Combination Therapy and Nanoparticulate Systems: Smart Approaches for the Effective Treatment of Breast Cancer
Abstract
:1. Introduction
2. Treatment Strategies for Breast Cancer
2.1. Current Treatment Approaches
2.1.1. Therapeutic Options for Luminal Breast Cancer
2.1.2. Treatment Options for HER2-Positive BC
2.1.3. Management of Triple-Negative Breast Cancer (TNBC)
2.2. Novel Treatment Approaches for Breast Cancer by Targeted Therapy
2.2.1. Therapy of Luminal Breast Cancer (LBC)
CDK4/6 Inhibitors
PI3K/AKT/mTOR Pathway Inhibitors
Steroid Sulfatase Inhibitors
2.2.2. Therapy for HER2 Positive Breast Cancers
PI3K/AKT/mTOR Inhibitors
Monoclonal Antibodies (MAbs)
Tyrosine Kinase (TK) Inhibitors
Antibody-Drug Conjugates (ADCs)
Immunotherapy
2.2.3. Therapy of TNBC
Poly (ADP-ribose) Polymerase (PARP) Inhibitors
Anti-Angiogenic Agents
Immunotherapy
Monoclonal Antibody
RANKL and RANK System
3. Multidrug-Resistant (MDR) BC
4. Nanomedicine Used in the Management of Breast Cancer
4.1. Polymer-Based Nanoparticles (PBNP)
4.2. Lipid-Based Drug Carriers
4.3. Dendrimers (DM)
4.4. Aptamer
4.5. Inorganic Nanoparticles
4.6. Carbon Nanotubes (CNTs)
4.7. Nanoshells (NSs)
4.8. Viral Nanoparticles
5. Artificial Intelligence in Personalized BC Therapy
6. Toxicity Associated with Advanced Nano-Based Therapy of BC
7. Summary and Future Perspective
8. Conclusions
Funding
Conflicts of Interest
References
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Agent | Cyclin-Dependent Kinase IC50 (in nM) | |
---|---|---|
CDK6 | CDK4 | |
Ribociclib | 39 | 10 |
Palbociclib | 15 | 11 |
Abemaciclib | 9.9 | 2 |
Drug | Combination With | Description | ClinicalTrials.Gov Identifier NCT Number | Phase |
---|---|---|---|---|
Palbociclib | Endocrine therapy (exemestane, fulvestrant, letrozole, tamoxifen) Chemotherapy (capecitabine, epirubicin, paclitaxel, vinorelbine) | To evaluate/compare palbociclib in combination with endocrine therapeutic agents and with chemotherapeutic agents in HER2-positive or HER2-negative metastatic BC patients | NCT03355157 | IV |
Palbociclib | Fulvestrant, exemestane, letrozole, anastrozole | To evaluate eHealth-support in locally advanced or metastatic BC patient’s life quality when treated with palbociclib with endocrine therapy | NCT03220178 | IV |
Ribociclib | Endocrine therapy | To study the effectiveness of ribociclib with endocrine therapy in the ER-positive BC patients | NCT03285412 | II |
Ribociclib | Letrozole/anastrozole, goserelin | To evaluate the safety and efficacy of 400 mg of ribociclib when given in combination with aromatase inhibitors in the post- and pre-menopausal women with HR-positive/HR-negative patients with advanced BC | NCT03822468 | II |
Ribociclib | Letrozole 2.5 mg, doxorubicin, cyclophosphamide, paclitaxel | To evaluate the efficacy and safety of ribociclib (LEE011) with multi-agent chemotherapy or letrozole in postmenopausal patients with luminal B/HER2 negative BC | NCT03248427 | II |
Ribociclib | Non-steroidal aromatase inhibitors- letrozole 2.5 mg/day or anastrozole 1 mg/day orally, LHRH agonist-triptorelin 3.75 mg or leuprolide 3.75 mg or goserelin 3.6 mg, as injectable | Ribociclib in combination with a non-steroidal aromatase inhibitor/LHRH agonist in HR-Positive/HER2-negative patients with advanced BC | NCT03944434 | II |
