Morphological transformation enhances Tumor Retention by Regulating the Self-assembly of Doxorubicin-peptide Conjugates

Abstract

Rationale: Both spatial accuracy and temporal persistence are crucial in drug delivery, especially for anti-tumor intravenous nanomedicines, which have limited persistence due to their small particle sizes and easy removal from tumors. The present study takes advantage of morphological transformation strategy to regulate intravenous nanomedicines to display different sizes in different areas, achieving high efficient enrichment and long retention in lesions. Methods: We designed and synthesized functional doxorubicin-peptide conjugate nanoparticles (FDPC-NPs) consisting of self-assembled doxorubicin-peptide conjugates (DPCs) and an acidic-responsive shielding layer named the functional polylysine graft (FPG), which can regulate the assembly morphology of the DPCs from spherical DPC nanoparticles (DPC-NPs) to DPC-nanofibers (DPC-NFs) by preventing the assembly force from π-π stacking and hydrogen bond between the DPC-NPs. The morphology transformation and particle changes of FDPC-NPs in different environments were determined with DLS, TEM and SEM. We used FRET to explore the enhanced retention effect of FDPC-NPs in tumor site in vivo . HPLC-MS/MS analytical method was established to analyze the biodistribution of FDPC-NPs in H22 hepatoma xenograft mouse model. Finally, the antitumor effect and safety of FDPC-NPs was evaluated. Results: The FDPC-NPs were stable in blood circulation and responsively self-assembled into DPC-NFs when the FDPC-NPs underwent the acid-sensitive separation of the shielding layer in a mildly acidic microenvironment. The FDPC-NPs maintained a uniform spherical size of 80 nm and exhibited good morphological stability in neutral aqueous solution (pH 7.4) but aggregated into a long necklace-like chain structure or a crosslinked fiber structure over time in a weakly acidic solution (pH 6.5). These acidity-triggered transformable FDPC-NPs prolonged the accumulation in tumor tissue for more than 5 days after a single injection and improved the relative uptake rate of doxorubicin in tumors 31-fold. As a result, FDPC-NPs exhibited a preferable anti-tumor efficacy and a reduced side effect in vivo compared with free DOX solution and DOX liposomes. Conclusions: Morphology-transformable FDPC-NPs represent a promising therapeutic approach for prolonging the residence time of drugs at the target site to reduce side effect and enhance therapeutic efficacy. Our studies provide a new and simple idea for the design of long-term delivery systems for intravenous chemotherapeutic drugs.

Nanofiber Carriers of Therapeutic Load: Current Trends

“…In situ self-assembly extends the administration of NFs from the usual local delivery and activity towards intravenous delivery route for targeted stimuli-induced activity or therapeutic agent delivery. For example, the addition of acid-responsive poly(L-Lys) to doxorubicin-polypeptide conjugates enabled morphological transformation from spheric nanoparticles (NP) to NFs [ 27 ] ( Figure 2 ).…”

“… The self-assembly of Dox-polypeptide conjugates (FDPC-NPs) and the morphologic transformation of the acid-responsive FDPC-NPs in vitro and in vivo. Change in tumor site pH causes disintegration of micelle shell (1) and subsequent assembly of nanofibers (2) driven by π–π stacking, leading to long-term drug retention in the tumor [ 27 ]. Reprinted with permission from [ 27 ], Copyright 2022, Ivyspring International Publisher.…”

“…Change in tumor site pH causes disintegration of micelle shell (1) and subsequent assembly of nanofibers (2) driven by π–π stacking, leading to long-term drug retention in the tumor [ 27 ]. Reprinted with permission from [ 27 ], Copyright 2022, Ivyspring International Publisher.…”

Light-triggered nitric oxide release and structure transformation of peptide for enhanced intratumoral retention and sensitized photodynamic therapy

“…Besides, long rod-like NPs are less efficient in extravasation from the leaky tumor vessel [ 8 ]. To resolve this challenge, scientists put forward the exploitation of nanomaterials with transformable property to enhance the retention of nanomedicines in tumor tissues [ 9 , 10 ]. This strategy harnesses the advantages of small NPs with spherical shape in rapid influx and their transformed counterparts in prolonged retention upon appropriate stimulation.…”

Dual-ligand supramolecular nanofibers inspired by the renin-angiotensin system for the targeting and synergistic therapy of myocardial infarction

“…Small molecular amphiphilic peptides are widely used to prepare supramolecular self-assembly nanostructures in nanomedicine 18 - 20 , tissue engineering 21 - 23 , regenerative medicine 24 - 26 , and cell signaling studies 27 - 29 owing to their remarkable properties, including excellent biocompatibility, programmable primary structure, and easy availability. The interest in peptides-based nanomaterials primarily stems from their unique biological advantages (e.g., preferential binding affinity to proteins or direct mimicking of bioactive molecules) as well as the benefits these offer as nanocarriers (such as targeted delivery and high tissue permeability) 30 - 33 . Through the incorporation of amphiphilic motifs, bioactive peptides can self-assemble into supramolecular nanostructures with enhanced tissue retention capacity and improved bioavailability 34 , 35 .…”