Table 2.

List of nanoformulations for codelivery of anticancer drugs with phytochemicals.

Type of Nanoformulation	Anticancer Drug	Phytochemical	Type of Cancer	Result Outcomes	References
SLNs	Paclitaxel	Naringenin	Glioblastoma multiforme	Exhibited 1.7–2.8 times improved Cmax and AUC0−t for both paclitaxel and naringenin from the SLNs than their drug suspension whilst no significant change in Tmax was observed. Moreover, cyclic RGD-modified SLNs possessed more improved drug absorption than plain SLNs. It also exhibited improved cytotoxicity than drug suspension.	[89]
SLNs	Paclitaxel	Curcumin	Lung cancer	Exhibited 1.40 and 2.28 times improved AUC for curcumin and paclitaxel, respectively, provided 6.94 and 6.46 times extended residence time for curcumin and paclitaxel, respectively, achieving long circulation. The rate of tumour suppression of SLNs was 78.42% higher than 40.53% and 51.56% for paclitaxel and a combination of curcumin with paclitaxel.	[90]
SLNs	5-fluorouracil	Curcumin	Liver cancer	SLNs of curcumin with layered double hydroxide 5-fluorouracil provided a synergetic effect on SMMC-7721 cells more strongly than plain drugs in combination. FACS analysis exposed that SLNs of combination prompted 80.1% apoptosis in SMMC-7721 cells.	[158]
SLNs	Docetaxel	Curcumin	Breast cancer	Possessed a noteworthy improvement in AUC of 594.21 ± 64.34 μg/mL h than 39.05 ± 7.41 μg/mL h of Taxotere® and MRT of 31.14 ± 19.94 h than 7.24 ± 4.51 h of Taxotere®. Moreover, the accumulation of docetaxel was reduced in the heart and kidney compared to Taxotere®. Targeting efficiency towards MCF-7 cells was also revealed using fluorescence microscopy.	[159]
NLCs	Tamoxifen citrate	Coenzyme Q10	Breast cancer	Revealed increased % cell viability for normal WISH cell line reaching 100% at 0.25 μg/mL. The lipid nanocarrier exhibited LC 50 on the MCF-7 cell line of 1.6 μg/mL as compared to 4.8 μg/ml on the WISH cell line.	[54]
NLCs	Paclitaxel	α-Tocopherol succinate	Retinoblastoma	Possessed anticipated physicochemical properties and might lead to an efficacious therapeutic option to treat retinoblastoma.	[160]
NLCs	Tamoxifen	Sulforaphane	Breast cancer	Provided 5.2- and 4.8-fold improved oral bioavailability of tamoxifen and sulforaphane along with reduction in tamoxifen-associated toxicity in vivo.	[161]
NLCs	Doxorubicin	Lapachone	Breast cancer	Exhibited improved retention of doxorubicin on MCF-7 ADR cells. In vivo studies on MCF-7 ADR tumour-bearing animal models exhibited improved efficacy.	[162]
NLCs	Docetaxel	Curcumin	Lung cancer	Demonstrated significantly improved cytotoxic activity towards NCI-H460 cells.	[163]
NLCs	Temozolomide	Curcumin	Brain cancer	Demonstrated accumulation of drugs at brain and cancer sites. The inhibitory effect is due to arresting of the S phase cell cycle along with induced apoptosis. Moreover, the toxic effects were absent at normal doses.	[164]
NLCs	Doxorubicin	Β-element	Lung cancer	Displayed improved cytotoxicity, synergistic antitumor effect and insightful tumour inhibition ability.	[165]
NLCs	Docetaxel	Curcumin	Lung cancer	Provided considerably improved apoptotic, anti-proliferative, anti-angiogenic and anti-metastatic activities than Taxotere®. NLCs displayed considerably reduced adverse effects of docetaxel	[166]
Lipid chitosan hybrid nanoparticles	Cisplatin	Curcumin	Ovarian cancer	Provided significant cytotoxicity than cisplatin-loaded nanoparticles as well as curcumin-loaded nanoparticles after 48 hours of treatment.	[167]
Hybrid nanoparticles	Cisplatin	Oleanolic acid	Gastric carcinoma	Exhibited Induced tumour cells apoptosis, reduced adverse effects and reversal of multidrug resistance	[168]
Hybrid nanoparticles	Methotrexate	Beta-carotene	Breast cancer	Provided the highest apoptosis index against MCF-7 cells. Moreover, methotrexate-induced renal and hepatic toxicity was reduced by codelivery of beta-carotene.	[169]
