Table 2. Examples of nanocarrier-based co-delivery of synergistic drug combination (small molecules) in cancer therapy. All studies were performed both in vitro and in vivo with *the nanoparticle formulation in clinical trials.

Nanocarriers	Tumor Model	Results	Reference
CPX-1 liposomes* (irinotecan: floxuridine)	Patients with advanced colorectal cancer; Subcutaneous HT-29 human colon cancer	Simultaneous release of drugs at synergistic ratios from the liposome and maintained the synergistic ratio up to 12 h; improved efficacy in clinical trial.	[32, 49, 50, 69, 71]
CPX-351 liposomes* (cytarabine:daunorubicin)	Patients with refractory acute myeloid leukemia; i.v. inoculation of Murine P388, L1210 and WEHI- 3B leukemia; i.v. inoculation Human HL- 60B & CCRF-CEM human leukemia	Maintaining an optimized drug ratio greater than 24 h in phase I dose- limiting studies; Significant improvement of patient survival, response and low adverse effects in phase III randomized trial; Drug ratio of antagonism in vitro correlates with low survival and maximum tolerated dose.	[33, 82]
Triolimus* (paclitaxel: rapamycin:17- AAG)	In clinical trial for angiosarcoma. Subcutaneous A549 human lung cancer and MDA-MB-231 human breast cancer	Triple-loaded polymeric micelle simultaneously targeting different cellular sites; strong synergistic anticancer effect against multiple human cancer cell lines; enhanced efficacy and low toxicity.	[34-36]
Prodrug-based nanocarriers (paclitaxel:baicalein)	A549/PTX human lung cancer (inoculation method is unknown)	Combination of dual targeting ligands (folate and hyaluronic acid) and dual loading drugs showed the most tumor regressions in MDR human lung cancer model;	[79]
Telodendrimer (cisplatin: paclitaxel)	Subcutaneous SKOV-3 human ovarian cancer	Co-encapsulating two drugs with distinct physical properties (i.e. hydrophobic paclitaxel and metallic cisplatin) at various ratios (2:1, 4:1 etc) maximized synergy by fine tuning the nanoparticles	[80]
Polymeric nanoparticles (oxaliplatin:gemcitabine)	Subcutaneous AsPc-1 & BxPc-3 human pancreatic ductal adenocarcinoma	Nanoparticles with dual-loaded drugs can inhibit two different types of tumor growth at very low dose versus high dose free drug combination exhibited severe adverse effect and low tumor response	[76]
Polymer-lipid hybrid nanoparticles (DOX:MMC)	Orthotopic murine EMT6 (sensitive and resistant) and human MDR-MB-435 human breast tumor (sensitive and resistant) models	Precise delivering synergistic ratio of DOX and MMC within nanoparticles to tumor with reduced formation of cardiotoxic DOX metabolite, doxorubicinol; reduced tumor growth and prolonged survival in MDR breast tumor with attenuated cardiotoxicity	[39, 53-56]
Polymeric nanoparticles (ABT-737:camptothecin)	Subcutaneous MC38 human colon cancer	Synergistically inducing cancer cell apoptosis in vitro and in vivo and synergy involves molecular regulation including activation of caspase 3/7/8/9, up-regulation of p53 and down-regulation of Bcl-2	[77]
Polymer micelles (rapamycin:paclitaxel)	Orthotopic MDA-MB-468 human breast cancer	Maintained precise synergistic drug ratio within breast tumor for 48 hours; Mechanism involves suppression of feedback loop Akt phosphorylation resulting in increased cancer cell apoptosis, decreased oncogenic protein translation and cell cycle progression.	[70]
Polymeric micelles (DOX: disulfiram)	Subcutaneous MCF- 7/ADR human breast cancer	pH-sensitive release of two drugs at subcellular level and disulfiram (P-gp inhibitor and apoptosis inhibitor) released first before DOX to increased DOX cytotoxicity.	[72]
EGFR-polymer nanoparticles (lonidamine:paclitaxel)	Orthotopic MDA-MB-231 hypoxic human breast cancer	Targeted EGFR nanoparticles showed advantage of improved PK compared to non-targeted nanoparticles and improved tumor regression.	[75]
CPX-571 Liposomes (irinotecan:cisplatin)	Subcutaneous H69 & NSCLC H1299 human lung cancer & HT29 human colon cancer & Capan-1 human pancreatic cancer	In vitro screening showed the zone of antagonism of irinotecan/cisplatin between molar ratio of 1:2 and 1:4. Synergy of irinotecan/cisplatin between 5:1 and 10:1 was optimal. Superior antitumor activities were observed in multiple different tumor types in liposome co-loaded synergistic ratio of 7:1.	[38, 51]