The success of this study would see advances in the use of macromolecular drugs as an alternative therapy for tumours.
Cancer treatments like chemo-, immuno-, and radiotherapy have proven to be rather successful in the clinic, however, these therapies come with several non-specific toxicities that limit their clinical benefits. Several studies have been conducted to find an alternative approach to eliminating these toxicities and yet, with new approaches like passive/active targeting and nanoparticle drug delivery, it comes with its own set of issues as well.
In the search for new tumour treatment strategies, scientists have looked towards clustering non-internalising, cell surface receptors to bring about apoptosis without using any conventional drugs. This works by using drug-free macromolecules to induce the clustering of cell surface receptors to activate intracellular apoptosis signalling pathways. Since targeted receptors are overexpressed in cancer cells, clustering can be contained within these cells and will pose little harm to normal healthy cells. Yet, most reported drug-free macromolecular therapeutics involve a “two-step” administration and lack in vitro studies, hindering its widespread application.
To address this, a team of researchers led by Professor Du Yongzhong at the College of Pharmaceutical Sciences, Zhejiang University have developed a light-controlled “drug-free” macromolecule that would cluster CD20 receptors and induce cell apoptosis.
To allow for better control via light, the team looked to incorporate photo-crosslinking into their polymer. Photo-crosslinking is a method of using ultraviolet (UV) irradiation to induce the cross-linking of photocrosslinkable groups like cinnamic acid, which has been widely applied in surface coating and fabrication of hydrogels.
Taking CD20-positive B-cell lymphoma as the model disease, the team introduced poly(2-hydroxyethyl methacrylate) (pHEMA) with pendants of photocrosslinkable groups onto nanoparticles, and then functionalised with anti-CD20 aptamers to give their “drug-free” macromolecule called Apt-pHEMA(CA)@UCNP. Administration of the novel macromolecules accumulated at tumour sites mediated by aptamers and precisely localised to receptors on the surface of tumour cell membranes.
After a local application of NIR laser, the up-conversion nanoparticles in the macromolecules could harvest the light and convert it into UV light, which would trigger the cross-linking of the photocrosslinkable groups. This in-situ cross-linking of Apt-pHEMA(CA)@UCNP then caused CD20 receptors to cluster and induced cell apoptosis. In light free sites, no apoptosis was observed. This means that tumours could be accurately treated in a safe and efficient manner. The results were further validated in tumour animal models.
“This near-infrared up-conversion controlled, in-situ synthesised drug-free macromolecular therapeutics expands the repertoire of macromolecular drugs and opens a new avenue for tumour therapy,” said Prof. Du. [APBN]
Source: Wang et al. (2022). Spatiotemporally light controlled “drug-free” macromolecules via upconversion-nanoparticle for precise tumor therapy. Nano Today, 42, 101360.