Hybrid nanoparticles	Docetaxel	Resveratrol	Lung cancer	Exhibited significant synergistic potential along with best cancer inhibition ability and minimal systemic toxicity.	[170]
Hybrid nanoparticles	Cisplatin	Curcumin	Cervical cancer	Exhibited significantly improved cytotoxic effects and demonstrated the highest anticancer potential compared to other formulations.	[171]
Hybrid nanoparticles	Doxorubicin	Gallic acid	Leukemia	Displayed protruding cytotoxicity and the best synergistic effect. Nanoparticles revealed improved inhibition of tumour growth.	[172]
Calcium carbonate nanoparticles	Cisplatin	Oleanolic acid	Hepatocellular carcinoma	Exhibited improved HepG2 cell apoptosis along with alleviation of drug-induced hepatotoxicity.	[173]
Nanosponge particles	Tamoxifen	Quercetin		Provided alleviation of the hepatotoxicity produced during the treatment along with improvement in the uptake of tamoxifen.	[174]
Lipid nanoparticles	Doxorubicin	Curcumin	Hepatocellular carcinoma	Demonstrated synergistic activity on the apoptosis, proliferation and angiogenesis of hepatocellular carcinoma. Moreover, the mRNA levels of MDR1, bcl-2 and HIF-1α and protein levels of P-gp, Bcl-2 and HIF-1α were reduced.	[175]
Ph-sensitive galactosylated nanoparticles	Sorafenib	Curcumin	Hepatocellular carcinoma	Possessed the smallest tumour volume of 239 ± 14 mm3 along with an inhibition rate of 77.4% employing pH-sensitive lactosylated nanoparticles.	[176]
Dual targeting nanoparticles	5-fluorouracil	Curcumin	Hepatocarcinoma	Exhibited synergistic antitumor efficiency established by cytotoxicity and animal studies. These provided improved cellular uptake and stronger cytotoxicity for cancer cells.	[62]
PLGA nanoparticles	Methotrexate	Curcumin	Breast cancer	Exhibited 2.5 and 1.7 fold lower IC50 values after 24 and 48 h, respectively, than methotrexate nanoparticles. The cytotoxic property was greater than in other formulations and tumour incidence and size were reduced in the case of PLGA nanoparticles entrapped with both methotrexate and curcumin than other formulations.	[177]
PLGA nanoparticles	Salinomycin	Curcumin	Breast cancer	Provided higher efficacy of CD44 cell surface glycoprotein-functionalized PLGA nanoparticles against breast cancer stem cells by the convincing arrest of G1 cell cycle and restraining epithelial–mesenchymal transition.	[178]
PLGA nanoparticles	Topotecan	Thymoquinone		Demonstrated the sustained release of both the drugs, having a minimal burst release and a total percentage release of more than 90% in 96 h.	[179]
PLGA nanoparticles	Tamoxifen	Quercetin	Breast cancer	Exhibited improved efficiency revealed by increased cellular uptake, nuclear co-localization and cytotoxicity in MCF-7 cells. Provided 5- and 3-fold improved oral bioavailability for tamoxifen and quercetin, respectively. Possessed a higher rate of tumour suppression against a DMBA-induced breast cancer model.	[180]
PLGA nanoparticles	Doxorubicin	Resveratrol	Breast cancer	Exhibited noteworthy cytotoxicity on MDA-MB-231/ADR cells and MCF-7/ADR cells. Moreover, co-encapsulated nanoparticles delivered the drugs to cancer tissue.	[181]
PLGA-PEG nanoparticles	Gemcitabine	Betulinic acid	Solid tumor	Provided increased cytotoxicity than native drugs solution. Moreover, suppression of tumour growth was more efficient in the solid tumour model than the native gemcitabine and betulinic acid at the same concentrations.	[182]
PLA nanoparticles	Sorafenib	Plantamajoside	Hepatocellular carcinoma	Provided improved anticancer effect of sorafenib on hepatocellular carcinoma cells due to reversal of drug resistance.	[183]
PLA nanoparticles	Daunorubicin	Glycyrrhizic acid	Leukemia	Exhibited a tremendous synergistic effect leading to ominously greater cell inhibition. Cell apoptosis was improved but did not influence MDR1 expression.	[184]
PLGA nanoparticles	Doxorubicin	Berberine	Breast cancer	Exhibited significant improvement in mitochondrial membrane permeability along with the arrest of progression of the cell cycle at the sub-G1 phase.	[185]
