《现代食品工程高新技术》课程教学资源（文献资料）食品粉碎、微胶囊包埋新技术 Recent advances in novel drug delivery systems and approaches for management of breast cancer：A comprehensive review.pdf

Contents lists available at ScienceDirect Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst Recent advances in novel drug delivery systems and approaches for management of breast cancer: A comprehensive review Umme Hania,∗ , Mohamed Rahamathullaa , Riyaz Ali Osmanib , Honnavalli Yogish Kumarc , Deeparani Urolagind , Mohammad Yousuf Ansarie , Kamal Pandeyf , Keerthana Devig , Sabina Yasminh a Department of Pharmaceutics, College of Pharmacy, King Khalid University, Guraiger, Abha, 62529, Saudi Arabia b Postdoctoral Research Associate, Indian Institute of Technology, Bombay, India c Department of Pharmaceutical Chemistry , JSS College of Pharmacy,JSS Academy of Higher Education and Research, S S Nagar, Mysuru-570015, Karnataka, India d Department of Pharmaceutics, Aditya BIPER, Bangalore, Karnataka, India e Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Industrial Area, Hajipur, Bihar, 844102, India f Product Development officer, Asian Pharmaceuticals Private Limited, Nepal g Saveetha College of Pharmacy, Chennai, Tamil Nadu, 600128, India h Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Guraiger, Abha, 62529, Saudi Arabia ARTICLE INFO Keywords: Breast cancer Liposomes Hydrogels Exosomes Dendrimers Microspheres Microbubbles Phytosomes Micelles ABSTRACT Breast Cancer (BC) is a carcinoma of breast tissues, the major recurrent cancer in women and also the foremost cause of death with approximate 5 million annual deaths worldwide. The most developed regions of the world show the highest incidence rate of BC when compared to less developed regions. However, the mortality rate was found to be higher in developing countries. In women with less than 40 years of age, approximately 7% diagnosed as suffering from BC and in women with less than 35 years of age, it was less than 4%. Presently less curative options are available for such patients. Emerging novel delivery systems may result in a promising approach for its early recognition and efficient treatment. Currently, cancer research focuses on improving BC treatment using various novel delivery systems of chemotherapeutic agents such as nanoformulations, liposomes, hydrogels, exosomes, dendrimers, microspheres, microbubbles, phytosomes, micelles, etc. The present review encloses existing assorted novel drug delivery systems and approaches intended for diagnosis and treatment of BC. 1. Introduction The breast cancer (BC) is the most frequent cancer having immense mortality among women worldwide that estimated by the International Agency for Research on Cancer (IARC) as over two million new cases and approximately five million deaths (2014). It is the most lethal cancers in spite of the incredible advancement of diagnosis and treatments [1,2]. In a breast, the terminal duct of lobule unit having epithelial cells lining are main origin of breast cancer (BC). This cancer cells can be classified as non-invasive or in situ (in the same place). This cancer cells are present inside basement membrane of the elements of draining duct and terminal duct of lobular unit. . When the cancer cell spreading occurs exterior to the basement membrane of the lobules and ducts into the neighboring adjacent normal tissues it is called invasive BC [3]. There are different types of BC that include like ductal carcinoma, lobular carcinoma, and in- flammatory mammary cancer [4]. The Tumor, Node, Metastasis (TNM) is the system used to classify various stages of breast carcinoma. The early stages of invasive carcinoma are the TNM stage I, TNM stage II and TNM stage IIIA and most of these tumors are considered operable traditionally. Fig. 1 depicts the various stages of BC. More than 90% of BC diagnoses are made early and can potentially cured by following therapies are surgery, radiation and systemic. In early BC patients receiving appropriate treatment, 5 year survival rates are in excess of 75% [5]. Now a day's less curative options are available for the treatment of the BC patients. Emerging novel delivery systems may result in promising approach for the early recognition and its possible treatment. Currently, cancer research focuses on improving BC treatment using various novel delivery systems of chemotherapeutic agents. These novel drug delivery systems include nanoformulations [6], liposomes [7], https://doi.org/10.1016/j.jddst.2020.101505 Received 12 February 2019; Received in revised form 25 December 2019; Accepted 5 January 2020 ∗ Corresponding author. E-mail addresses: uahmed@kku.edu.sa, ummehaniahmed@gmail.com (U. Hani). Journal of Drug Delivery Science and Technology 56 (2020) 101505 Available online 08 January 2020 1773-2247/ © 2020 Elsevier B.V. All rights reserved. T

