Treatment of ovarian cancer is challenging due to late stage diagnosis, acquired drug resistance mechanisms, and systemic toxicity of chemotherapeutic agents. Combination chemotherapy has the potential to enhance treatment efficacy by activation of multiple downstream pathways to overcome drug resistance and reducing required dosages. Sequence of delivery and the dosing schedule can further enhance treatment efficacy. Formulation of drug combinations into nanoparticles can further enhance treatment efficacy. Due to their versatility, polymer-based nanoparticles are an especially promising tool for clinical translation of combination therapies with tunable dosing schedules.
Nanoparticle | Drugs | In Vitro | Key Results In Vitro | In Vivo | Key Results In Vivo | Source | ||||||||||||||
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Key Results In Vitro | In Vivo | Key Results In Vivo | Source |
Nanoparticle | Drugs | In Vitro | Key Results In Vitro | In Vivo | Key Results In Vivo | Source | ||||||||||||||
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Folic acid (FA)-PEGylated calix[4]arene nanoparticle | carboplatin/paclitaxel | SKOV-3, HO-8910 | Encapsulation increased the cell mortality rate of SKOV-3 by 2.5-fold; conjugation further increased the cell mortality rate by 3-fold in vitro | SKOV-3 xenograft (armpit) treated once every other day via intratumor injection | Reduced tumor volume compared to the free drug |
[73] |
[31] |
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Folic acid (FA)-PEGylated-polypeptide-nanogels | cisplatin/paclitaxel | A2780/Luc | 2-fold decrease in IC50 after 24 h using FA | |||||||||||||||||
Nanoparticle | Drugs | In Vitro | Key Results In Vitro | In Vivo | Key Results In Vivo | Source | |||||||||||||||||||||
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Cyclodextrin nanocarries | |||||||||||||||||||||||||||
Polyelectrolyte coated liposome | paclitaxel/curcumin | Cisplatin/olaparib or talazoparib | A2780, SKOV-3 | Syngeistic (CI ~ 0.65) when compared to free drugs (CI ~ 1) | |||||||||||||||||||||||
Folate-PEG-PLGAnanoparticles | docetaxel/gemcitabine | - | - | SKOV-3 | [85] |
[ |
3.59-fold drop in the IC50 and improve cytotoxicity in SKOV-3 cells as compared to free drug combination |
43] |
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SKOV-3 xenograft treated every 2 days for 3 weeks via tail vein injections | Reduced tumor volume and rate of tumor growth compared to free drug combination with no organ toxicity | OVCAR-8 and COV362 | [93] | [51] | enhanced potency (reduced IC50) compared to free drugsA2780/Luc xenograft (IP) treated once every 4 days via tail vein injection | Increased cisplatin accumulation in tumor tissue; improved tumor inhibition and survival compared to single drug formulations | PEI-g-stearic acid micelles coated with hyaluronic acid |
[75] |
[33] |
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paclitaxel/curcumin | SKOV-3 and SKOV-3-TR30 (multi-drug resistant) | ||||||||||||||||||||||||||
mPEG-PLA polymer micelles | 17.3-fold lower IC50 in SKOV-3 cells and 115-fold lower in SKOV-3-TR30 cells compared to free paclitaxel | every other day for 5 times via tail vein injection | doxorubicin/gemcitabine | Reduces tumor volume compared to free drug (t-test, 5%) and PTX only nanoparticles ( |
SKOV-3 | t |
drug internalization via endocytosis | -test 10%) | - |
[86] |
[44] |
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- | [ | 94 | ] | [ | 52 | ] | Poly(2-oxazoline) micelles | ||||||||||||||||||||