PLGA nanoparticles	Paclitaxel	Curcumin	Brain cancer	Provided synergistic effect on inhibition of cancer growth via cell cycle arrest and apoptosis induction. Efficient brain deposition of the drug was demonstrated.	[186]
PEGylated nanoparticles	Paclitaxel	Dihydroartemisinin	Colorectal cancer	Exhibited improved apoptosis in colorectal HT-29 cells. Moreover, nanoparticles displayed significantly improved accumulation in the cancer site due to the increased permeability and retention effect.	[187]
Polymeric nanoparticles	Doxorubicin	Curcumin	Lymphoma	Exhibited improved intracellular delivery along with increased cytotoxic effect, induced sophisticated rates of apoptosis in BJAB cells. BJAB cells provided inhibited tumour growth than doxorubicin alone.	[188]
Polymeric nanoparticles	Paclitaxel	Curcumin	Breast cancer	Provided substantial inhibition of cancer growth with elongated survival time along with reduced adverse effects.	[189]
Polymeric nanoparticles	Paclitaxel	Resveratrol		Demonstrated improved anticancer effect along with improvement in the sensitivity of multidrug-resistant cancer cells to the drug.	[190]
PLGA-PEG-PLGA polymeric nanoparticles	5-Fluorouracil	Chrysin	Colon cancer	Exhibited considerably improved growth inhibitory activities in the HT29 cell line.	[191]
Polymeric nanoparticles	Doxorubicin	Curcumin		Exhibited improved cytotoxicity against HCT-116 cells. Cellular uptake of drugs was improved via active targeting.	[192]
Polymeric nanoparticles	Doxorubicin	Epigallocatechin gallate	Gastric cancer	Exhibited internalization into gastric tumour cells via CD44 ligand recognition and subsequent inhibition of cell proliferation.	[193]
Polymeric nanoparticles	Paclitaxel	Silybin	Breast cancer	Demonstrated effective accumulation of the drug in tumour site and inhibition of tumour growth as well as sensitization effect of silybin on paclitaxel cytotoxic chemotherapy.	[194]
Self-assembled Ph-sensitive nanoparticles	Methotrexate	Ganoderma lucidum Polysaccharide	Breast cancer	Demonstrated improved cancer suppressive activities with fewer adverse effects.	[195]
Gold nanoparticles	Methotrexate	Curcumin		Provided increased cytotoxic effect against C6 glioma and MCF-7 cancer cell lines along with high hemocompatibility. It also possessed active targeting proficiency against MCF-7 cancer cells due to the presence of the “antifolate” drug methotrexate.	[196]
Gold nanoparticles	Doxorubicin	Resveratrol	Cervical cancer	Provided strong deposition of the drug in the tumour cells.	[197]
Gold nanoparticles	Doxorubicin	Epigallocatechin-3-gallate	Prostate cancer	Exhibited inhibition of the proliferation of PC-3 tumour cells along with the enzyme-responsive intracellular release of doxorubicin.	[198]
Hybrid nanoparticles	Paclitaxel	Curcumin		Provided significantly improved early and late apoptosis along with induction of a stronger G2/M arrest and significantly increased subG1 cell population	[199]
Hybrid nanoparticles	Doxorubicin	Curcumin		Exhibited improved cytotoxicity against A549 cells along with increased cellular uptake.	[200]
Mixed polymeric micelles	Paclitaxel	Naringin	Breast cancer	Exhibited increased intracellular uptake along with 65% in vitro cytotoxicity against breast cancer cells at its lower dose of 15 µg/Ml	[75]
Micelles	Doxorubicin	Curcumin		Exhibited strongest cytotoxic properties as well as improved cell apoptosis-inducing activities against doxorubicin-resistant MCF-7/Adr cells.	[201]
Polymeric micelles	Docetaxel	Resveratrol	Breast cancer	Provided a stronger synergistic effect, elongated release profiles and improved cytotoxicity in MCF-7 cells.	[202]
Polymeric micelles	Triptolide	SN-38	Gastric cancer	Provided reduced Cancer-associated fibroblasts activity and inhibited Cancer-associated fibroblasts, induced proliferation, migration and chemotherapy resistance of gastric cells.	[203]
Polymeric micelles	Doxorubicin	Curcumin		Exhibited induced apoptosis.	[204]