Ribociclib | PDR001, fulvestrant | Ribociclib (LEE011), in combination with PDR001 an immunotherapeutic drug and fulvestrant in HR-positive, HER2-negative patient for metastatic hormone-receptor-positive (HR+), HER2-negative BC. | NCT03294694 | I |
Ribociclib (LEE011) | Paclitaxel | To assess the safety and dose escalation of paclitaxel with ribociclib in retinoblastoma (Rb)-positive patients with advanced BC. | NCT02599363 | I |
Abemaciclib | Fulvestrant | To compare the effectiveness of combination therapy of abemaciclib with fulvestrant and chemotherapy in HR-positive, HER2-negative patients with metastatic BC (visceral Metastases) | NCT04031885 | IV |
Abemaciclib | Fulvestrant | To compare fulvestrant alone with a combination of fulvestrant and abemaciclib in progression-free survival in HR-positive and HER2-negative patients. | NCT02107703 | III |
Abemaciclib | Atezolizumab (MPDL3280A), bevacizumab, entinostat, exemestane, fulvestrant, ipatasertib, tamoxifen | To evaluate the safety, efficacy, and pharmacokinetics of immunotherapy-based combination with CDK 4/6 inhibitor and anti-estrogen agents in advanced or metastatic HR-positive and HER2-negative patients. | NCT03280563 | I |
Receptor | Drugs | Mechanism of Action |
---|---|---|
PI3K | Taselisib (GDC0032), pilaralisib (XL147), alpelisib (BYL719), buparlisib (BKM120), pictilisib (GDC0941), MLN1117 | PI3K inhibition |
AKT | Capivasertib (AZD5363), uprosertib (GSK2141795), miransertib (ARQ092), MK2206 | Inhibition of AKT 1,2,3 isoforms |
mTORC1 | Sirolimus, ridaforolimus, everolimus, temsirolimus | Allosteric inhibition of mTORC1 |
PI3K and mTOR | Dactolisib (NVP-BEZ235), gedatolisib (PF05212384), LY3023414 | Dual inactivation of PI3K and mTOR |
mTORC1 and mTORC2 | Vistusertib (AZD2014), sapanisertib (TAK-228), CC-223, AZD8055, MLN0138, | Allosteric inhibition of mTORC1 and mTORC2 |
Drug | Combination With | Study Arm | Description | ClinicalTrials.Gov Identifier: NCT Number | Phase |
---|---|---|---|---|---|
Taselisib | Taselisib, trastuzumab emtansine, pertuzumab, trastuzumab paclitaxel | Arm A: Taselisib with trastuzumab emtansine Arm B: Taselisib with trastuzumab emtansine and pertuzumab Arm C: Taselisib with pertuzumab and trastuzumab Arm D: Taselisib with pertuzumab, trastuzumab, and paclitaxel | Combination of taselisib (GDC-0032) with anti-HER2 therapies in participants with advanced HER2+ breast cancer—a Phase Ib dose-escalation trial | NCT02390427 | Ib |
Pilaralisib (XL147) | Letrozole (Femara) | Arm A: Pilaralisib with letrozole | A Phase 1/2 dose-escalation study of XL147 (SAR245408), or XL765 (SAR245409) in combination with letrozole performed on subjects with hormone receptor-positive and HER2-negative breast cancer refractory to a nonsteroidal aromatase inhibitor | NCT01082068 | Completed |
Pilaralisib (XL147) | Trastuzumab, Paclitaxel | Arm A: Pilaralisib with trastuzumab Arm B: Pilaralisib with trastuzumab and paclitaxel | To study the efficacy of a combination of pilaralisib with trastuzumab or paclitaxel and trastuzumab in patients with metastatic -BC | NCT01042925 | Completed |
