Vladimir Torchilin: Engineering of novel pharmaceutical drug delivery systems for combination therapy of multidrug resistant cancer
YUCOMAT & WRTCS 2022
YUCOMAT & WRTCS 2022
Herceg Novi, Montenegro, 2022
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Herceg Novi, Montenegro, 2022
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IISS

Vladimir Torchilin

 

Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA

 

Multidrug resistance (MDR) significantly decreases the therapeutic efficiency of anti-cancer drugs. Downregulation of MDR-related proteins with siRNA is a promising way to reverse the MDR. The delivery of small molecule drugs simultaneously with siRNA can enhance the efficiency of chemotherapy by dual action in MDR cells. Different nanocarrier systems have been developed for the combination treatment and drug co-delivery for MDR tumors.

Continuing our studies, we conjugated the dendrimer, generation 4 polyamido amine (G4 PAMAM), with a polyethylene glycol (PEG)-phospholipid copolymer. The amphiphilic conjugates obtained spontaneously self-assemble into a micellar nanopreparation, which can be co-loaded with siRNA onto PAMAM moieties and poorly water soluble drugs into the lipid core. This system was co-loaded with doxorubicin (DOX) and Pgp siRNA and tested for cytotoxicity against human MDR cells. The combination nanopreparation effectively downregulated P-gp in MDR cells and reversed the resistance towards DOX.

Modification of nanoparticle surfaces with PEG has been considered the gold standard. However, PEGylation presents serious challenges including lack of functionality, hindered cellular interaction, allergic reactions, and stimulation of IgM production accelerating nanoparticles blood clearance. We developed novel liposomal formulations surface-modified with a low molecular weight, branched polyethyleneimine (bPEI)-lipid conjugate for use as an alternative to PEG. The formulations had very good stability, and protein adsorption onto the liposomal surface did not interfere with the cellular interaction. bPEI-modified liposomes (PEIPOS) showed enhanced association with different cell lines by up to 75 times compared to plain or PEGylated liposomes and were without carrier toxicity. They also penetrated the deeper layers of 3D spheroids. Encapsulating paclitaxel (PTX) into PEIPOS did not change its main mechanism of action. PEIPOS complexed and intracellularly delivered siRNAs and downregulated resistance-associated proteins. Finally, tumor growth inhibition was observed in a mouse ovarian xenograft tumor model, without signs of toxicity, in animals treated with the siRNA/PTX co-loaded formulation.

These simple-in-design novel formulations constitute viable and promising additions to the family of combination preparation to treat MDR cancers.

Plenary lectures - YUCOMAT 2019

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