Polymeric micelles	Paclitaxel	Capsaicin	Breast cancer	Provided prolonged circulation time and privileged tumour tissue buildup compared to the taxol solution. Micelles displayed greater antitumor activity.	[205]
PCM micelles	Paclitaxel	Cucurbitacin B	Gastric cancer	Exhibited reduced tumour but the loss of bodyweight was not significant.	[206]
Nanomicelles	Dooxorubicin	Rhein	Ovarian cancer	Demonstrated improved cytotoxicity and increased apoptosis-inducing actions in SKOV3/DOX cells. Micelles displayed better targeting ability towards cancer along with reduced toxicity.	[207]
Nanomicelles	Docetaxel	Curcumin	Ovarian cancer	Demonstrated stronger inhibition and proapoptotic activities on A2780 cells. Micelles provided inhibition of tumour proliferation, suppression of tumour angiogenesis and promotion of tumour apoptosis.	[208]
Nanomicelles	Gemcitabine	Camptothecin	Breast cancer	Provided superior accumulation of nanomicelles at the cancer site, which could enhance therapeutic activity and reduce side effects.	[209]
Self-assembling micelles	Dooxorubicin	Honokiol	Glioma	Displayed inhibition of glioma growth more ominously. Micelles increased the antitumor effect of doxorubicin by increasing tumour cell apoptosis, suppressing tumour cell proliferation and inhibiting angiogenesis.	[210]
Responsive micellar system	Paclitaxel	Curcumin	Breast cancer	Demonstrated the maximum level along with achieving greater tumour inhibition effect.	[211]
Nano liposomes	Cisplatin	Curcumin	Hepatocellular carcinoma	Exhibited improved anticancer activity against HepG2 cells having the IC50 of 0.62 Μm. Moreover, provided increased intracellular ROS levels during the HCC cell treatment. It also demonstrated the prolonged retention time and increased antitumor effect.	[105]
Liposomes	Doxorubicin	Curcumin		Provided distinct inhibition of tumour growth in mice. Inhibition of tumour growth was 2–3 fold less in mice than in formulations having drugs individually.	[212]
Liposomes	Irinotecan	Berberine	Pancreatic cancer	Exhibited significant inhibition of tumour growth in the BXPC-3 pancreatic cancer model than Onivyde and decreased the gastrointestinal toxicity in mice caused by irinotecan.	[213]
Liposomes	Doxorubicin	Berberine	Triple-negative breast cancer	Provided significant inhibition of tumour growth in 4T1 murine mammary carcinoma model than Doxil and completely combat the myocardial rupture toxicity caused by Doxil in mice.	[214]
Liposomes	Doxorubicin	Pachymic acid and dehydrotumulosic acid	Breast cancer	Exhibited significantly increased anticancer effect of doxorubicin in cancer-bearing mice than other monotherapy groups.	[215]
Liposomes	Cisplatin	Curcumin	Breast cancer	Exhibited 10 times greater apoptosis than liposomes of cisplatin only. Codelivery of cisplatin liposomes with curcumin decreased the viability of breast cancer cells by 82.5%.	[216]
Liposomes	Doxorubicin	Schisandrin B	Lung cancer	Demonstrated improved cytotoxicity, improved cardiotoxicity and inhibition of the invasion and metastasis of tumours.	[217]
Liposomes	Combretastatin A4 phosphate	Curcumin	Liver cancer	Exhibited improved cytotoxicity and increased accumulation in the tumour site. Moreover, liposomes displayed stronger inhibition of tumour proliferation.	[218]
Nanoemulsion	Paclitaxel	Curcumin	Ovarian cancer	Demonstrated effective delivery of drug intracellularly in both SKOV3 and SKOV3(TR) cells. Administration of curcumin inhibits NFkappaB activity and down-regulates P-glycoprotein expression in resistant cells.	[138]
Double nanoemulsion	5-fluorouracil	Curcumin	Breast cancer	Demonstrated improved cytotoxicity against the MCF-7cells.	[219]
Multiwalled CNTs	Docetaxel	Piperine	Breast cancer	Demonstrated improved anticancer activity and stronger cytotoxicity in MCF-7 cells	[147]
Multiwalled CNTs	N-Desmethyl tamoxifen	Quercetin	Gastric cancer	Exhibited decreased IC50 values along with improved cellular uptake in drug-resistant MDA-MB-231 cells. The drug availability in blood circulation was also increased.	[220]