Self‐Stabilized Supramolecular Assemblies Constructed from PEGylated Dendritic Peptide Conjugate for Augmenting Tumor Retention and Therapy

Abstract

Supramolecular self-assemblies of dendritic peptides with well-organized nanostructures have great potential as multifunctional biomaterials, yet the complex self-assembly mechanism hampers their wide exploration. Herein, a self-stabilized supramolecular assembly (SSA) constructed from a PEGylated dendritic peptide conjugate (PEG-dendritic peptide-pyropheophorbide a, PDPP), for augmenting tumor retention and therapy, is reported. The supramolecular self-assembly process of PDPP is concentration-dependent with multiple morphologies. By tailoring the concentration of PDPP, the supramolecular self-assembly is driven by noncovalent interactions to form a variety of SSAs (unimolecular micelles, oligomeric aggregates, and multi-aggregates) with different sizes from nanometer to micrometer. SSAs at 100 nm with a spherical shape possess extremely high stability to prolong blood circulation about 4.8-fold higher than pyropheophorbide a (Ppa), and enhance tumor retention about eight-fold higher than Ppa on day 5 after injection, which leads to greatly boosting the in vivo photodynamic therapeutic efficiency. RNA-seq demonstrates that these effects of SSAs are related to the inhibition of MET-PI3K-Akt pathway. Overall, the supramolecular self-assembly mechanism for the synthetic PEGylated dendritic peptide conjugate sheds new light on the development of supramolecular assemblies for tumor therapy.

A Dendritic Polymer‐Based Nanosystem Mediates Drug Penetration and Irreversible Endoplasmic Reticulum Stresses in Tumor via Neighboring Effect

“…[9] Recently, we have reported that a PEGylated dendritic peptide-pyropheophorbide a (Ppa) conjugate, PDPP, can assemble into self-stabilized NPs with enhanced tumor retention and stable delivery of Ppa for highly-efficient photodynamic therapeutic effects. [10] This study demonstrates that self-stabilized NPs based on PEGylated dendritic peptides are promising for tumor therapy. However, challenges remain to improve the antitumor efficacy because Ppa cannot be released from PDPP to achieve the neighboring effect for deep tumor penetration.…”

“…In our previous report, we developed an amphiphilic conjugate, PDPP, which was capable to be utilized as a nano-carrier to deliver payloads (drugs, genes, or dyes) with ultrahigh stability and high tumor retention for PDT of tumors. [10] Herein, we exploited the ultrahigh stable nature of PDPP to design dual-responsive NPs (PDPP@D), which could not only achieve delayed release of DOX/Ppa for combination therapy, [12] but also amplify the neighboring effect to eliminate the entire tumor tissue.…”

“…Then, PDPP was prepared in accordance with previously reported studies (Scheme S2 and Figures S3-S7, Supporting Information). [10] Subsequently, both PDPP and DOX were dissolved thoroughly in dimethyl sulfoxide (DMSO) at the feed ratio recommended from DPD simulations, and the mixture was dropwise added into an aqueous medium under ultrasonic conditions. Supramolecular interactions drove the formation of self-assembly NPs and synchronous encapsulation of DOX.…”

“…These results substantiated previous observations that nanocarriers from PEGylated dendritic peptides could effectively decrease the cytotoxicity of chemotherapeutic agents and photosensitizers against cancer because of their high biocompatibility. [10,17] The effect of DOX encapsulation on the antitumor activity of PDPP@D was then investigated. Notably, the lowest viability was achieved at a molar ratio of 2:1 for Ppa to DOX in PDPP@D. The synergy of PDPP@D was quantified by calculating the combination index (CI) at different fraction affected (fa) values for each drug at the ratio of 2:1 (Figure 5C,D and Table S6, Supporting Information).…”

Reactive Oxygen Species-Sensitive Nanophotosensitizers of Methoxy Poly(ethylene glycol)-Chlorin e6/Phenyl Boronic Acid Pinacol Ester Conjugates Having Diselenide Linkages for Photodynamic Therapy of Cervical Cancer Cells

“…For example, Duan et al, reported that nanomedicine based on glycopolymer-pyropheophorbide a conjugates and poly[ N -(2-hydroxypropyl) methacrylamide have superior specificity against tumor cells [ 42 ]. Furthermore, their group also reported that supramolecular self-assemblies of dendritic peptides possess high stability to prolong blood circulation and enhance tumor retention compared to pyropheophorbide a [ 43 ].…”