Nanotherapeutics for Cancer Cell Targeting

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  1. Chemotherapy

Cancer therapies now restrained to surgery, radiation, and chemotherapy. All methods risk damage to normal tissues or incomplete eradication of cancer. Nanotherapeutics offers the means to aim therapies directly and selectively at cancerous cells.

Nanocarriers. Conventional chemotherapy employs drugs that kill cancer cells effectively. However, these cytotoxic drugs destroy normal cells with tumor cells, leading to side effects, for instance,nausea, neuropathy, hair loss, fatigue, and compromised immune function. NPs used as drug carriers for chemotherapeutics to deliver medication directly to the tumor without damage to normal tissue. Nanocarriers have some benefits over conventional chemotherapy: they can protect drugs from degraded in the body already they reach their target; augment the absorption of drugs into tumors and into the cancerous cells themselves; better control over the timing and distribution of medications to the tissue, creating it easier for oncologists to evaluate how well they work; prevent drugs from interacting with normal cells, thus avoiding side effects.

Passive Targeting.There are now several nanocarrier based drugs on the market, which depend on passive targeting viaa process known as”EPR.” Despite their size and surface properties, certain NPs can escape via blood vessel walls into tissues. Also, tumors tend to have leaky blood vessels and inadequate lymphatic drainage, causing NPs to aggregate in them, thus concentrating the attached cytotoxic drug where it needed, protecting healthy tissue and greatly reducing adverse side effects.

Active Targeting. NPs will actively target drugs to cancerous cells, based on the molecules that they express on their cell surface. The NPs that attached to particular cellular receptors cause targeted cells expressing the receptor. Active targeting used to bring drugs into the cancerous cell, by inducing the cell to absorb the nanocarrier. Active targeting combined with passive targeting to reduce the interaction of carried drugs with healthy tissue. Nanotechnology enabled active and passive targeting; also increase the efficacy of a chemotherapeutic, achieving greater tumor reduction with lower doses of the drug.

PC is one of the deadliest and quickly fatal human cancers with a 5-year mortality rate close to 100%. Its prognosis is very poor, mainly due to its antagonistic biological behavior and late onset of symptoms for clinical diagnosis; these cause limitations on therapeutic interventions. Factors contributing to the difficulties in treating PC included: high rate of drug resistance, fast metastasis to other organs, poor prognosis and recurrenceof the tumor after therapy. Gemcitabine (Gem) is the first line and the gold standard drug for all stages of advanced PC(Afterapproved by US FDA 1997,). Nevertheless, its efficacy is insufficient, generally because of;its chemical instability and poor cellular uptake, causing in an extremely short half-life and low bioavailability. To solve these drawbacks and increase the therapeutic outcome remarkable progress achieves in the field of nanotechnology and offers a promising and efficient alternative. Novel nanocarriers with better tumor targeting efficiencies and maximum treatment outcome to treat this deadly due gave much attention [123].

Table 3. Different types of nanocarriers, they use with chemotherapies drugs in ETC.

To improve the delivery of Gem for PC, the numerous NPs platforms developed. The some of them that could see in Table 3 and checked in ahead.  For example, PEGylated drug-carrying liposome and polyethyleneimine (PEI)/polyethylene glycol (PEG)-coated mesoporous silica nanoparticle (MSNP) for molecularbindingto a small molecule TGF-β inhibitor, LY364947, developed with drug encapsulate up to 20% w/w. The copolymer coating eases systemic biodistribution and retention at the tumor site. Because of the high loading capacity and pH-dependent LY364947 release from the MSNPs, a rapid IV injected liposomes and MSNPs at the PDAC tumor site have done. This two-wave method provided sufficient shrinkage of the tumor xenografts beyond 25 days, compared to the treatment with a free drug or Gem-loaded liposomes only.Not only does this approach overcome stromal resistance to drug delivery in PDAC, but it also presents the concept of using a stepwise engineered method to address a range of biological impediments that interfere in nanotherapeutics spectrum of cancers[124] (Fig 7).