hydrogels [8], exosomes [9], dendrimers [10], microspheres [11], microbubbles [12], phytosomes [13], micelles [14], Nosrati H et al. reported the preparation modified iron oxide magnetic nanoparticles (IONPs) functionalized with L-lysine (Lys) and L-phenylalanine (PhA) loaded with curcumin (CUR). They were studies for their effects, loading capacity, the release profile of CUR, biocompatibility and anticancer activity. CUR loaded amino acids modified iron oxide magnetic nanoparticles (F@AAs@CUR NPs). The anticancer activity results of free CUR was found to be more than the activities of F@Lys@CUR NPs and F@PhA@CUR NPs due to the CUR releases pattern from the F@ Lys@CUR NPs and F@PhA@CUR NPs are slower than the diffusion of free CUR [15]. Danafar H et al. established a reliable micellar delivery system using monomethoxypoly (ethylene glycol)–poly (e-caprolactone) (mPEG–PCL). The encapsulation of SF inside mPEG–PCL as a nano-carrier was established and the cytotoxicity assay against human breast cancer cell line was evaluated. Based on the cytotoxicity results of mPEG–PCL micelles against human breast cancer cell line (MCF-7) suggested that SF/mPEG–PCL micelles can be an effective breast cancer treatment strategy in the future [16]._ENREF_15. Hence, most up-todate conclusions and any crucial findings of BC treatment required to be broadly spread to scientific, medical and research societies. Like our previously published article on cervical [17] and prostate [18] cancer in the present review, we have focused on diverse delivery systems existing for BC treatment and an outline has depicted in Fig. 2. 2. Pathophysiology of breast cancer Breast cancer is a proliferative carcinoma type originated from breast tissue [19]. Signs of the BC may include the shape changes, dimpling skin, nipple leakage [20]. Symptoms of spread may include swelling of breast tissue, lump associated with pain and discoloration [21]. Proliferative breast lesions include ductal hyperplasia, sclerosing adenosis, fibroadenomas and intraductal papillomas [22]. In ductal carcinoma, hydroxyl radicles cause lesions and lead to cancer pathogenesis [23]. Epidemiology of BC suggests that stimulation of estrogen in the absence of cyclic progesterone secretion develops breast carcinogen, as the estrogen receptor alpha has a vital role in the normal development of breast cells. Depletion in the chances of BC can be done via the protective action of breastfeeding; which reduces the level of sex hormones responsible for cancer [24]. Structural classification of BC includes, cancer originating in lobules, ducts, skin, and molecular point of view which includes estrogen receptor-negative tumors and enriched human epidermal growth factor receptor (EGFR) 2. There are estrogen receptors positive tumor subtypes viz. luminal A tumor and luminal B tumor [25]. Based on the receptor (progesterone, estrogen) on the cell nucleus and it is over-expression, the type of BC can be identified [26]. Cancer of the breast is very common among women. Factors responsible for cancer are hormonal, environmental, personal and genetic risk factors [22]. Woo et al. have suggested that antimutagenic agents have induced cell death in MCF7 BC cells by EGFR expression reduction. The down-regulation of EGFR was caused by protein destruction [27]. Franco et al., suggests that altered expression of the different gene isoforms can cause carcinogenesis and gene isoforms essential for epithelia generation. In the recent investigation, it is found that altered gene isoform expressions have a significant role in BC development [28]. Cellular morphology of breast cancer is depicted in Fig. 3. 3. Nanotechnology-based novel drug delivery systems Nanotechnology-based therapeutics is highly used in cancer therapy for enhancing drug solubility, stability, and decreasing multidrug resistance as well as to enhance the safety and efficacy of cancer treatment. Nanoparticles, dendrimers, polymeric micelles, liposomes, polymeric drug conjugates, exosomes, and polymersomes are some of the efficient carriers in nanotechnology-based drug delivery systems; which Fig. 1. Different stages of breast cancer with cell cytology. Fig. 2. Diverse delivery systems and approaches are available for breast cancer therapy. U. Hani, et al. Journal of Drug Delivery Science and Technology 56 (2020) 101505 2

