Carrier-Free Cisplatin–Dactolisib Nanoparticles for Enhanced Synergistic Antitumor Efficacy

TL;DR

Researchers developed a new nanoparticle system combining cisplatin and dactolisib to improve cancer treatment by boosting drug synergy and reducing side effects.

Contribution

A carrier-free nanoparticle system that self-assembles cisplatin and dactolisib to enhance antitumor efficacy through synergistic drug delivery.

Findings

Cisplatin–dactolisib nanoparticles showed increased cytotoxicity in cancer cells due to drug synergy.

The nanoparticles inhibited tumor migration and metastasis in both in vitro and in vivo models.

The system activated mitochondria-dependent apoptosis and enhanced DNA damage in cancer cells.

Abstract

Cisplatin (CDDP)
is one of the most commonly used chemotherapeutic
agents for solid tumors and hematologic malignancy. However, its therapeutic
outcomes have remained unsatisfactory due to severe side effects,
a short elimination half-life, the emergence of drug resistance, and
the induction of metastasis. Combination with other chemotherapeutic
agents has been proposed as one strategy to address the drawbacks
of CDDP-based therapy. Therefore, this study aimed to boost the antitumor
efficacy of cisplatin (CDDP) with a PI3K/mTOR dual inhibitor, dactolisib
(BEZ), via a carrier-free codelivery system based on the self-assembly
of the coordinated CDDP–BEZ. The synthesized CDDP–BEZ
nanoparticles (NPs) possess sensitive pH-responsiveness, facilitating
the delivery of both drugs to cancer cells. CDDP–BEZ NPs specifically
enhanced cytotoxicity in cancer cells due to the synergy between cisplatin
and dactolisib, resulting in augmented DNA damage, activation of mitochondria-dependent
apoptosis, and increased inhibition on the PI3K/mTOR signaling axis.
The inhibition of tumor migration and metastasis by CDDP–BEZ
NPs was observed both in vitro and in vivo. Our data suggest that
CDDP–BEZ NPs could serve as a safe and effective platform to
maximize the synergy between both drugs in combating cancer, presenting
a strategy to promote the therapeutic efficacy of platinum-based chemotherapeutic
agents by combining them with PI3K inhibitors.

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