Alpelisib (BYL719) | Fulvestrant | Arm A: Alpelisib (300 mg; oral; once daily with fulvestrant (500 mg; IM-injection) | To assess the safety and efficacy in men and postmenopausal women patients with advanced-BC | NCT02437318 | III |
Alpelisib | Fulvestrant | Arm A: Alpelisib 300 mg oral daily with fulvestrant 500 mg intramuscular on in first cycle 1st day and 15th day, and thereafter every 28-day cycle. | To study the molecular features in HR-positive and HER2-negative postmenopausal women with a PIK3CA mutation | NCT03439046 | III |
MK2206 | Arm A: MK-2206 mg orally once a week | To study the efficacy of MK2206, an AKT inhibitor in patients with advanced BC and having AKT mutation and/or PTEN Loss/PTEN mutation and/or PIK3CA mutation | NCT01277757 | Completed | |
Everolimus, | Letrozole, everolimus, TRC105 | Arm A: Letrozole 2.5 mg + everolimus 5 mg + TRC105 15 mg/kg i.v Arm B: Letrozole 2.5 mg + everolimus 10 mg + TRC105 15 mg/kg i.v Arm C: Letrozole 2.5 mg + everolimus 5 mg + 10 mg/kg i.v Arm D: Letrozole 2.5 mg + 5 or 10 mg + TRC105 15 or 10 mg/kg i.v. | To study how well a combination of letrozole, TRC105 everolimus works in patients with stage 2 and 3 BC, and how well it is tolerated | NCT02520063 | I/II |
Everolimus | Palbociclib, exemestane | Palbociclib, everolimus, exemestane are administered in a cycle of 28 days | To study the efficacy of a combination of palbociclib, everolimus, exemestane in HR-positive and HER2-negative patients with metastatic-BC | NCT02871791 | I/II |
Temsirolimus | Bevacizumab, cetuximab valproic acid | Arm A: Temsirolimus, bevacizumab, cetuximab Arm B: Temsirolimus, bevacizumab, valproic acid Arm C: temsirolimus, bevacizumab | To study the efficacy of bevacizumab and temsirolimus alone or combination with valproic acid or cetuximab in patients with advanced or metastatic- BC | NCT01552434 | I |
Gedatolisib (PF05212384) | Trastuzumab biosimilar (herzuma) | Arm A: Herzuma + Gedatolisib | To evaluate the safety and antitumor activity of Herzuma® with gedatolisib in HER-2 positive patients with metastatic-BC | NCT03698383 | II |
Vistusertib (AZD2014) | Palbociclib, fulvestrant | Arm A: A triple combination of AZD2014 + palbociclib +fulvestrant | To study the efficacy of a combination of AZD2014, palbociclib, fulvestrant, in ER-positive patients with metastatic-BC | NCT02599714 | I |
Drug | Combination With | Study Arm | Description | ClinicalTrials.Gov Identifier: NCT Number | Phase |
---|---|---|---|---|---|
Cisplatin | Romidepsin, nivolumab | Arm A: cisplatin (75 mg/m2) + romidepsin (8 mg/m2) Arm B: romidepsin (10 mg/m2) + cisplatin (75 mg/m2) Arm C: romidepsin (12 mg/m2) + cisplatin (75 mg/m2) Arm D: romidepsin MTD (maximum tolerable dose) + cisplatin (75 mg/m2) + nivolumab 360 mg | To study the efficacy of cisplatin in combination with romidepsin and nivolumab in patients with TNBC or BRCA mutation or metastatic-BC | NCT02393794 | I/II |
MM-310 | Arm A: MM-310 i.v., 21-day cycle. | MM-310 is a docetaxel loaded liposomal formulation with targeting ability of EphA2 receptor. In this study, safety and efficacy of MM-310 in patients with TNBC was studied | NCT03076372 | I | |
Carboplatin | Everolimus | Arm A: Carboplatin alone Arm B: Carboplatin + everolimus | To study the safety and efficacy of carboplatin alone and carboplatin in combination with everolimus in patients with advanced TNBC | NCT02531932 | II |