are presently investigated extensively for augmented cancer therapy [29]. 3.1. Nanoparticles Nanoparticles (NPs) are rapidly emerging nanocarriers which can be defined as ultradispersed solid supramolecular structures with size ranging between 10 and 1000 nm. Potential interest in the field of nanopharmaceuticals has generated several advancements recently. NPs has a potential impact on the treatment of cancer, in which the drugs can be either, encapsulated, entrapped, dissolved or attached to an NP matrix acting as a reservoir for drug [17,30]. Poly (lactic-co-glycolic acid) [PLGA], polyethylene glycol (PEG) and modified PLGA have commonly used polymers for the preparation of NPs. A diverse work has been carried out by a few researchers to prepare NPs using PLGA and PEG. Star-shaped copolymer (of mannitol core PLGA-TPGS diblock) based NPs loaded with docetaxel were prepared using a modified nanoprecipitation method. The resulting NPs showed a significantly greater level of cytotoxicity; which may be due to increased encapsulation efficiency and drug loading in comparison with commercially available Taxotere® formulation. Moreover, the higher antitumor efficacy of prepared NPs was revealed from in vivo studies [31]. A novel polymeric nanocarrier, Cholic acid-core star-shaped PLGA based NPs loaded with simvastatin were developed to achieve controlled and sustained delivery of drug consequently resulting in a significantly greater level of cytotoxicity. As expected, developed NPs effectively inhibited the growth of tumors for a longer time period by internalizing into MDA-MB-231 human BC cells and dramatically inhibited the expression of the cell cycle protein cyclin D1 when compare to pristine simvastatin and linear PLGA NPs loaded with simvastatin [32]. NPs can also aid in enhancing the solubility of poorly water-soluble drugs such as curcumin. Encapsulation of curcumin in PLGA NPs significantly protects curcumin from the environment and improves its bioavailability and thereby its release in cytoplasm resulting in G2 receptor blocking action on MCF-7 cancer cell lines [33]. PLGA NPs loaded with 1,7- bis [3,4-dimethoxyphenyl]-5-hydroxyhepta-1,4,6-trien-3-one [ASC-J9] were prepared to enhance the bioavailability of ASC-J9; which has been proposed for the treatment of BC. ASC-J9 release causes G2/M blocking effect on the cell cycle leading to inhibition of cellular growth [34]. To increase the lapatinib antitumor activity a novel polymer-lipid hybrid nanosystem having poly (lactide-co-glycolide)-Da-tocopheryl PEG 1000 succinate coated by a lipid layer of PEG was developed. The prepared nanosystem has efficiently induced carcinoma cell apoptosis when compared to free drug. NPs by dropping the uptake of the drug by the reticuloendothelial system (RES), have significantly prolonged its blood circulation time; which ultimately results in drug accumulation in cancer tissues and thereby resulting in a maximum therapeutic effect in the BC treatment [35]. As per another reported study, active triphosphates of fluxuridine, gemcitabine and cytarabine nucleoside analogs encapsulated in PEG-cl-PEI or F127-cl-PEI nano-gels exhibited similar cell cycle perturbation and cytotoxicity in vitro, equal tumor growth-inhibitory activity and faster cell accumulation in vivo at very low dose in comparison with free drug [36]. Hydrophobic drug paclitaxel (PTX) loaded dendrimer stabilized smart NPs prepared to achieve targeted delivery have showed a pHdependent release of a drug. The fabricated NPs were found to be stable at physiological pH, and quick release of drugs in the tumorous environment was noted with efficiently suppressed cancer cells growth and significantly induced apoptosis. These NPs were also reported to be extremely biocompatible than PTX [37]. PTX can also be delivered effectively with bioactive waterborne polyurethane nano-micelles, an effective novel nanocarrier proposed by Khosroushahi et al.; which significantly inhibits human BC MCF-7 cell growth and proliferation, and results in apoptosis due to liberation of cytochrome C in the cells [38]. Silica NPs loaded with dual drugs (PTX and suramin) using triple targeting ligands specific towards neoangiogenesis and cancer, for achieving synergistic targeting, were successfully synthesized by Veeranarayanan et al. Reportedly, elevated uptake of NPs was observed thereby imparting superior therapeutic efficacy against BC cells along