Size-transformable nanotherapeutics for cancer therapy

Abstract

The size of nanodrugs plays a crucial role in shaping their chemical and physical characteristics, consequently influencing their therapeutic and diagnostic interactions within biological systems. The optimal size of nanomedicines, whether small or large, offers distinct advantages in disease treatment, creating a dilemma in the selection process. Addressing this challenge, size-transformable nanodrugs have surfaced as a promising solution, as they can be tailored to entail the benefits associated with both small and large nanoparticles. In this review, various strategies are summarized for constructing size-transformable nanosystems with a focus on nanotherapeutic applications in the field of biomedicine. Particularly we highlight recent research developments in cancer therapy. This review aims to inspire researchers to further develop various toolboxes for fabricating size-transformable nanomedicines for improved intervention against diverse human diseases.

Keywords: Cancer therapy; Drug delivery; Self-assemble; Size-transformation; Smart nanomedicine.

Graphical abstract

Scheme 1

Schematic illustration of the size-transformation strategy in cancer therapy.

Figure 1

(A) Schematic of in situ self-assembly of nanofibers guided by cancer-associated fibroblasts (CAFs) for heightened tumor imaging, accompanied by the chemical structure of the probe featuring four motifs. Reprinted with permission from Ref. . Copyright © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) The process entails the specific identification, molecular cleavage, and on-site self-assembly of molecule 1. Initially, the X-linked inhibitor of apoptosis protein (XIAP) specifically recognizes molecule 1. Subsequently, the activated caspase-3/7, triggered by the identification process, cleaves the molecules. Following this cleavage, the molecules undergo rapid self-assembly in situ, forming fibrous β-sheet superstructures. Ultimately, these nanostructures made of β-sheets are crucial in enhancing the accumulation and retention of functional molecules within the tumor tissue. Reprinted with the permission from Ref. . Copyright © 2019 Springer Nature. (C) The Schematic of the enzyme-triggered supramolecular coassembly of compounds 1 and 2. Reprinted with the permission from Ref. . Copyright © 2015 American Chemical Society. (D) Illustration depicting the structural arrangement of compound 1 and its adaptive self-assembly into nanofibers within tumor sites, highlighting the amplification by stimulated emission of radiation (AIR) effect. Reprinted with the permission from Ref. . Copyright © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 2

(A) Illustration depicting the composition of the molecule, the mechanism behind shape transformation, and the strategy for drug homing. Reprinted with the permission from Ref. . Copyright © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) Schematic depiction of an acidity-triggered size transformation leading to enhanced photodynamic therapy (PDT). Reprinted with the permission from Ref. . Copyright © 2017 American Chemical Society.

Figure 3

(A) Schematic representation illustrating the intracellular restructuring of a GSH-responsive drug delivery system on transitioning from micelles into nanofibers. Reprinted with the permission from Ref. . Copyright © 2020 American Chemical Society. (B) Schematic of ROS-induced size-transformation with shape transition from nanospheres to nanofiber. Reprinted with the permission from Ref. . Copyright © 2019 American Chemical Society.

Figure 4

(A) Illustration depicting the light-triggered assembly of dendritic gold nanoparticles (dAuNPs). Reprinted with the permission from Ref. . Copyright © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) Schematic illustration depicting the change of IP@NPs@M nanoparticles from spherical micelles to nanofibers under 650 nm laser irradiation. Reprinted with the permission from Ref. . Copyright © 2020 Elsevier. (C) 1. The compositions of DEVD-DLPA and C3. 2. Illustration depicting the morphological transition from nanoparticles to nanofibers. 3. Schematic illustration portraying photodynamic therapy (PDT) triggered in situ intracellular polymerization, resulting in mitochondrial ROS burst and self-amplified circulation of tumor therapy. Reprinted with the permission from Ref. . Copyright © 2022 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 5

(A) Schematic illustration represents the legumain-induced aggregation and composition of AuNPs-DOX-A&C. Reprinted with the permission from Ref. . Copyright © 2016 American Chemical Society. (B) Diagram illustrating the behavior of the AuNPs system in vivo after intravenous injection, showcasing enhanced tumor retention and increased radiotherapy (RT). Reprinted with the permission from Ref. . Copyright © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (C) Schematic of the salt-induced aggregation of AuNPs that bear a negative charge with citrate. Reprinted with the permission from Ref. . Copyright © 2016 The Royal Society of Chemistry.