Leronlimab | Carboplatin | Arm A: leronlimab (350 mg) + AUC 5 carboplatin Arm B: leronlimab (525 mg) + AUC 5 carboplatin Arm C: leronlimab (700 mg) + AUC 5 carboplatin Arm D: leronlimab (MTD) + AUC 5 carboplatin | To study the safety and efficacy of leronlimab when given in combination carboplatin in the patients with advanced TNBC | NCT03838367 | Ib/II |
Nab-Paclitaxel | Mifepristone | Arm A: nab-paclitaxel 100 mg + mifepristone 300 mg Arm B: nab-paclitaxel 100 mg + placebo | To study the efficacy of Nab-paclitaxel alone and in combination with mifepristone in the glucocorticoid receptor-positive and TNBC patients | NCT02788981 | II |
L-NMMA | Docetaxel amlodipine pegfilgrastim Enteric-coated aspirin | Arm A: L-NMMA + docetaxel + amlodipine + pegfilgrastim + Enteric-coated aspirin | To study the L-NMMA’s MTD, dose-limiting toxicities and to find out the efficacy in combination with docetaxel in patients with advanced TNBC | NCT02834403 | Ib/II |
Mirvetuximab soravtansine | Gemcitabine hydrochloride | Arm A: mirvetuximab soravtansine + gemcitabine hydrochloride | To study the dose-escalation, tolerability safety and efficacy of mirvetuximab soravtansine in combination with gemcitabine hydrochloride in patients with folate receptor-positive ovarian and TNBC | NCT02996825 | I |
Atezolizumab | Paclitaxel | Arm A: atezolizumab (840 mg) and paclitaxel (90 mg/m2) Arm B: placebo and paclitaxel (90 mg/m2) | To study the efficacy of a combination of a PD-L1-antibody, atezolizumab, and paclitaxel in advanced TNBC patients | NCT03125902 | III |
Tak-228 | Tak-117 Cisplatin Nab-Paclitaxel | Arm A: Tak-228 and Tak-117 followed by cisplatin and nab-paclitaxel | To study the efficacy of TAK- 228 and TAK- 117 treatment followed by cisplatin and nab-paclitaxel treatment in patients with metastatic TNBC | NCT03193853 | II |
Onalespib | paclitaxel | Arm A: onalespib (i.v.) on day 7 + paclitaxel (i.v.) days 1, 8, and 15; 28-day cycle | To study the best dose and side effects of onalespib when given in combination with paclitaxel in advanced TNBC patients | NCT02474173 | I |
Product | Drug | Company | Nanoparticle | Composition | Particle Size | Indication | Approval by US FDA and others | Reference |
---|---|---|---|---|---|---|---|---|
Genexol-PM | Paclitaxel | Samyang/Biopharm | PEG-PLA polymeric micelle | Paclitaxel, monomethoxy poly (ethylene glycol)-block-poly (D,L- lactide) | 23.91 nm | Breast, lung, ovarian cancer | 2007 (South Korea) | [114,115,116] |
Abraxane | Paclitaxel | Abraxis/Celgene | Nanoparticle-bound albumin | Paclitaxel, human albumin | 130 nm | In breast, pancreatic and non-small cell lung cancer | 2005 | [117,118] |
Doxil | Doxorubicin | Johnson and Johnson | Liposome | N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (DSPE-PEG 2000), hydrogenated soy phosphatidylcholine, and cholesterol | 85 nm | Kaposi’s sarcoma Ovarian cancer Breast cancer Multiple myeloma | 1995 1999 2003 2007 (Europe, Canada) | [119,120] |
Myocet | Doxorubicin | Cephalon | Liposome | Egg phosphatidylcholine and cholesterol with Doxorubicin citric acid aqueous core | 190 nm | Breast cancer | 2000 (EU) | [119,120] |
