Hybrid nanoparticles for combination therapy of cancer

Abstract

Nanoparticle anticancer drug delivery enhances therapeutic efficacies and reduces side effects by improving pharmacokinetics and biodistributions of the drug payloads in animal models. Despite promising preclinical efficacy results, monotherapy nanomedicines have failed to produce enhanced response rates over conventional chemotherapy in human clinical trials. The discrepancy between preclinical data and clinical outcomes is believed to result from the less pronounced enhanced permeability and retention (EPR) effect in and the heterogeneity of human tumors as well as the intrinsic/acquired drug resistance to monotherapy over the treatment course. To address these issues, recent efforts have been devoted to developing nanocarriers that can efficiently deliver multiple therapeutics with controlled release properties and increased tumor deposition. In ideal scenarios, the drug or therapeutic modality combinations have different mechanisms of action to afford synergistic effects. In this review, we summarize recent progress in designing hybrid nanoparticles for the co-delivery of combination therapies, including multiple chemotherapeutics, chemotherapeutics and biologics, chemotherapeutics and photodynamic therapy, and chemotherapeutics and radiotherapy. The in vitro and in vivo anticancer effects are also discussed.

Keywords: Co-delivery; Combination therapy of cancer; Hybrid nanoparticle; Synergistic effect.

Figure 1

(a) Surfactant-free synthesis of NMOFs [39]. (b,c) Representative TEM image of NMOFs synthesized by nanoprecipitation (b) [45] and SEM image of NMOFs synthesized by solvothermal method (c) [48]. Reproduced with permission from reference [39, 45, 48]. Copyright (2008, 2014), with permission from American Chemical Society.

Figure 2

(a) Surfactant-templated NMOF synthesis based on reverse microemulsions or surfactant-assisted solvothermal reactions [39]. (b-c) Representative TEM image showing NMOFs synthesized by surfactant-templated method at room temperature and SEM iamge showing NMOFs synthesized by surfactant-templated method under heating [50, 52]. Reproduced with permission from reference [39, 50, 52]. Copy right (2008), with permission from Wiley Online Library. Copyright (2014), with permission from American Chemical Society.

Figure 3

Schematic representation of the synthesis of PSQ carrying a cisplatin prodrug [39]. Reproduced with permission from reference [39]. Copyright (2014), with permission from Elsevier.

Figure 4

Schematic illustration of hybrid MSN, AuNP, and IONP synthesis. a) For MSN, the surface is first modified followed by small molecule drug loading, and functionalization of polymers, peptides, and siRNAs. b) For AuNPs, the particles are coated by DNA, followed by the loading of positively charged drugs and then PEGylation. c) For IONPs, the surface is first decorated by surfactants and polymers followed by the incorporation of drug molecules.

Figure 5

Zn NCPs carrying oxaliplatin and gemcitabine for combination therapy. (a) Schematic representation of the Zn-Oxali&GMP synthesis. (b) Pharmacokinetics and biodistribution of Zn-Oxali&GMP in CT26 tumor bearing mice after i.v. injection. (c) Tumor growth inhibition curves of Zn-Oxali&GMP NCPs in a subcutaneous xenograft mouse model of human pancreatic cancer BxPC-3. The NCPs were intravenously injected to the mice every four days for a total of three injections. Reproduced with permission from reference [87]. Copyright (2015), with permission from Elsevier.

Figure 6

UiO NMOFs carrying a cisplatin prodrug and siRNAs escaped endosomal entrapment upon entering the cells and induced significant apoptosis in cisplatin-resistant ovarian cancer cells. (a) Schematic presentation of siRNA/UiO-Cis synthesis and drug loading. (b) TEM image of siRNA/UiO-Cis. (c) CLSM image showing that siRNA (TAMRA-labeled, red) successfully escaped from endosomes (Lysotracker Green stained, green). Nuclei were stained with DAPI. Bar=5 μm. (d) CSLM image showing the apoptosis induced by siRNA/UiO-Cis in human ovarian cancer cell SKOV-3. The apoptotic cells were stained with Alexa Fluor 488 Annexin V conjugate, and the nuclei were stained with DAPI. Bar=10 μm. (e) Cytotoxicity of siRNA/UiO-cis in SKOV-3 cells after 72-h incubation. Reproduced with permission from reference [88]. Copyright (2014), with permission from American Chemical Society.

Figure 7

(a) Schematic presentation of the core-shell structure of Zn-cis/siRNAs. (b) Zn-cis/siRNAs promoted the efficient endosomal escape of siRNA (red fluorescence). The endosome and nuclei were stained with Lysotracker Green (green fluorescence) and DAPI (blue), respectively. Bar=20 μm. (c) Tumor growth inhibition curve of Zn-cis/siRNAs. After local administration, Zn-cis/siRNAs showed significant tumor regression in a subcutaneous xenograft mouse model of cisplatin-resistant ovarian cancer. (d) The expression of drug resistant genes in the tumors of mice treated with Zn-cis/siRNAs was significantly down-regulated. Reproduced with permission from reference [89]. Copyright (2015), with permission from Elsevier.