Another instance is a combination of Nab-Paclitaxel (Abraxane®; a form of the chemotherapy drug Paclitaxel bound to the human protein albumin and contained in NPs) [125, 126] and cetuximab with Gemcitabine (Gemzar®) that investigated in an international randomized phase III trial and preclinical models, respectively. Patients who took the drug combination had a median survival of 8.5 months, compared with 6.7 months for patients treated with Gem alone. These results using a combination of cetuximab and Gem motivated, the researchers involved in cancer nanotechnology study to design better and alternative targeted drug delivery system (DDS) for the treatment of a variety of cancer, particularly PC. In this context, an NP-based targeted drug delivery system(DDS) developed which contains cetuximab (C225) anti-epidermal growth factor receptor (EGFR) antibody as the targeting agent, gemcitabine as the anti-cancer drug, and gold NPs as the delivery vehicle [127]. Management of this targeted delivery system caused by major inhibition of pancreatic tumor cell in vitro and pancreatic tumor growth in vivo [127-136]. Another NPs which it used in combination of Gem is superparamagnetic iron oxide NPs (SPIONs), the inorganic particles that functionalized as targeted drug vehicles with a stealth polymer coating and a specific antibody tag to recognize appropriate antigen expressing cells. The SPIONs are capable of targeted cell death of pancreatic cells by release of its chemotherapy payload Endocytosis of the SPIONs. When these NPs loaded with modified gemcitabine, SPIONs act as pH-triggered delivery vehicles capable of intracellular drug release. This could reduce off target effects leading to increased chemotherapy agent efficacy and offer the prospect for new treatments in PC[137]. Polymeric micelles (PMs) and its self-assembled NPs are another examples for improved Gem delivery with nanotechnology. Daman et al. utilized GemC18-loaded poly (ethylene glycol)–poly (D, L-lactide) (PEG–PLA) polymeric micelles as a promising agent for nanotherapeutics of PC. The improved formulation displayed aparticle size of about120 nm, encapsulation efficiency >90%, and a sustained release performance of the drug. In Panc-1 and AsPC-1 cell lines, both GemC18-loaded PMs and NPs were considerably more cytotoxic than the GemC18 solution. They could effectively decrease the viability of Gem high-resistant AsPC-1 cells in culture. However, the molar equivalent doses of Gem did not exhibit any acceptable cytotoxicity [138].

Gemcitabine triphosphate (GTP) encapsulated into a new Lipid/Calcium/Phosphate NP (LCP) platform as novel NPs carriers, Zhang said. The therapeutic efficacy of LCP-formulated GTP evaluated in a panel of human non-small-cell lung cancer (NSCLC) and human PC models after systemic administrations. GTP-loaded LCPs induced cell death and prevented the cell cycle in the S phase. In vivo effectiveness findings displayed that intravenously injected GTP-loaded LCPs triggered effective apoptosis of tumor cells, a significant reduction of tumor cell proliferation and cell cycle progression, leading to dramatic inhibition of tumor growth, with little in vivo toxicity [139].

When Hypoxia-inducible factor 1a (HIF1a) combined to Gem, could use as a promising new target for PC treatment. The biocompatible lipid-polymer hybrid NPs employed to co-deliver HIF1a siRNA (si-HIF1a) and Gem for PC treatment in subcutaneous and orthotopic tumor models. The cationic ε-polylysine copolymer (ENPs) can effectively absorb negatively charged si-HIF1a on the surface and encapsulate Gem to the hydrophilic core. LENPs can co-deliver Gem and si-HIF1a (LENP-Gem-si-HIF1a)into tumor cells andeffectively suppress theHIF1a expression both in vitro and in vivo. LENP-Gem-siHIF1a exhibited significant synergistic antitumor effects [140].

Immunogenic cell death (ICD) happens when apoptotic tumor cell causes a specific immune response, which may cause an anti-tumor effect. Zhao and colleagues used the nanomedicine; they believed that this approach might affect ICD due to their proven advantages in the delivery of chemotherapeutics; oxaliplatin (OXA) or gemcitabine (GEM) encapsulated as an ICD and a non-ICD inducer respectively, into the amphiphilic diblock copolymer NPs. Interestingly, NP-OXA treated tumor cells released and induced stronger immune responses of dendritic cells and T lymphocytes than OXA treatment in vitro. This general trend of enhanced ICD by NP delivery corroborated in evaluating another pair of ICD inducer and non-ICD inducer, doxorubicin, and 5-fluorouracil. Treatment with an NP encapsulated ICD inducer led to significantly enhanced ICD and consequently improved antitumor effects than the free ICD inducer [141].

The other NP platform based on nanoscale coordination polymer-1 (NCP-1) developed for simultaneous delivery of two chemotherapeutics, oxaliplatin andGemmonophosphate (GMP), at 30 wt. % and 12 wt. % drug loadings, respectively.A strong synergistic therapeutic effect of oxaliplatin and GMP observed in vitro against AsPc-1 and BxPc-3 PC cells. NCP-1 particles efficiently preventuptake by the mononuclear phagocyte system (MPS) in vivo with a long blood circulation half-life of 10.1 ± 3.3 h and competently prevent tumor development when compared to NCP particles transport oxaliplatin or GMP alone. NCP-1 is a unique nanocarrier for the co-delivery of two chemotherapeutics that have distinct mechanisms of action to disrupt multiple anticancer pathways with maximal therapeutic efficacy and minimal side effects, simultaneously [142].