triptolide/curcumin | |||||||||||||||||||||||||||
SKOV-3 | Higher apoptosis rate compared to free drugs | SKOV-3 xenografts (upper left axillary fossa) treated twice a week for 24 days via tail vein injection | Reduced tumor volume compared to free drugs |
[114] |
[68] |
Nanoparticle | Drugs | In Vitro | Key Results In Vitro | In Vivo | Key Results In Vivo | Source | |||||||||||||||||||||||||||||||||||||||||||||||
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PEG 3-generation telodendrimer micelles | cisplatin/paclitaxel | SKOV-3, ES-2 | Antagonistic at 1:1 ratio; synergistic at 2:1 ratio of cisplatin to paclitaxel (CI | OVCAR-8 xenografts treated by tail vein injection once a week | Reduced tumor burden and metastasis as well as increasing survival |
[101] |
[59] |
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= 0.21 for SKOV-3) | SKOV-3 xenograft (flank) treated 3 times at 4-day intervals via tail vein injection | highest accumulation in the tumor tissue, decreased tumor volume, increased survival time, and reduced renal toxicity compared to free cisplatin, cisplatin loaded telodendrimers, or paclitaxel loaded dendrimers |
[119] |
[73] |
PEGylated lipid nanoemulsion | paclitaxel/curcumin | |||||||||||||||||||||||||||||||||||||||||||||||
PLA/PLGA/PEG dendrimers | cisplatin prodrug/aspirin prodrug | SKOV-3, SKOV-3TR (drug resistant) | A2780/CP70 (cisplatin resistant) | enhanced cytotoxicity and increased apoptosis, slightly synergistic (CI = 0.93) in SKOV-3 and additive in SKOV-3TR compared to free drugs | ~4-fold decreased IC50 in nanoparticle formulation | - | - | - | - |
[104] |
[62] |
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[ | ] |
[74] |
PEO-PCL nanoparticles | cisplatin/paclitaxel | PEG stabilized microemulsion | ||||||||||||||||||||||||||||||||||||||||||||||||
PEG dendrimers | paclitaxel/tamoxifen | A2780 and A2780cis (platinum resistant) | SKOV-3, SKOV-3TR | 40:3 ratios of PTX to C6CP resulted in combination indexes less than 0.2 in A2780CisR cells; CI highly dependent on the drug ratio | A2780/Luc xenograft (right flank) treated once every 4 days via tail vein injection | 10-fold decrease in IC50 of paclitaxel (SKOV-3), CI ~ 0.4 and (CI ~ 0.7) in SKOV-3TR | |||||||||||||||||||||||||||||||||||||||||||||||
mPEG-PLA nanoparticles | brucea oil/tripterine | SKOV-3, SKOV-3TR xenograft (flank) treated at day 1 and day 24 through tail vein injectionreduced tumor growth, increased survival compared to single drug loaded micelles | suppressed tumor growth, lowering systemic toxicity, tamoxifen enhanced cytotoxicity of paclitaxel | doxorubicin/verapamil | Oxaliplatin/curcumin dendrimers[76 [87 |
A2780, SKOV-3, A2780/DOX, and SKOV-3/DOXR | ] |
SKOV-3 | micelles increased drug accumulation and enhanced apoptosis | ] |
[ |
[ |
A2780/DOXR and SKOV-3/DOXR xenograft treated every 3 days for 2 weeks via tail vein injection34]45] | ||||||||||||||||||||||||||||||||||||||||
SKOV-3/OVCAR-3 | inhibited tumor growth and increased survival time compared to free doxobucin with reduced side effects | ||||||||||||||||||||||||||||||||||||||||||||||||||||
CI | = 0.90 at an 20:1 w:w ratio of brucea oil to tripterine | - | CI 0.855 in SKOV-3/CI 0.708 in OVCAR-3 after 48 h of treatment (IC50) | - | - |
[ |
-105] |
[63] |
[122] | PEG-poly-(L-lysine) | mPEG-PCL polymer micelles | Cisplatin/doxorubicin | mPEG-b-poly[N-2-hydroxyethyl)-aspartamide]/phenylboronic acid | ||||||||||||||||||||||||||||||||||||||||