Depocyt | Cytarabine | Pacira | Liposome | Cholesterol, glycerol trioleate, triglyceride, phospholipids (dipalmitoyl phosphatidylglycerol), and dioleoyl phosphatidylcholine | 20 µm | Neoplastic meningitis | 1999 | [121,122,123] |
Lipo-Dox | Doxorubicin | Taiwan Liposome | Liposome | Cholesterol, N-(carbonyl-ethoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, hydrogenated soybean lecithin | 104.2 nm | Breast, ovarian cancer | 1998 (Taiwan) | [124,125] |
DaunoXome | Daunorubicin | Galen | Liposome | Cholesterol, distearoylphosphatidylcholine | 45 nm | Kaposi’s sarcoma | 1996 | [126,127] |
Nanoparticle Type | Type of Breast Cancer | Therapeutic Agent | Materials Used | Entrapment Efficiency (EE) and Particle Size | Key Outcome | Reference |
---|---|---|---|---|---|---|
Liposomes | luminal breast cancer | Anti-IL6R antibody, Doxorubicin | Cholesterol, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine 1,2-dioleoyl-sn-glycero-3-phosphocholine In (1:1:1 molar ratio) | 85.81% ± 0.4799% to 89.03% ± 0.143%, ∼100 nm | Formulation showed an enhanced tumor targeting efficacy with anti-tumor metastasis effects in BALB/c mice bearing 4T1 cells | [128] |
Liposomes | Luminal breast cancer- Estrogen positive BC | Doxorubicin | Estrone conjugated DPPC and DSPE-PEG2000-NH2 liposomes | EE not reported, 194 nm | Formulations showed significant uptake in ER-positive (MCF-7) and non- significant uptake in ER-negative (MDA-MB-231) cell lines | [129] |
Albumin nanoparticles | HER2 positive BC | 2-methoxy-estradiol | Bovine serum albumin | 89.85% ± 3.80% to 88.70% ± 2.95%, ∼238.8 ± 5.1 nm | Formulated NPs showed enhanced cytotoxicity and cellular uptake when compared with the free drug when assessed in SK-BR-3 and MCF-7 cell line and SK-BR-3, MCF-7 tumor-bearing mice | [130] |
chitosan nanoparticles | HER2 positive BC | doxorubicin | O-succinyl chitosan graft Pluronic® F127 and 5% to 10% anti-HER2 peptide | 73.69% ± 0.53% to 74.65% ± 0.44%, 34.92 to 50.79 nm | In vitro cytotoxicity and cellular-uptake study were performed on MCF-7 cell line which showed that the NP conjugated with anti-HER2 showed higher cytotoxicity when compared with free drug | [131] |
liposomal | HER2 positive BC | doxorubicin | HER2pep-K3-palmitic acid conjugate, DSPC, mPEG2000-DSPE | >98%, ~80 nm | In vitro cytotoxicity and cellular-uptake studies were performed on BT-474, SK-BR-3 and MCF-7. The formulation showed higher cytotoxicity and cellular uptake with lower systemic toxicity when compared with free drug | [132] |
Iron oxide | HER2 positive BC | siRNA | Iron oxide, caffeic acid, calcium phosphate and PEG-polyanion block copolymer | EE not reported, 130 nm | In vitro cytotoxicity and cellular-uptake studies were performed on HCC1954. After treating with NP, HER2 mRNA expression was decreased by 38% when compared with naked siRNA | [133] |
Polymeric nanoparticles | HER2 positive BC | Emtansine | D-α-tocopheryl polyethylene glycol 1000 succinate-poly (D, L-lactide) | 84–94%, 102–125 nm | In vitro cytotoxicity and cellular-uptake studies were performed on MDA-MB-453 cell lines and in vivo cytotoxicity study in MDA-MB-453 xenograft mice model. The nanoparticle showed superior antitumor effect when compared with the free drug | [134] |
