Figure 1: Schematic representation of supramolecular polylactide network, the hydrophilic PEG corona and the encapsulated anti-cancer drug (doxorubicin).
Figure 1: Schematic representation of supramolecular polylactide network, the hydrophilic PEG corona and the encapsulated anti-cancer drug (doxorubicin).
Figure 2: Cell viability after incubation of DOX-loaded NPs with (A) HeLa and (B) the multi-drug resistant KB-V1 cells after 48 h of incubation, as determined by MTT test. The half-maximal inhibitory concentration (IC50) for the DOX-loaded NPs for HeLa cells was similar to the free drug. However, DOX-loaded NPs had a profound lower IC50 value for KB-V1 MDR cells as opposed to free DOX, proving their potential for remedying drug resistance.
Figure 2: Cell viability after incubation of DOX-loaded NPs with (A) HeLa and (B) the multi-drug resistant KB-V1 cells after 48 h of incubation, as determined by MTT test. The half-maximal inhibitory concentration (IC50) for the DOX-loaded NPs for HeLa cells was similar to the free drug. However, DOX-loaded NPs had a profound lower IC50 value for KB-V1 MDR cells as opposed to free DOX, proving their potential for remedying drug resistance.

Multi-drug resistance of cancer cells is the leading cause for the failure of anti-cancer chemotherapeutics, resulting in minimal cell death and the expansion of drug-resistant tumours. In an effort to tackle this issue, scientists from the Freie Universität Berlin and the Polish Academy of Sciences have designed stimuli-responsive polymeric nanoparticles that consist of supramolecular polymer networks and could be used efficiently to reduce drug-resistant cancers [Brzezinski et al., European Polymer Journal (2018), doi.org/10.1016/j.eurpolymj.2018.08.060]. 

This network, composed of tailor-made polylactides that could further form supramolecular network through their reactive-ends, is able to deliver anti-cancer drugs directly to tumour cells. Polylactide was used to fabricate the nanoparticles due to its biodegradability and biocompatibility. Compared to typical stimuli-responsive drug delivery carriers, the researchers envisioned a 3D network that could be sensitive to both pH and temperature and able to yield dynamically reversible systems that could distinguish the intrinsic characteristics between cancer and normal tissues. The native form of polylactides, however, do not bear any functional groups that can sense differences in modest environmental fluctuations. For this reason, they introduced a self-complementary ureidopyrimidone (UPy) unit in the polylactide backbone that could form hydrogen bonds, therefore furnishing the nanoparticles with excellent reversibility. This unit is responsible for modulating the assembly and disassembly of the nanoparticles dissociation of a supramolecular network and consequently can modify the intracellular drug delivery properties.

The scientists incorporated a surfactant based on poly(ethylene glycol) (PEG)in their system so that they could eliminate possible aggregation of the nanoparticles, obtaining micellar-like nanoparticles in which the hydrophobic polylactides and the encapsulated anticancer drug, doxorubicin, are located in the core whereas the hydrophilic PEG creates a corona that forms a stabilizing shell around the nanoparticles.

“The modulated the assembly/disassembly and biodegradation of NPs and their pH-dependent releasing behaviour was of our particular interest in achieving the tumor-targeted DOX delivery with NPs and to minimize the dosage of the anticancer drug," explains first author of the study, Marek Brzezinski.

The supramolecular polylactides formed well-defined spherical nanoparticles,100-150 nm in size, with unique low-dimensional nanostructurescomposed of hierarchically assembled supramolecular polymers. 

To assess the feasibility of using these nanoparticles as an anticancer drug delivery agent, the group evaluated the drug loading and release behaviour of the supramolecular assembly in physiological conditions and in conditions that resemble the environment outside of a tumour, based on the thermo- and pH-sensitivity of their system. The group proved that the deformation of the supramolecular assembly and the release of the drug from the polymer matrix were accelerated in conditions which bear a resemblance to the intracellularenvironment of a tumour cell, due to the dissociation of the hydrogen bonds.

The 3D network presented low toxicity in HeLa and KB-V1 cell cultures, thereby indicating the high stability of the particles and the prevention of incessant drug releasing in normal biological media.

“The usage of our biodegradable and pH responsive nanoparticles, due to their unique features, can effectively increase the efficiency of chemotherapy against drug-resistant cancers,” comments Marek Brzezinski.

Whether these nanoparticles can be taken out of the lab and made into useful drug delivery carriers will require many clinical trials to discover. However, in a world crying out for new ways to tackle multi-drug resistant cancers, it seems an auspicious technology for effective drug delivery.