[ | ] | iRGD peptide Lipid-polymer hybrid nanoparticles | paclitaxel/tacrolimus (FK506) | Doxorubicin/irinotecan | paclitaxel/tetrandrine | A2780/A2780DDP (platinum resistant) | SKOV-3 | 2.5-to 3.3-fold decrease in IC50 of cisplatin, CI 0.21–55 |
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3-generation PEG-PAMAM dendrimers | Micelles increase IC50 compared to free drug; co-loaded micelles synergistic compared to single drug loaded (CI 0.3) | - | - | paclitaxel/borneol |
[ |
A2780/T (PTX resistant) | A2780/PTX cells (paclitaxel resistant) | - |
A2780/PTX (paclitaxel resistant) | CI77 |
5.3-fold decrease in IC50 compared to PTX only micelles; | 0.49–0.64 depending on drug ratios; increased intracellular paclitaxel accumulation apoptosis when co-loaded] |
- | - |
[35] |
[ |
- | - | 88] |
[46] |
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[ | 95 | ||||||||||||||||||||||||||||||||||||||||||||||||||||
3-fold lower IC50 value compared to the free drug combination | - | A2780/PTX xenograft (back) once every two days for 7 tail vein injections | [96] | [54] | |||||||||||||||||||||||||||||||||||||||||||||||||
decrease in tumor volume, compared with the free drug combination | [ | ] |
[64] |
[123] |
[76] |
PLGA-PEG | Chitosan/alginate nanocapsules |
Pluronic® F-127 micelles | cisplatin/paclitaxel | paclitaxel/lapatnib | |||||||||||||||||||||||||||||||||||||||||||
Lipid-templated polymer-caged nanobins | resveratrol co-loaded with quercetin or curcumin in NPs with free adriamycrin | SKOV-3 | cisplatin/doxorubicin | ES2-Luc, A2780, and A2780ADR, ES2-Luc | OVCAR-3 | OVCAR-3 | The co-loaded formulation was significantly more potent than prodrug stabilizer (3600-fold decrease in IC50) | Increased cytotoxicity compared to PTX | Up to 10 –fold reduction in IC50 and synergistic (CI < 0.5) in A2780 and A2780ADR cells | - | |||||||||||||||||||||||||||||||||||||||||||
Linear-dendritic telodendrimers | enhanced cytotoxicity compared to both free drug and single-drug nanobins; CI between 0.27 and 0.67 depending on drug ratio compared | - | ES2-Luc and A2780ADR xenografts treated with weekly injections for 4 weeks via tail vein injection | Significant tumor reduction and cardioprotective effect compared to ADR alone | doxorubicin/bortezomib | SKOV-3 | Synergistic effects observed at bortezomib: doxorubicin ratios between 1:1 and 1:10; antagonistic at lower ratios | - | - |
SKOV-3 xenograft (flank) treated every 4 days for a total of 3 tail vein injections | - |
[74] |
[32] |
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[ | ] | [47] |
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] | [ | 53 | ] | decreased toxicity delayed tumor growth compared to free drugs | [97] | [55] | |||||||||||||||||||||||||||||||||||||||||||||||
- | [ | ] |
[65] |
[124] |
[77 |
PLGA-PEG NPs | cisplatin/wortmannin (DNA repair inhibitor) | PS-PEG nanoparticles | A2780 and A2780cis (platinum resistant) | synergistically enhanced efficacy of A2780cis (CI |
paclitaxel/lapatinib ~ 0.04) with a 21-fold decrease in IC50, but were additive in A2780 cells (CI ~ 0.9–1.2) | A2780 and A2780cis xenograft (right flank) treated once by trail vein injection | reduced tumor growth rates compared to the free drugs; Increased cisplatin localization in the tumor | OVCA-432 | 1500-fold decrease in IC compared to free drug; co-loaded formulation 4.4 fold decrease in IC50 concentration compared to PTX only formulation; CI 0.23; co-loaded formulation more potent than two single drug loaded nanoparticle (CI 0.40) | - | mPEG-b-PLA micelles | - | [78] |