Polymeric nanoparticles | TNBC | Paclitaxel | Poly(lactic-co-glycolic acid) NP coated with hyaluronic acid | 84–98.34%, 225.1±0.43 nm | In vitro cell viability and cellular-uptake studies were performed on MDA-MB-231. The prepared NP showed an improved cellular uptake and thereby higher cytotoxicity in cancer cells when compared with free drug | [135] |
SLN | TNBC | Di-allyl-disulfide | SLN prepared with palmitic acid, soya lecithin and pluronic F-68 and surface modified with glycation end products antibody | 79.23%, 116.20 nm | Formulated NP demonstrated a high cellular uptake by MDA-MB231 cell line and thereby reduction in systemic side effect of the drug and increased activity at tumor site | [136] |
Polymer nanoparticles | TNBC | Curcumin, | Chitosan NPs with apoptosis-inducing ligand (TRAIL) | 51.67%, 652 ± 10 nm, | The NPs showed a reduced tumor volume when compared to control when tested in BALB/c mice | [137] |
Iron oxide NPs | TNBC | Baicalein | PEG-coated iron oxide magnetic nanoparticles | 95.3%, 100 nm | Significantly inhibited the MDA-MB-231 cell growth when tested in vitro and showed significant anti-apoptotic activity | [138] |
Polymeric NPs | TNBC | Thymoquinone | Hyaluronic acid conjugated Pluronic® P123 and Pluronic® F127 NPs | EE not reported, 22.0 ± 3.1 nm | Formulations retarded cell growth and migration of MDA-MB-231. Studies in Balb/c mice showed significant reduction in tumor load when treated with formulations | [139] |
Product | Drug | Manufacturer | Indications | US FDA Approved Date/Clinical Trial Status |
---|---|---|---|---|
Doxil (Caelyx) | Pegylated doxorubicin | Orthobiotech, Schering-Plough | Ovarian/breast cancer | November 1995 |
Myocet | Liposome-encapsulated Doxorubicin | Elan/Sopherion Therapeutics | Breast cancer | 2000, Approved in Europe and Canada |
LEP-ETU | Liposomal Paclitaxel | Neopharma | Ovarian/breast/lung cancers | Phase I/II |
EndoTAG-I | Paclitaxel | Medigene/SynCore Biotechnology | Breast cancer/pancreatic cancer | Phase II |
Genexal-PM | Paclitaxel-loaded polymeric micelle | Samyang | Breast cancer/small cell lung cancer | Marketed in Europe, Korea |
Nektar -102 | Irinotecan, PEGylated liposome | Nektar therapeutics | Breast/colorectal cancer | Phase III |
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Gadag, S.; Sinha, S.; Nayak, Y.; Garg, S.; Nayak, U.Y. Combination Therapy and Nanoparticulate Systems: Smart Approaches for the Effective Treatment of Breast Cancer. Pharmaceutics 2020, 12, 524. https://doi.org/10.3390/pharmaceutics12060524
Gadag S, Sinha S, Nayak Y, Garg S, Nayak UY. Combination Therapy and Nanoparticulate Systems: Smart Approaches for the Effective Treatment of Breast Cancer. Pharmaceutics. 2020; 12(6):524. https://doi.org/10.3390/pharmaceutics12060524
Chicago/Turabian StyleGadag, Shivaprasad, Shristi Sinha, Yogendra Nayak, Sanjay Garg, and Usha Y. Nayak. 2020. "Combination Therapy and Nanoparticulate Systems: Smart Approaches for the Effective Treatment of Breast Cancer" Pharmaceutics 12, no. 6: 524. https://doi.org/10.3390/pharmaceutics12060524
APA StyleGadag, S., Sinha, S., Nayak, Y., Garg, S., & Nayak, U. Y. (2020). Combination Therapy and Nanoparticulate Systems: Smart Approaches for the Effective Treatment of Breast Cancer. Pharmaceutics, 12(6), 524. https://doi.org/10.3390/pharmaceutics12060524