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Miniatured Fluidics-Mediated Modular Self-Assembly of Anticancer Drug–Amino Acid Composite

Miniatured Fluidics-Mediated Modular Self-Assembly of Anticancer Drug–Amino Acid Composite Microbowls for Combined Chemo-Photodynamic Therapy in Glioma


A particulate carrier with the ability to load a combination of therapeutic molecules acting via diverse modes to initiate cancer cell ablation would help heighten anticancer therapeutic outcomes and mitigate harmful side effects due to high doses of mono drug therapy. Moving a step closer, herein, they have developed doxorubicin–curcumin–amino acid-based composite microbowls (CMBs) following miniaturized fluid flow-based self-assembly. The CMBs were further exploited as dual chemo-photodynamic therapeutic agents in C6 glioma cells cultured in both two-dimensional (2D) monolayer and as three-dimensional (3D) spheroids. These CMBs showed synergistic and visible (blue)-light-sensitive cell-killing effects in both C6 cells and 3D spheroids. Furthermore, these bowl-shaped structures also demonstrated good stability and excellent in vitro cytocompatibility in C6 glioma cells. Their results indicated that CMBs with asymmetric cavities could potentially be used as a combinatorial drug carrier enabling simultaneous chemo- and phototherapy for effective cancer treatment. The use of blue light, from the visible part of the electromagnetic system, to generate the phototherapeutic effect further advocates for the ease and widespread applicability of the systems.



Recently, self-assembled structures with hollow interiors such as nanobowls, hollow colloidosomes, hollow spheres, hollow fibers, and metallo-triblock-based self-assembled hollow nanostructures have received an enormous amount of attention in microencapsulation of therapeutic molecules because of their large surface area and well-defined nanosized morphology with tunable pore size. Studies have demonstrated that hollow core–shell structures with void interior cavities can provide wider opportunities for the encapsulation and delivery of functional molecules. Additionally, hollow structures having a bowl-like shape would provide more adsorption or reaction sites for bioactive molecules to get encapsulated at lower densities.


However, most of the studies reported on the formation of hollow structures entirely depended on template-based approaches, which were more tedious, time-consuming, and non-environmentally friendly. Hence, it would be worthwhile to resort to alternate methods such as polymeric self-assembly as a simplistic strategy to prepare hollow structures such as bowl-shaped nano/microparticles to overcome the aforesaid drawbacks. Additionally, the formation of bowl-shaped structures from biocompatible molecules like amino acids or peptides can be further beneficial in the field of drug delivery. Following this, a recently published study by their group represented a new microfluidic-based flow fabrication method to form self-assembled single amino acid (Fmoc-Cys(Trt)-OH)-based nanobowls (NBs). They demonstrated that on controlling the flow rates of the chosen solvent systems through the designed microfluidic channels, Fmoc-Cys(Trt)-OH, self-assembled into bowl-shaped nanostructures, whereas the bulk mixing of Fmoc-Cys(Trt)-OH favored the formation of spherical particles. Owing to their unique hollow cavity and core–shell-like morphology, these single amino-acid-based NBs can serve as a novel platform to deliver combinatorial therapeutics. Hence, in the current work,they further tried to explore this amino-acid-based hollow bowl-like system for combinatorial anticancer therapy using two anticancer drugs, doxorubicin (Dox) and curcumin (Cur).



Dox acts as a broad-spectrum anticancer drug, which when administered alone or in combination with other chemotherapeutics can provide a first-line therapy for different types of cancers. But the desired efficacy can only be achieved at high doses of Dox because of its shorter circulation half-life, which results in significant cardiac toxicity. To tackle this issue, many nano- or microparticulate-based delivery systems have been explored for enabling effective Dox delivery and channelizing its release at the tumor sites.


Curcumin, [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is a yellow-colored polyphenol plant product with several health benefits having anticancer, antiamyloid, and antioxidant properties. Despite Cur’s many potent therapeutic activities along with high-safety profile, several limitations, including poor aqueous solubility leading to low systemic bioavailability, limit its successful therapeutic translation. To address this issue, several nano- or microparticulate-based delivery agents enabling effective Cur delivery have been explored and their therapeutic potential was validated in many cellular and animal models. Additionally, numerous Cur-based self-assembled nanostructures, either in native form or in the presence of suitable co-assembling moieties, have been explored. On top of displaying potent anticancer activity, Cur has also been found to act as a photosensitizer and generate photoinduced reactive oxygen species (ROS) against cancer cells and several other disease-causing microbes. Compared to conventional treatment methods with poor prognosis and serious side effects, ROS-based antitumor and anti-inflammatory therapies, which include both chemo- and photodynamic dual therapies (CT/PDT), have gradually attracted wide attention.


Many bactericidal drug molecules with ROS production-based antibacterial strategies have also been explored. Du et al. have recently reported metal-porphyrin-based nanosized particles with outstanding ROS catalytic activity and enhanced therapeutic efficacies for treating melanoma. Adhikari et al. reported citrate-functionalized trimanganese tetroxide nanoparticles (C-Mn3O4-NPs) with excellent therapeutic efficacy using both ROS production as well as ROS scavenging abilities in cell and animal models. Du et al. reported Pd-porphyrin-based polymeric biocatalysts, for trimodal (chem-/sono-/photo) tumor therapies with superior catalytic •OH production. Chen et al. reported ROS production using boron dipyrromethene-conjugated hyaluronic acid nanoparticles (NPs) for combined photodynamic (PDT) and photothermal (PTT) based anticancer therapy.



Prompted by this rationale, we here reported an easy and straightforward method to fabricate novel Dox–Cur–amino acid composite microbowls (CMBs) by the co-assembly of Cur, Dox, and Fmoc-Cys(Trt)-OH on a microfluidic device. Their dual-drug-carrying CMBs were further exploited for their combined chemo- and phototherapeutic activities toward achieving synergistic cytotoxicity in monolayer two-dimensional (2D) and three-dimensional (3D) glioma tumor spheroid models.


Miniatured Fluidics-Mediated Modular Self-Assembly of Anticancer Drug–Amino Acid Composite Microbowls for Combined Chemo-Photodynamic Therapy in Glioma Sonika Chibh, Vibhav Katoch, Manish Singh, Bhanu Prakash, and Jiban Jyoti Panda ACS Biomaterials Science & Engineering 2021 7 (12), 5654-5665 DOI: 10.1021/acsbiomaterials.1c01023