[36] |
Chetomin/Everolimus[90] |
[48 | |||||||||||||||||||||||||||||||
ES-2, OVCAR-3, TOV-21G | ] | Combination index for co-loaded micelle was <1 compared to single drug loaded micelles |
Hyaluronic acid micelles |
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EGFR-peptide-PCL nanoparticles | cisplatin/EGCG | SKOV-3 | |||||||||||||||||||||||||||||||||||||||||||||||||||
] | DSPE-PEG micelles | paclitaxel/tanespimycin (17-AAG) | - | - | ES-2 treated with weekly injections for 3 weeks via tail vein injection | SKOV-3 xenograft (flank) with sequential delivery of paclitaxel (free or NPs) once a week and followed by 17-AAG (free or NPs) 3 days later for 3 weeks, administed through tail vein injection | Significant tumor reduction compared to empty micelles and saline control | increased tumor accumulation by 2-fold,~2-fold reduction in tumor mass after 43 days significant tumor growth arrest compared to free drug combinations | [98] | [56] | |||||||||||||||||||||||||||||||||||||||||||
[ | ] | [66] |
paclitaxel/lonidamine | Amphiphilic drug-drug conjugate nanopartpices | floxuridine-chlorambucil | Slight decrease in cell viability compared to single drug loaded NPs. Intracellular uptake was possible facilitating Pt accumulation. | SKOV-3-Luc xenograft (IP) treated once a week for 3 weeks by IP injection | increased the Pt accumulation in the tumor and reduced tumor volume as well as increased survival rate compared to free cisplatin | SKOV-3, SKOV-3TR, OVCAR-5 (MDR) | [ |
2-fold decrease in IC50 of paclitaxel in OVCAR-5 cells under hypoxic conditions (no change in IC50 under noroxative conditions or other cell types) | - | ] |
- | |||||||||||||||||||||||||||||||||||||||
Core-shell DOPA, DSPE-PEG, and cholesterol nanoparticles | [ | 37] |
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OVCAR-3 | carboplatin/gemcitabine | Combination index was nanodrugs~0.3 compared to~0.7 for the free drug |
[91] |
[49] |
PCL-based triblock co-polymer micelle carriers | ||||||||||||||||||||||||||||||||||||||||||||||||
PEG-b-PCL micelles | oxoplatin/curcumin | paclitaxel/cyclopamine/gossypol | A2780 | strong synergistic interaction (CI ~ 0.3) | SKOV-3, ES-2 | - | - | 2D model: no increased potency compared to paclitaxel micelles; 3D model: disaggregation of the spheroid | [80] |
[ |
ES-2, SKOV-3 xenografts via IP injection once a week for 3 weeks via IP injection |
38] |
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significantly reduced tumor volume and extended survival time compared to free paclitaxel | [ | ] |
[50] |
poly(norbornene)-co-poly(ethylene glycol) | Cisplatin/doxorubicin camptothecin | OVCAR-3 | The triple drug co-loaded formulation was more potent than the single drug (cisplatin) or two drug loaded combination as indicated by the decrease in IC50 (up to 11-fold) | - | - |
[81] |
[39] |
Nanoparticle | Drugs | In Vitro | |||||
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- | |||||||
- | [ | 99 | ] | [ | 57 | ] |
SKOV-3, A2780/CDPP (platinum resistant cells) | |||||||
CI | |||||||
~0.5 comparable to free drugs | |||||||
SKOV-3, A2780/CDDP (platinum-resistant) xenografts (right flank) injected by IP once every 3 days for a total of 3 injections | reduced tumor weight by 12-fold compared to free drug combination |
[113] |
[67] |
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mPEG-DPPE/calcium phosphate nanoparticle |