Recent Advances and Challenges in Controlling the Spatiotemporal Release of Combinatorial Anticancer Drugs from Nanoparticles

Abstract

To overcome cancer, various chemotherapeutic studies are in progress; among these, studies on nano-formulated combinatorial drugs (NFCDs) are being actively pursued. NFCDs function via a fusion technology that includes a drug delivery system using nanoparticles as a carrier and a combinatorial drug therapy using two or more drugs. It not only includes the advantages of these two technologies, such as ensuring stability of drugs, selectively transporting drugs to cancer cells, and synergistic effects of two or more drugs, but also has the additional benefit of enabling the spatiotemporal and controlled release of drugs. This spatial and temporal drug release from NFCDs depends on the application of nanotechnology and the composition of the combination drug. In this review, recent advances and challenges in the control of spatiotemporal drug release from NFCDs are provided. To this end, the types of combinatorial drug release for various NFCDs are classified in terms of time and space, and the detailed programming techniques used for this are described. In addition, the advantages of the time and space differences in drug release in terms of anticancer efficacy are introduced in depth.

Keywords: controlled release; nano-formulated combinatorial drug; ratiometric; sequential; spatiotemporal.

Figure 1

Schematic illustration of various spatiotemporal types of combinatorial anticancer drug release. (A) Ratiometric drug delivery and simultaneous release for synergistic drug interaction. (B) Sequential drug release to achieve both intercellular and intracellular drug action. (C) Intracellular sequential release of adjuvant and primary drug for enhanced drug efficacy.

Figure 2

Ratiometric drug delivery of combinatorial drugs using nanoparticles is more advantageous in terms of pharmacokinetics and biodistribution of drug combinations compared to free combinatorial drugs. Reproduced with permission from [40], Journal of Controlled Release, 2016.

Figure 3

Schematic diagram of pH-sensitive core–shell nanoparticles for ratiometric drug release. The curcumin/doxorubicin co-loaded on the pH-sensitive core–shell nanoparticles is released at a constant ratio in cancer cells. Reproduced with permission from [28], Drug delivery, 2018.

Figure 4

(A) Schematic diagram of PLGA-PEG-Anisamide NP (PLGA NP) including a dioleoyl phosphatidic acid (DOPA)-coated cisplatin core (CP core) and DOPA-coated gemcitabine monophosphate core (GMP core) through solvent substitution method. (B) Ratiometric drug delivery of CP core and GMP core co-loaded PLGA nanoparticles (combination NP) into cancer cells. Reproduced with permission from [30], Advanced Functional Materials, 2014.

Figure 5

Sequential release of hydrophobic, hydrophilic drugs from polymer gatekeeper hollow mesoporous silica nanoparticles (PHMSNs). PHMSNs become positively charged in the pH condition of the tumor and are rapidly internalized into cells. Then, by the swelling of the polymer gatekeeper, the hydrophilic drug verepamil∙HCl is initially released to inhibit P-glycoprotein, and the hydrophobic anticancer drug doxorubicin is later released causing cell apoptosis. Reproduced with permission from [33], Advanced Functional Materials, 2017.

Figure 6

Cascade amplification release nanoparticle (CARN) formation process and its sequential release system. (A) Structure of BDOX, β-lapachone, and PEG-PMAN constituting CARN. (B) CARNs, which move through blood vessels, are accumulated in cancer cells. When β-lapachone is initially released from the nanoparticles, it amplifies reactive oxygen species (ROS). The amplified ROS blocks P-glycoprotein (P-gp), preventing DOX from escaping out of the cell. It also changes BDOX to DOX, causing apoptosis. Reproduced with permission from [35], Advanced Materials, 2017.

Figure 7

Sequential release by prodrug nanosystem. (A) Structure and nanoparticle formation process for β-lapachone (LPC), oxidation-responsive thioether-linked linoleic acid paclitaxel conjugates (PTX-S-LA), and PEG-b-poly(d,l-lactic acid) (PEG-PDLLA) (B) Upon intravenous injection, LPC/PTX-S-LA polymeric micelles (PMs) migrate into cancer cells due to the enhanced permeability and retention (EPR) effect. These nanoparticles release LPC first, overexpressing nicotinamide adenine dinucleotide (phosphate) (NAD(P)H):quinone oxidoreductase-1 (NQO1), and raising the ROS level. Then, ROS promotes the release of PTX from PTX-S-LA, and PTX induces apoptosis. Reproduced with permission from [37], American Chemical Society, 2019.

Figure 8

Combinatorial drug-loaded nanospheres capable of spatially sequential drug release using matrix metalloproteinase-2 (MMP-2) sensitive peptide. Celecoxib is first released into the tumor tissue by MMP-2, which is then activated in the tumor environment; paclitaxel (PTX)-loaded nanospheres are positively charged and internalized into cancer cells, and PTX is released intracellularly, causing apoptosis. Reproduced with permission from [38], American Chemical Society, 2019.