with complete immobilization disabling the migration ability of activated endothelial cells [39]. To increase the aqueous solubility of pyropheophorbide, it was entrapped in organically modified folate receptor-targeted silica NPs. It has been observed that the uptake of pyropheophorbide in squamous cell carcinoma was increased with a decline in pH of the incubation media and uptake was not influenced for plain NPs [40]. Phosphorylated drugs can be delivered efficiently in a sustained manner with the aid of nanoformulations. Considering this fact, researchers have fabricated polymeric conjugates of nucleoside analog for the augmented treatment of drug-resistant tumors. It has been observed that the developed system exhibited rapid enzymatic release of floxuridine 5'phosphate resulting in enhanced cytotoxicity. Hence, the fabricated system was claimed to be significantly effective in the management of drug-resistant tumors [41]. Antioxidants such as Vitamin C and E encapsulated NPs and silver NPs were prepared from Hibiscus rosa-sinensis petal extracts and chitosan. The polymer chitosan posses targeting ability and is biocompatible, biodegradable and cationic. Prepared nanoformulations were found to be extremely haemocompatible and showed good encapsulation efficiency of about 76%. Moreover, significantly higher anticancer activity was observed against BC cell lines (MCF-7) [42]. Human monoclonal antibody trastuzumab was employed to target human EGFR-2 positive cancer cells. Trastuzumab guided lipid-based NPs along with rapamycin composition (an imaging agent) were analyzed for targeted BC therapy. The results revealed improved therapeutic efficacy of the drug in NPs formulations compared to pure drug. The developed targeted multifunctional NPs exhibited excellent bioimaging in 2D monolayer and 3D tumor spheroid models and hence claimed for potential implications in better cancer management [43]. Self-assembled chitosan NPs were prepared in another research vocation encapsulating damnacanthal; an upcoming potential candidate for suppressing cyclin D1 expression at the post-translational level in dose and time-dependent manner. The prepared NPs exhibited good yield, drug loading and revealed better inhibition of cell growth when compared to that of non-encapsulated damnacanthal [44]. Fig. 3. Cellular morphology of breast cancer. U. Hani, et al. Journal of Drug Delivery Science and Technology 56 (2020) 101505 3

Gold NPs can be targeted to mitochondria of BC cells and could helpinduce apoptosis and trigger cell death; which can be used in photothermal therapy of BC [45]. Enzyme sensitive amphiphilic peptide dendritic copolymer-based doxorubicin (DOX) NPs exhibits effi- cient apoptosis of cancer cells in vitro by retaining and accumulating within tumor cells for a longer time period and also reduces DOX-induced toxicities. Hence, these can be a prospective drug delivery vehicle for augmented BC therapy [46]. A significantly high antitumor activity can be achieved by an enzyme response peptide dendrimer DOX conjugate based NPs which can induce cell death on the 4T1 breast tumor model [47]. The pH-responsive NPs of dendronized heparin DOX conjugate for cancer therapy had been proven to provide high antiangiogenesis effects, strong antitumor activity and induce apoptosis in BC cells [48]. Physical instability is a common drawback of nanoformulations. In an approach, researchers used D-glucose to stabilize the gelatin/collagen-based matrix wall to deliver the Calendula officinalis powder and oil. NPs loaded with Calendula officinalis powder in comparison with free powder, has significantly improved the anti-cancer activity towards human breast adenocarcinoma MCF7 cells and human hepatoma SKHep1 cells [49]. Free rhodium citrate and rhodium citrate loaded maghemite NPs have proved systemic action in treating BC; which was analyzed by hemogram, alanine aminotransferase, iron and creatinine serum level, and histology of kidney, liver, and lungs [50]. Triple-negative breast cancer (TNBC) is considered as one the most invasive cancer with a yearly increase in a number of incidences; demanding urgent development of effective therapeutic options and strategies. In a research approach particle, size-reducible and angiopep-2 modified NPs were fabricated with the aim of increasing accumulation and penetration deep down in tumor tissue. In this work for enhancing NPs cancertargeting efficiency, angiopep-2 was anchored on NPs surface to smooth the progress of accumulation through binding with