Simultaneous Delivery of siRNA and Paclitaxel via a “Two-in-One” Micelleplex Promotes Synergistic Tumor Suppression

Abstract

Combination of two or more therapeutic strategies with different mechanisms can cooperatively prohibit cancer development. Combination of chemotherapy and small interfering RNA (siRNA)-based therapy represents an example of this approach. Hypothesizing that the chemotherapeutic drug and the siRNA should be simultaneously delivered to the same tumoral cell to exert their synergistic effect, the development of delivery systems that can efficiently encapsulate two drugs and successfully deliver payloads to targeted sites via systemic administration has proven to be challenging. Here, we demonstrate an innovative "two-in-one" micelleplex approach based on micellar nanoparticles of a biodegradable triblock copolymer poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) to systemically deliver the siRNA and chemotherapeutic drug. We show clear evidence that the micelleplex is capable of delivering siRNA and paclitaxel simultaneously to the same tumoral cells both in vitro and in vivo. We further demonstrate that systemic administration of the micelleplex carrying polo-like kinase 1 (Plk1) specific siRNA and paclitaxel can induce a synergistic tumor suppression effect in the MDA-MB-435s xenograft murine model, requiring a thousand-fold less paclitaxel than needed for paclitaxel monotherapy delivered by the micelleplex and without activation of the innate immune response or generation of carrier-associated toxicity.

miR-27b synergizes with anticancer drugs via p53 activation and CYP1B1 suppression

“…In addition, miR-27b-based combinational therapy was effective in vivo even though the dose of doxorubicin was used much lower than that in clinical routine, representing an important advance for the rational use of traditional chemotherapeutic compounds, which are still the first choice in developing countries. In the future, miR-27b and anticancer drugs might be applied as an encapsulated "cocktail" to ensure delivery to the same tumor cell and achieve maximal synergistic effect [53].…”

Design Advances in Particulate Systems for Biomedical Applications

“…A very interesting example is that of micelles composed by the biodegradable triblock copolymer poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) (PEG-b-PCL-b-PPEEA), which exhibit capacity to co-deliver siRNA and paclitaxel. [ 152 ] In vitro and in vivo studies showed the synergistic effects of siRNA and placlitaxel which might provide more effi cient tumor treatments. Paclitaxel is entrapped in the micelle core via hydrophobic interactions with PCL, while siRNA is adsorbed onto the micelle surface through ionic interactions with the PPEEA block.…”

“…These micelles have just one compartment, but by playing with the interactions between materials and bioactive agents it was possible to obtain a co-delivery system where the therapeutics are immobilized in distinct sites of the particles. [ 152 ] Core-shell nanoparticles can also provide domains with different polarities suitable for hosting drugs or genes in separate regions. For example, coaxial electrospraying allows for one-step preparation of nanoparticles from two polymer dispersions in solvents of different polarity and containing different drugs.…”

MicroRNA modulation combined with sunitinib as a novel therapeutic strategy for pancreatic cancer

“…Indeed, combining two or more therapeutic approaches with different mechanisms can exert a synergistic effect over cancer progression and tumor resistance to chemotherapeutic drugs. 54 In this regard, we investigated whether a two-step, sequential treatment involving the modulation of aberrantly expressed microRNAs to sensitize tumoral cells to the action of drugs, and the subsequent treatment with chemotherapeutic agents could result in a significant and synergistic antitumor effect. For this purpose, we evaluated the in vitro antitumor activity mediated by HSA-EPOPC:Chol/AMOs (+/-) (4/1) lipoplexes, containing oligonucleotides against miR-221, miR-222, or miR-21 (since these AMOs presented the most promising results in terms of tumor suppressor gene modulation in our PDAC model) in combination with small amounts of chemotherapeutic drugs, docetaxel, gemcitabine, or sunitinib malate.…”