Recent advances in delivery of drug-nucleic acid combinations for cancer treatment

Abstract

Cancer treatment that uses a combination of approaches with the ability to affect multiple disease pathways has been proven highly effective in the treatment of many cancers. Combination therapy can include multiple chemotherapeutics or combinations of chemotherapeutics with other treatment modalities like surgery or radiation. However, despite the widespread clinical use of combination therapies, relatively little attention has been given to the potential of modern nanocarrier delivery methods, like liposomes, micelles, and nanoparticles, to enhance the efficacy of combination treatments. This lack of knowledge is particularly notable in the limited success of vectors for the delivery of combinations of nucleic acids with traditional small molecule drugs. The delivery of drug-nucleic acid combinations is particularly challenging due to differences in the physicochemical properties of the two types of agents. This review discusses recent advances in the development of delivery methods using combinations of small molecule drugs and nucleic acid therapeutics to treat cancer. This review primarily focuses on the rationale used for selecting appropriate drug-nucleic acid combinations as well as progress in the development of nanocarriers suitable for simultaneous delivery of drug-nucleic acid combinations.

Keywords: 5-FU; 5-fluorouracil; AAV-2; AON; ASCL1; BENSpm; CXCL12; CXCR4 cognate ligand SDF-1; CYP3A; Cancer treatment; Combination therapy; DOPE; DOX; Drug delivery; EGFR; Gene delivery; HA; HNSCC; IL-12; IL-24; MDR; MDR1; MSN; MVP; Multifunctional nanocarriers; N(1),N(11)-bisethylnorspermine; NFκB; P-glycoprotein; PAMAM; PEI; PLGA; PTX; Pgp; QDs; TMZ; TNF-α; TRAIL; VEGF; achaete–scute complex-like 1; adeno-associated virus-2; antisense oligonucleotides; cytochrome P450 3A; dioleoylphosphatidylethanolamine; doxorubicin; epidermal growth factor receptor; head and neck squamous cell carcinoma; hyaluronic acid; interleukin-12; interleukin-24; major vault protein; mesoporous silica nanoparticles; multidrug resistance; multidrug resistance protein 1; nuclear factor kappa-light-chain-enhancer of activated B cells; pDNA; pERK; paclitaxel; phosphorylated extracellular signal-regulated kinase; plasmid DNA; poly(d,l-lactide-co-glycolide); polyamidoamine; polyethylenimine; quantum dots; shRNA; siRNA; siRNA delivery; small hairpin RNA; small interfering RNA; temozolomide; tumor necrosis factor-alpha; tumor necrosis factor-related apoptosis-inducing ligand; vascular endothelial growth factor; β-CD; β-cyclodextrin.

Figure 1

Antitumor activity for mice bearing orthotopic U87 tumors using a combination of doxorubicin (DOX) with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy and a simultaneous dendrimer-based delivery system. Survival curves are shown for mice treated with the co-delivery system DGDPT/pORF-hTRAIL, which contains DOX-conjugated dendrimer (DGDPT) and complexed TRAIL plasmid (pORF-hTRAIL), (red line). Controls consisted of saline (black line), DOX only (blue line), DGDPT/pGL-3 co-delivery system containing a control Luc gene (pink line), DGDP/pORF-hTRAIL co-delivery system without targeting ligand peptide (brown line), and TRAIL gene monotherapy DGPT/pORF-hTRAIL using DOX-free vector (green line) (adapted from [57]).

Figure 2

A combination of systemic paclitaxel (PTX) therapy with local interleukin-12 (IL-12) gene therapy in immunogenic, PTX-sensitive EMT-6 murine breast cancer model. Tumor growth curves of mice treated with the combination of systemic PTX (PCT16mg) and local IL-12 plasmid (PCT16 mg+IL-12) compared with untreated control, local IL-12 monotherapy (wIL-12) and chemotherapy only (PCT16 mg) (adapted from [25]).

Figure 3

System for delivery of doxorubicin (DOX)/siRNA combination based on quantum dots (QDs) modified with β-cyclodextrin (β-CD) (adapted from [33]).

Figure 4

Mechanism of action of dual-function polycations as CXCR4 antagonists and gene-delivery vectors (adapted from [81]).