TNBC overexpressed low-density lipoprotein-receptor related protein (LRP). Whereas, for attaining high penetration and increased tumor retention, particle size-reducible NPs were fabricated using gelatin NPs (GNP) comprising of dendrigraft poly-lysine (DGL) loaded with doxorubicin (DOX). These NPs were found efficient in tumor targeting as evident by in vitro cellular uptake studies and ex vivo imaging. The larger size NPs were size reduced (from 185.7 nm to 55.6 nm) via degradative action of matrix metalloproteinase-2 (MMP-2). Moreover, NPs ability to penetrate was dominantly improved in tumor spheroids post-incubation with MMP-2. Because of the combinatorial approach of tumor targeting and enhancing penetration; developed NPs were promisingly effective in tumor growth inhibition (with tumor growth inhibition rate of 74.1%) in a mouse model bearing 4T1 BC. In short, efficacy and potential applicability of nanoplatforms based combinatorial approach for the treatment of TNBC were put forth through this study [51]. In another study of the same basis, Ruan et al. have reported a new-fangled multistage system exhibiting targeting effect as well as size changeable properties to inhibit tumor growth and metastasis. The multistage system was comprised of numerous small size gold NPs (AuNPs) fabricated onto the surface of matrix metalloproteinase-2 (MMP-2) degradation prone gelatin nanoparticles (GNPs). Anticancer agent DOX was then tethered on AuNPs through a pH-sensitive hydrazone bond followed by surface decoration using a tandem peptide of arginylglycylaspartic acid (RGD) and octarginine for improving the efficiency of tumor targeting. The fabricated NPs based system (G-AuNPs-DOXRRGD) was reported to release DOX in pH-dependent mode and exhibited shrinking behavior post 24 h incubation with MMP-2 (from 185.9 nm to 71.2 nm). Superior penetration efficiency was confirmed from collagen diffusion and tumor spheroid penetration study results. In vivo evaluation of G-AuNPs-DOX-RRGD in 4T1 xenograft bearing mice revealed active targeting of 4T1 tumor followed by interstitial matrix penetration and deep tumor accumulation. Hence, researchers concluded exceptional anti-tumor potential of developed multistage nanosystems which has been attributed to the adopted synergistic approach [52]. Mesoporous silica nanoparticles (MSNs) are found to be excellent nanotechnology for anticancer drug delivery. They were found to be stable by virtue of their interesting properties for biomedical applications such as high chemical stability, large surface area, and tunable pores diameters and volumes, allowing the incorporation of large amounts of drugs. Sabio RM et al. presented an overview of preparation methods of MSNs and their properties that affect drug delivery [53]. Methotrexate (MTX) with glycine (F-Gly NPs) coated magnetic nanoparticles (MNPs) to get conjugates (F-Gly-MTX NPs) were prepared by an amidation reaction via the co-precipitation method. Biocompatibility was determined by hemolysis assay and cytotoxicity studies on HFF-2 and HEK-293 cell lines. In these MNPs, the drug delivery depends on the release of the MTX by peptide bond cleavage inside the compartment of lysosomes [54]. Magnetic nanoparticles (MNPs) plays a vital role in the identification of cancerous lesions. At cellular levels, MNPs having specific magnetic characteristics and biological interactions. MNPs created a revolution in the diagnosis and clinical treatment of the disease. Arginine functionalized Iron oxide MNPs were conjugated with MTX. Cell cytotoxicity test on the normal cell line (HFF-2) and hemolysis assay confirmed that synthesized nanoparticles were biocompatible. Release study was performed in low pH conditions with and without proteinase K. Here, MTX was released through peptide bond cleavage with proteinase K at acidic pH [55]. Tamoxifen (TMX) loaded L-tyrosine natural amino acids (Tyr) modified Fe3O4 magnetic nanoparticles (F@Tyr@TMX NPs). Tyrosine, which was containing phenol groups was selected to study their effects on biocompatibility, loading capacity and release profile of TMX. It was observed that F@Tyr@TMX NPs exhibited a more cytotoxic effect compared to that of free TMX [56]. A novel dual-target recognition sandwich strategy for selective capture and detection of MCF-7 breast cancer cells based on core-shell magnetic mesoporous silica (Fe3O4@nSiO2@mSiO2@apt) nanoparticles was developed. This assay showed high specificity and sensitivity to the target MCF-7 cells. Therefore, the approach proposed here