Filomicelles Deliver a Chemo-Differentiation Combination of Paclitaxel and Retinoic Acid That Durably Represses Carcinomas in Liver to Prolong Survival

Abstract

Drug resistance and relapse is common in cancer treatments with chemotherapeutics, and while drug combinations with naturally occurring, differentiation-inducing retinoic acid (RA) provide remission-free cures for one type of liquid tumor, solid tumors present major problems for delivery. Here, inspired by filoviruses that can be microns in length, flexible filomicelles that self-assemble from an amphiphilic block copolymer (PEG−PCL) are shown to effectively deliver RA and paclitaxel (TAX) to several solid tumor models, particularly in the liver. These hydrophobic compounds synergistically load into the cores of the elongated micelles, and the coloaded micelles prove most effective at causing cell death, ploidy, and durable regression of tumors compared to free drugs or to separately loaded drugs. RA-TAX filomicelles also reduce mortality of human lung or liver derived cancers engrafted at liver, intraperitoneal, and subcutaneous sites in immunodeficient mice. In vitro studies show that the dual drug micelles effectively suppress proliferation while upregulating a generic differentiation marker. The results highlight the potency of dual-loaded filomicelles in killing cancer cells or else driving their differentiation away from growth.

Delivering Combination Chemotherapies and Targeting Oncogenic Pathways via Polymeric Drug Delivery Systems

“…PEG is the most popular choice for the hydrophilic block. Polyethylethylene [60], polybutadiene [61], polydimethylsiloxane [62], polycaprolactone (PCL) [63], PLA [64], PLGA [65], and polystyrene [66] are some of the polymers that have been used as hydrophobic blocks. Beside molecular weight (chain size), other properties that can be altered include charge/zeta potential, polydispersity, and crystallinity.…”

“…Paclitaxel acts as the cytotoxic agent here, while the ‘differentiative’ agent aims to irreversibly differentiate surviving cells into a quiescent state, incapable of initiating tumor regrowth [146]. Combination of Paclitaxel with Retinoic acid—a metabolite of Vitamin A that possesses differentiative properties—reduced resistance and relapse in liver and lung tumor xenografts [63]. Cylindrical micelles coloaded with retinoic acid and paclitaxel was found to be more cytotoxic in vitro.…”

“…These nanoparticles degraded by hydrolysis and photoirradiation and reduced the cell viability of OVCAR-3 ovarian cancer cells in vitro. Similar to the chemodifferentiative therapy of paclitaxel and retinoic acid discussed above [63], Sun et al used PEG–PLA nanoparticles to codeliver doxorubicin and retinoic acid [167]. MDA-MB-231 breast cancer cells exhibit higher drug accumulation compared to the administration of soluble doxorubicin.…”

“…The cause of any synergy between two drugs might be due to a cross-talk between their main pathways/targets. A modification in signaling or the pharmacokinetics of drugs either by (1) the introduction of nanoparticles and/or (2) improved nanocarrier-based delivery may be the difference between success and failure in clinic ([63] and the success of Doxil and Abraxane).…”

Manipulating the mechanics of extracellular matrix to study effects on the nucleus and its structure

“…For example, early studies have shown that while crawling on the scars, well-spread cells polarize more with greater persistence (several hours longer) along the scar's long axis than less spread cells, suggesting that responses for spreading and non-spreading cells could be divergent. Mouse liver cancer cells (Dox-inhibitable MYC-expressed EC4 cells (Anderton et al, 2017;Nair et al, 2018)) cultured on stiff substrate exhibit more nuclear spreading and higher proliferation (4N population) than that on soft matrices (Fig. 2B).…”