Figure 6

(A) 1. The chemical structure of PEG-TMCI-TMC terpolymers and the protonation of imidazole moieties induced chemical transformation at low pH. 2. Drug-loaded multilamellar nanovectors (MLNs) are generated through direct hydration and undergo structural reconfiguration at low pH, resulting in their transformation into cationic nanovectors (CNs). 3. The anticipated mode of action of MLNs in vivo involves the localized pH reduction in the tumor microenvironment, thereby enhancing the internalization of CNs and improving tumor penetration. Reprinted with the permission from Ref. . Copyright © 2018 American Chemical Society. (B) The chemical structure of PCL-CDM-PAMAM/Pt and the process of self-assembly and structural changes of iCluster/Pt in tumor responses. Reprinted with the permission from Ref. . Copyright © 2016 National Academy of Sciences. (C) Schematic representation of the structure of DMA-based nanomicelles and the illustration of pH-responsive size shrinkage. Reprinted with the permission from Ref. . Copyright © 2020 American Chemical Society. (D) 1. Diagram depicting the creation of multifunctional two-component nanoparticles (PP NPs) facilitated by electrostatic interactions between PA1 and PA2. 2. Illustration of the tumor-targeting and size-transformable characteristics of PP NPs for enhanced tumor penetration and efficient photochemical combined anticancer therapy. Reprinted with the permission from Ref. . Copyright © 2022 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 7

(A) Schematic illustration of the nuclear entry mechanism of size-shrinking polymer micelles (PELESS-DA) overcoming multidrug resistance (MDR). Reprinted with the permission from Ref. . Copyright © 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) Schematic illustration of the hybrid micelle PSPD/P123-Dex-mediated synergistic size strategy for anticancer drug delivery. Reprinted with the permission from Ref. . Copyright © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (C) 1. Schematic illustration of amphiphilic Aza-BODIPY-1 transforming from nanofibers to micelles under near-infrared light irradiation. 2. Long circulation of nanofibers in the bloodstream and deep penetration of spherical micelles into tumors. Reprinted with the permission from Ref. . Copyright © 2020 American Chemical Society.

Figure 8

(A) Diagram illustrating the preparation of nanomedicines and the process of charge reversal catalyzed by GGT. 2. The positive charge is rapidly internalized via vesicle-mediated endocytosis, enhancing deep penetration into the tumor stroma. Reprinted with the permission from Ref. . Copyright © 2020 American Chemical Society. (B) Self-assembly and disassembly process of positively charged three-arm star-shaped multifunctional prodrug t-P(DTPA(Gd)-co-CPTM-co-CS)-b-PGEMA. 2. In vivo evaluation of SPNs for drug delivery with deep tumor penetration monitored through progressively enhanced magnetic resonance (MR) signals. 3. Structures of all polymers. Reprinted with the permission from Ref. . Copyright © 2020 American Chemical Society. (C) Shell-core nanoparticles (SNP) can achieve size reduction in reaction to the tumor's acidic pH. Reprinted with the permission from Ref. . Copyright © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (D) MMP-2 is highly expressed in the extracellular matrix of tumor cells, triggering the contraction of HA-pep-PAMAM from 200 to 10 nm, enabling its deep penetration into the tumor tissue. Reprinted with the permission from Ref. . Copyright © 2017 American Chemical Society. (E) Schematic illustration of the acid-labile nano-platform rapidly degrades into positively charged DOX@MSN-NH2 and small-sized WS2-HP, enhancing their tumor-penetrating abilities. Reprinted with the permission from Ref. . Copyright © 2017 American Chemical Society. (F) Accumulation and size reduction schematic of DGL/DOX@PP at the tumor site to surmount biological obstacles and penetrate deep into the tumor. Reprinted with the permission from Ref. . Copyright © 2018 The Royal Society of Chemistry.