may have great potential for early breast cancer diagnosis [57]. Asgari M et al. presented their research work on a novel method based on an inverse microemulsion system to synthesize monodisperse magnetic mesoporous silica nanoparticles (MMSN) with core-shell structure. The preparation is basically w/o microemulsion system which is silica precursor containing cyclohexane as a continuous phase and magnetic seeds (Fe3O4 nanoparticles) with urea containing water droplets as an aqueous phase along with cetyltrimethylammonium bromide (CTAB) and 1-butanol as a surfactant and co-surfactant. The results displayed that the prepared magnetic mesoporous silica nanocomposite has great potential for cancer drug delivery applications [58]. Fan C et al. developed oxidized mesoporous carbon nanoparticles (oMCNs) with size lesser than 200 nm and excellent water dispersibility were synthesized using a mild oxidation method. Pores of oMCNs with high drug loading efficiency (24.8% w/w) were encapsulated with resveratrol (3, 4’, 5-trihydroxy-trans-stilbene) RES. oMCNs exhibited good excellent cellular uptake and good biocompatibility. PARP and Caspase-3 protein cleavage in triple-negative breast cancer (TNBC) cell line mediated, in vitro cytotoxicity assay and apoptosis analysis showed that oMCNs-RES induced enhanced the cytotoxic effect and proapoptosis effect [59]. MTX-conjugated L-lysine coated IONPs (F-Lys-MTX NPs) were prepared by coating iron oxide magnetic nanoparticles (IONPs) with L-lysine and further conjugated with MTX through peptide linkage on IONPs surface. Significant anticancer effect for breast cancer cell lines was observed with F-Lys-MTX NPs [60]. Nosrati H et al. prepared and characterized for the potential therapeutic efficiency of curcumin (CUR)-loaded dendrimer-modified citric acid-coated Fe3O4 NPs (F@Cit@PAMAM@CUR NPs). Polyamidoamine (PAMAM, generation G5) was used to encapsulate citric acid-coated Fe3O4 nanoparticles. F@Cit@PAMAM@CUR NPs showed a suppression effect better than free curcumin on a human breast adenocarcinoma (MCF-7) cell lines [61]. Manjili HK et al. synthesized five series of mono methoxy poly U. Hani, et al. Journal of Drug Delivery Science and Technology 56 (2020) 101505 4

(ethylene glycol)-poly (e-caprolactone) (mPEG-PCL) diblock copolymers. The structure of the copolymers was characterized by H NMR, FTIR, DSC, and GPC techniques. Singel steps the nano-precipitation method was adopted to encapsulate curcumin, within micelles to get CUR-loaded mPEG-PCL(CUR/mPEG-PCL) micelles. In vivo results showed that multiple injections of CUR-loaded micelles could prolong the circulation time and increase the therapeutic efficacy of curcumin, Hence, mPEG-PCL micelles provided a convenient and appropriate system for delivery of CUR to breast cancer cells [62]. Nosrati H et al. synthesized mono methoxy poly (ethylene glycol)-poly (ecaprolactone) (mPEG-PCL) di block copolymers. In vitro anticancer activity of MTX, mPEG–PCL polymersomes and MTX-loaded polymersomes, when MTX was encapsulated with the mPEG–PCL polymersomes, the total inhibited concentration was decreased than free MTX [15]. To enhance the efficacy of BC therapy and to diminish toxicity, various novel drug delivery systems have been developed and consistently researched nowadays, a few of which are mentioned in Table 1. 3.2. Dendrimer For transportation of anticancer drugs into tumor cells and to obtain the controlled release of the delivered drug molecule the perspective nanocarriers called ‘dendrimers or dendritic polymers’ can be used [63]. These are the best-known group of NPs consisting of a core and several branches; which can be used as a carrier for diverse types of molecules. The branched structure is responsible for effective protection against the premature release of the drug into the circulatory system. Targeted therapy can be achieved by modifying the surface of dendrimers using site-specific ligands and monoclonal antibodies. It is a well recognized fact that in numerous BC cases over-expression of human EGFR-2 occurs. Hence, trastuzumab, a recombinant and humanized monoclonal antibody can be directed against this receptor for effective management of BC [64]. Humanized anti-human EGFR-2 antibody (Herceptin®) conjugated Polyamidoamine (PAMAM) dendrimers containing gold nanoparticles and gadolinium can be used for early detection and treatment of human EGFR-2-positive cancer [61,65]. Encapsulation of hydrophobic anticancer agents such as Acetyl shikonin and curcumin, in PAMAM dendrimers, results