Transformable nanoparticles to bypass biological barriers in cancer treatment

Abstract

Nanomedicine based drug delivery platforms provide an interesting avenue to explore for the future of cancer treatment. Here we discuss the barriers for drug delivery in cancer therapeutics and how nanomaterials have been designed to bypass these blockades through stimuli responsive transformation in the most recent update. Nanomaterials that address the challenges of each step provide a promising solution for new cancer therapeutics.

Fig. 1. Biological barriers in drug delivery to tumors. Several barriers preclude drug delivery to tumors. These include severe destabilizing conditions during circulation, targeting the tumor location and extravasation into the tumor blood vessel. Next, the drug must penetrate the excess extracellular matrix (ECM) proteins and reach the tumor cells and finally, the drug must be retained in the tumor cells and avoid premature efflux. Made using Biorender.com.

Fig. 2. Schematic illustration of the TMRET nanotechnology and DESI utilizing GSH responsive transformation. Mn²⁺ conjugated to pheophorbide a serves as both an ‘enhancer’ in the T₁ MRI signal and a ‘quencher’ in the T₂ MRI signal, whereas the SPIO nanoparticle acts as an ‘enhancer’ in the T₂ MRI signal and a ‘quencher’ in the T₁ MRI signal. P–Mn and SPIO were coloaded into a disulfide crosslinked micelle to form TMRET nanoparticles. Upon interaction with reduced GSH (glutathione) the disulfide bond is cleaved allowing for signal measurement. Reproduced with permission from (ref. 29). © Springer Nature, 2020.

Fig. 3. Design of transformable STICK-NPs and detailed multibarrier tackling mechanisms to brain tumors. The pair of targeting moieties selected to form sequential targeting in crosslinking (STICK) were maltobionic acid (MA), a glucose derivative, and carboxyphenylboronic acid (CBA), one type of boronic acid, and they were built into our well-characterized self-assembled micelle formulations (PEG–CA8). STICK-NPs were assembled by using a pair of MA4–PEG–CA8 and CBA4–PEG–CA8 with a molar ratio of 9 : 1 while intermicelle boronate crosslinkages, STICK, were formed between MA and CBA resulting in a larger nanoparticle size. Excess MA moieties were on the surface of the nanoparticles, while CBA moieties were first shielded inside the STICK to avoid nonspecific bindings. Hydrophobic drugs were loaded in the hydrophobic cores of secondary small micelles, while hydrophilic agents were trapped in the hydrophilic space between small micelles. In the following studies, we included several control micelle formulations including NM (no targeting), MA–NPs (single BBB targeting), and CBA–NPs (single sialic acid tumor targeting) nanoparticles (inserted table). In detail, STICK-NPs could overcome barrier 1 (destabilizing condition in the blood) by the intermicellar crosslinking strategy, barrier 2 (BBB/BBTB) by active GLUT1 mediated transcytosis through brain endothelial cells, and barrier 3 (penetration & tumor cell uptake) by transformation into secondary smaller micelles and reveal the secondary active targeting moiety (CBA) against sialic acid overexpressed on tumor cells in response to acidic extracellular pH in solid tumors. Reproduced with permission from (ref. 33). © Wiley (2020).

Fig. 4. Tumor targeting with BAQ ONNs. (a) An interdisciplinary drug design strategy is proposed to integrate the conventional fields of medicinal chemistry and nanomedicine. Drugs are named as one-component new-chemical-entity nanomedicines (ONNs), which are designed according to the strategies of conventional drug design and molecular self-assembly so that they could acquire the advantages from the perspectives of both drug discovery and drug delivery. (b) The proof-of-concept experiment in this work: discovery of self-delivering lysosomotropic bisaminoquinoline (BAQ) derivatives for cancer therapy. The BAQ derivatives, generated from the hybridisation of lysosomotropic detergents and the BAQ-based autophagy inhibitor, can self-assemble into BAQ ONNs that show enhanced functions in vitro, excellent delivery profiles and significant in vivo therapeutic effects as single agents. Moreover, they also possess high drug-loading efficiency to deliver an additional drug into tumour sites, thus generating a promising application of combination therapy. Reproduced from (ref. 43) (CC BY 4.0).

Fig. 5. Tumor retention through transformation into nanofibers and nanofibrils. (a) Synthesis of single small molecule-assembled mitochondria targeting nanofibers (PQC NFs). The PQC monomer is a conjugate of PA and quinolinium. PQC NFs exhibited nanomolar cytotoxicity by mediating mitochondria-targeting phototherapy and they were retained long-term at the tumor site. With these advantages, PQC NFs achieved robust anticancer effects in vivo with a 100% complete cure rate after the administration of only a single dose. (b) Chemical structure of the PBC monomer containing pheophorbide a (PA) and bisaminoquinolone derived Lys05. Self-assembling and transformation behaviors of PBC at pH 7.4 and pH 5.0. PBC transformation into nanofibrils allowed for long term retention in the tumor site in oral cancer xenograft models. Reproduced with permission from (ref. and 52). © Wiley (2020 and 2022).

Mythili Ramachandran

Zhao Ma

Kai Lin

Cristabelle De Souza

Yuanpei Li