalization. However, it remains challenging for the morphology-persistent nanomedicines to further simultaneously overcome the delivering barriers and optimize pharmokinetics.
Self-assembly of peptides has been demonstrated as versatile strategies to precisely create nanostructures with a controllable morphology or artificial functional biomaterials with great potential in cancer therapy and tissue regeneration [[23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43]]. In this context, we have created peptide nanostructures exhibiting a pH-ultrasensitive morphology based on rational design of short peptides with a non-canonical residue, i.e. 4-amino proline (Amp) [44]. The peptide assemblies adopt superhelices and nanoparticles under the neutral and mild acidic conditions, respectively, and undergo a reversible morphological transition between superhelices and nanoparticles upon pH changes, due to the pH-sensitive isomerization of the Amp amide bonds [45]. Hence, the resulting peptide assemblies might serve as morphology-adaptable platforms for simultaneous prolongation of blood circulation of drugs due to the large aspect ratio of superhelices, improvement of tumor penetration upon the transformation of nanoparticles, and eventually enhancement of tumor accumulation and retention following the reformation of superhelices in cytoplasm. Despite creation of the adaptable nanostructures with an unraveled morphological transition mechanism, their role in drug delivery has not been elucidated thus far. Herein, we report on the efficient delivery of drugs, i.e. camptothecin, by the adaptable platforms and investigate the combinatorial chemo-photodynamic therapy by incorporating a new indocyanine green photosensitizer.
Tumor microenvironment is the essential matrices for cancer cells and presents a considerable number of biomarkers distinct from the normal tissues, including low pH, hypoxia, overexpressed enzymes, and glutathione [[46], [47], [48], [49], [50], [51]]. These cancer biomarkers have been broadly utilized as the internal stimuli for controllable drug release [[52], [53], [54], [55], [56]]. For instance, acid-cleavable bonds have been employed to reverse the charge of amine groups, thus facilitating the penetration and internalization of nanomedicines into cancer cells [[57], [58], [59], [60]]. The overexpressed glutathione (GSH) allows for efficient intracellular release of drugs via reduction of disulfide bonds [[61], [62], [63]]. In addition, the matrix metal proteases enable to cleave peptide sequences at specific sites, thus regulating the intercellular drug release or drug assembly [[64], [65], [66], [67], [68]]. Based on the widely present biomarkers, we developed the adaptable delivering platforms for combinatorial chemo-photodynamic therapy by integrating pH-sensitive self-assembly of peptides with GSH-cleavable linkages between platforms and drugs.
In current study, the morphology-adaptable nanomedicines were created via co-assembly of three components, including one pentapeptide FF-AmpF-FF (AmpF) and two derivatives functionalized with camptothecin (CPT-AmpF) and new indocyanine (IR820-AmpF) (Scheme 1), resulting in nanomedicine ACI. Drug CPT was connected with pentapeptide AmpF through a disulfide bond that allows for release of original CPT driven by GSH reduction, whereas the IR820 unit served as the photosensitizer to generate singlet oxygen for photodynamic therapy. As a consequence, the resulting nanomedicine ACI undergoes a reversible morphological transition between superhelices and nanoparticles upon alternating exposure to neutral and mild acidic conditions (Scheme 1, top). We hypothesize that nanomedicine ACI adopts superhelices in blood vessels after intravenous injection, and transforms into nanoparticles when meeting the acidic tumor microenvironment, and re-forms superhelices in cytoplasm after cellular internalization. Release of CPT moiety induced by GSH reduction and production of ROS under laser irradiation give rise to combinatorial chemo-photodynamic therapy against in vivo tumors. Simultaneously, we prepared another nanomedicine PCI with a morphology persistent to medium pH on the basis of co-assembly of pentapeptide FFPFF (PF), CPT-AmpF, and IR820-AmpF (Fig. 1a) to elucidate the advantage of the adaptable platforms in drug delivery.
Section snippets
Results and discussion
Combining the considerations on maintaining the pH-responsive morphological transition and tuning the combinatorial therapeutic efficacy of the chemodrug and the photosensitizer, the primary nanomedicine ACI was prepared by co-assembly of peptides AmpF, CPT-AmpF, and IR820-AmpF in a molar ratio of 75:5:20, whereas nanomedicine PCI was created via integrating peptides PF, CPT-AmpF, and IR820-AmpF in a molar ratio of 75:5:20 (Fig. 1a). In addition, to illustrate the individual therapeutic
Conclusion
In summary, we have designed and created morphology-adaptable nanomedicines for enhanced combinatorial chemo-photodynamic cancer therapy based on simultaneous optimization of the pharmokinetics and improvement of the drug delivering efficiency. The nanomedicines consist of a pentapeptide containing a 4-amino proline residue and its two derivatives functionalized with chemodrug and photosensitizer moiety. Morphological characterizations in solution demonstrate that the adaptable nanomedicines
Author contribution
Z. Cheng and Y. Cheng contributed equally to this work. Z. Cheng, Z. Yu, Y. Wang, and H. Wang conceived and designed the study. Z. Cheng, M. Li, and Y. Ning performed the characterizations of the conformation and self-assembly of peptides. Z. Cheng, Y. Cheng, Q. Chen, J. Wang, H. Liu, M. Li, Y. Wang, and H. Wang designed and carried out the in vitro and in vivo studies. Z. Cheng, Z. Yu, and H. Wang wrote the paper. All authors discussed the results and have given approval to the final version
Acknowledgments
This work was supported by the National Natural Science Foundation of China (21774065,81972903, and51725302), the Fundamental Research Funds for the Central Universities (Nankai University, ZB19100123 and63186058).
Conflicts of interest
The authors declare no competing financial interests.
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