in increased solubility leading to enhanced Cytotoxicity and activity of drugs on the proliferation of cancer cells [66,67]. Cytotoxicity of trastuzumab found to be enhanced when it was conjugated to G4 PAMAM dendrimers derivatized with 30 DTPA chelators against human EGFR 2- positive BC cells [68]. Conjugate form of curcumin (obtained from the plant Curcuma longa) with dendrimer has more water solubility and capable of inducing apoptosis on BC cell effectively [69,70]. Dendrosomal curcumin can interact with NF-κB a key regulatory molecule and inhibit migration and invasion of cancer angiogenesis thereby exhibiting chemoprotective effect on BC metastasis [71]. PAMAM half-generation G4.5 dendrimer was developed containing fluorescein isothiocyanate which can enter the tumor tissue cells and can be efficiently used in diagnosis and treatment of BC [72]. G3 PAMAM-NH2 dendrimerchlorambucil conjugate have shown significantly high apoptosis in BC cells by inhibiting collagen biosynthesis than chlorambucil [73]. PAMAM dendrimers stabilized silver nanoparticles loaded with 5- fluorouracil to exhibit synergistic anticancer effect in MCF-7 human BC cell line was developed and from the results it was concluded that the Table 1 List of Nanotechnology based drug delivery systems and drugs employed for the delivery system with their application for Breast Cancer therapy. Delivery systems Drug Applications References Nanoparticles Docetaxel To carry higher levels of drug than linear polymer. [31] Simvastatin To achieve a significantly increased level of cytotoxicity. [32] Lapatinib To achieve an optimal therapeutic effect by reducing the dosage regimen. [35] Paclitaxel To deliver drug/gene/siRNA targeting. [37] Curcumin Enhanced the solubility of the drug. [33] Damnacanthal For better inhibition of cell growth. [44] Doxorubicin To get effective inhibiting proliferation and in inducing apoptosis. [46] Dendrimer Trastuzumab A recombinant and humanized monoclonal antibody as a targeted therapy. [64,65] Herceptin A humanized anti-human EGFR-2 antibody for early detection and treatment of cancer. [65] Doxorubicin To abolish drug toxicity and increases drug potency. [79,80] 5-Fluorouracil To synergistically induce apoptosis. [74] Curcumin To get enhanced solubility and cytotoxicity. [66,67] PTX To target cancer cells and get higher therapeutic efficacy. [76,77] Epirubicin To inhibit the tumor growth by targeting the tumor and providing pH-dependent drug release. [86] Docetaxel To reduce both weights and volume of the tumor cell and thereby efficiently increased killing of cancel cells. [88] Gemcitabine To get desirable tumor penetration and accumulation and greater anticancer activity. [84] Micelles PTX To get higher toxicity in comparison with taxol. [95] Curcumin To get a synergistic effect. [93] Doxorubicin To reverse multidrug resistance. [94] Liposomes PTX To improve chemotherapeutic efficiency [96] Oxaliplatin To enhance MT-3 breast cancer treatment and metastases in a mouse xenograft [97] Rapamycin To develop Human EGFR 2-positive breast cancer cells cytotoxicity [98] Gemcitabine To enhance cytotoxicity [99] Doxorubicin To build up productive delivery of the drug to EGFR2 overexpressing cells [100] PTX and Resveratrol To overcome multidrug resistance [101] PTX and Rapamycin To enhance the therapeutic effect and to limit pharmacokinetics drawbacks [102,103] Raloxifene To get effective inhibition against tumor responsible MMP-2 enzyme and angiogenesis initiation. [105] Sinitinab and Vinorelbine To get targeted delivery [106] Epirubicin and Quinacrine To exhibit high inclusive anticancer efficacy and to prevent the degeneration from VM channels after chemotherapy [107] Salinomycin & Doxorubicin To target cancer stem cells [108] Mitoxantrone To target the plasma membrane, to enhance anti-cancer activity and to decrease drug toxicity [109] Anastrozole To treat breast cancer in advanced stages in post-menopausal women [110] Exosomes Adiramycin To offer greater drug resistance via delivery of miR-222 as a transport mechanism [120] Docetaxel To controls the cell apoptosis via the transfer of specific miRNA intercellular [130] Hydrogels Cisplatin To enhance antitumor activity against MCF-7 BC cells and human colorectal cancer cells [155] Taxol To get targeted delivery and higher in vitro antitumor efficacy [156] PTX To enhance in vitro and cytotoxic effects of PTX [157] Docetaxel To enhance oral bioavailability [8] U. Hani, et al. Journal of Drug Delivery Science and Technology 56 (2020) 101505 5