Figure 8

(a) Schematic showing the composition of the self-assembled NCP@pyrolipid core-shell nanoparticle with PEG and pyrolipid in the outer lipid layer. (b) Pharmacokinetics and biodistribution of Zn-cis@pyrolipid in CT26 tumor bearing mice after intravenous injection. (c) In vivo anticancer efficacy of Zn-cis@pyrolipid. PBS, Zn-cis, porphysome, or Zn-cis@pyrolipid was intravenously injected to human head and neck cancer SQ20B subcutaneous xenograft murine models at a cisplatin dose of 0.5 mg/kg or pyrolipid dose of 0.5 mg/kg followed by irradiation (670 nm, 100 mW/cm²) for 30 min 24 h post injection. Mice receiving Zn-cis@pyrolipid without irradiation also served as a control. The drug administration and irradiation were performed once a week for twice total. Data expressed as means±SD (N=5). Black and red arrows in (a) and (d) represent the time of drug administration and irradiation, respectively. “+” and “-” in the figure legends refer to w/and w/o irradiation, respectively. Reproduced with permission from reference [98]. Copyright (2015), with permission from American Chemical Society.

Figure 9

PSQ nanoparticles carrying a cisplatin prodrug and their anticancer efficacy in human lung cancer xenograft murine models by chemoradiotherapy. TEM (a) and SEM (b) images of cisplatin-PSQ. (c) Schematic showing the chemical structure of cisplatin-PSQ. (d) In vivo chemoradiotherapy efficacy assay against mice bearing A549 xenografts. Cisplatin-PSQ was administrated by tail vein injection. Reproduced with permission from reference [99]. Copyright (2015), with permission from Elsevier.

Figure 10

(a) TEM image of phosphonate-MSNP before and after coating with the 10 kD PEI polymer. The arrows indicate that the polymer decorates the MSNP surface but leaves the porous interior accessible to drug loading. (b) MCF-7/MDR cancer cells were subcutaneously injected into mice 7 days before treatment with MSNP by i.v. injections. The mice received six i.v. injections every 3-6 days for 30 days. Comparison of the tumor inhibition effect of Dox-loaded MSNP containing P-gp siRNA versus other treatment groups: saline, empty MSNP, free Dox, free siRNA, Dox-loaded MSNP without siRNA, and Dox-loaded MSNP containing scrambled siRNA. Reproduced with permission from reference [100, 101]. Copyright (2010 and 2013), with permission from American Chemical Society.

Figure 11

(a) Schematic illustration of the preparation of pGNPs. (b) In vivo antitumor activities of control group, laser only without drug injection, hollow Au nanoshells with laser irradiation, pGNPs, HCPT NPs, HCPT NPs with laser irradiation, pGNPs with laser irradiation group on 4T1-tumor-bearing BALB/c mice administered intravenously. Relative tumor volume after treatment administration in different groups was measured. Laser wavelength = 808 nm; power density = 1 W cm⁻²; irradiation time = 10 min (24 h post-injection). (c) Survival curves of mice after various treatments; Mice were removed from the study (considered dead) when their tumor burden exceeded 1000 mm³. Reproduced with permission from reference [103]. Copyright (2014), with permission from Wiley Online Library.

Figure 12

(a) Temperature elevation and (b) the corresponding infrared thermal images of PBS, GNR-DNA or GNR@DOX injected tumors upon 655 nm laser irradiation for 80 s (power output of 500 mW/cm); (c) Representative whole-body bioluminescent imaging (BLI) images of 4T1-Luc tumor-bearing mice taken at 25th day post first intraperitoneal injection (the black arrows indicated the position of primary tumors); (d) Tumor growth and (e) tumor weights of mice injected intratumorally with GNR@DOX nanoparticles and treated laser irradiation, the black arrows indicated the time points for GNR@DOX injection and laser irradiation of each mouse group (n=6, **p<0.01, compared with PBS injected mouse controls); (f) Representative photographs of tumors with different treatment (top to bottom: PBS, DOX, GNR-DNA, GNR-DOX plus NIR irradiation, GNR@DOX or GNR@DOX plus NIR irradiation, respectively). Reproduced with permission from reference [78]. Copyright (2014), with permission from Elsevier.

Figure 13

(a) A549 tumor growth in mice i.v. treated with 10% trehalose (control), free Dox, HGNP, Dox-HGNP, radiation (IR), NIR laser irradiation and radiation (NIR+IR) and combination of Dox-HGNP, NIR laser irradiation and radiation (Dox-HGNP+ NIR+IR). (b) Tumor doubling time after each treatment corresponding the tumor growth. Reproduced with permission from reference [104]. Copyright (2015), with permission from Elsevier.

Figure 14

(a) Relative tumor volume of mice 12 days post various intravenous treatments in resistant human K562/A02 leukemia xenograft mouse model. (b) Tumor inhibition rate of mice at day 4 after treatment. Reproduced with permission from reference [105]. Copyright (2012), with permission from Elsevier.