Dai et al. showed that mesoporous silica vesicles (MSVs) with large pore sizes could use as a novel drug delivery system. Gem loaded into the MSVs via “nano casting” method. In vitro drug release experiments of gemcitabine- loaded MSVs showed an accelerating release of gemcitabine in acidic condition. They utilized fluorescently labeled MSVs on both a human (BxPC-3) and a mouse PC cell lines (Pan02). Cell viability assays showed that Gem-loaded MSVs revealed greater anticancer activity in inhibiting the proliferation of BxPC-3 and Pan02 cells compared with free Gem, while the MSVs alone showed no significant cytotoxicity. MSVs might represent a promising novel drug delivery platform for the treatment of PC[143]. Herceptin conjugated gemcitabine-loaded chitosan NPs (HER2-Gem-CS-NPs) can use for PC therapy, Indolfi and co-worker said. The targeted NPs displayed superior anti proliferative activity along with an enhanced S-phase arrest, leading to apoptosis in comparison with unconjugated gemcitabine loaded NPs and free Gem due to higher cellular binding with eventual uptake and prolonged intracellular retention. Thus, HER2-Gem-CS-NPscan provide an efficient and targeted delivery of gemcitabine for PC treatment[144].

Redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin NPs formulated as a targeted vector for systemic delivery of gemcitabine therapy in PC. The surface of the PEGylated-NPs used to enhanced circulation time or with EGFR targeting peptide to confer target specificity. In vitro findings in Panc-1 human pancreatic ductal adenocarcinoma cells prove that Gem encapsulated in EGFR-targeted gelatin NPs, released through disulfide bond cleavage, had a significantly improved cytotoxic profile [145].Gemcitabine-loaded poly(lactide-co-glycolide) (PLGA) nanospheres also used as targeting agent in PC. The images showed that the gemcitabine loaded was 180 nm and optimized encapsulation efficiency of gemcitabine was 15%. It observed that 100% of gemcitabine released from the PLGA nanospheres for 41 days in phosphate buffered saline (PBS) at pH 7.4. The uptake of nanospheres in MiaPaCa-2 cells was studied using sulforhodamine B loaded PLGA nanospheres, and the results showed that the nanospheres were taken up within 3 h. Furthermore, the cytotoxicity of PLGA nanospheres loaded with gemcitabine showed a relative decrease in IC50 in MiaPaCa-2 and ASPC-1 PC cells in comparison to free gemcitabine [146].

Single wall carbon nanotubes (SWCNTs) also use as drug delivery agent in cancer therapy. SWCNT-PEG-Gem (functionalized through carboxylation, acylation, amidation, PEGylation and finally Gem conjugation) indicated high loading capacity. MTT assay on the human lung carcinoma cell line (A549) and the human pancreatic carcinoma cell line (MIA PaCa-2) showed that the SWCNT-Gem was more cytotoxic than SWCNT-PEG-Gem and Gem alone. The SWCNT-PEG-Gem conjugates present higher efficacy in suppressing tumor development than SWCNT-Gem and Gem in B6 nude mice. The findings show that the new formulation of Gem is a useful strategy for improving the antitumor efficacy of Gem [147, 148].

There is also other NPs platform; they did not use of Gem for PC therapy. For example the CKAAKN peptide, which recognized by phage display, as an efficient homing device within the pancreatic pathological microenvironment. The enchanting advantage of the squalenoylation platform, the CKAAKN peptide conjugated to squalene (SQCKAAKN), and then co-nano precipitated with the squalenoyl prodrug of gemcitabine (SQdFdC) giving near monodisperse NPs for safe intravenous injection, Wang-Gillam and coworker developed it [149]. The antitumor efficiency of SQdFdC-MP nanoassemblies (NAs) on chemoresistant and chemosensitive pancreatic adenocarcinoma models investigated also. Cell viability assays showed that SQdFdC-MPNAs demonstrated higher antiproliferative and cytotoxic effects, mainly in chemoresistant pancreatic tumor cells. In in vivo studies, SQdFdC-MP NAs decreased the growth (70%) of human MiaPaCa2 xenografts, moreover preventing tumor cell invasion, while native dFdC did not display any anticancer activity when tumor growth inhibition was only 35% with SQdFdC NAs. [150].

Nanoliposomal irinotecan has shown activity in phase II studies in solid tumors, including metastatic PC, previously treated with gemcitabine-based therapy. In patients with metastatic PC previously treated with gemcitabine-based therapy, nanoliposomal irinotecan in combination with fluorouracil and folinic acid increased overall survival, progression-free survival, and time to treatment failure, reduced carbohydrate antigen 19-9 (a pancreatic tumor biomarker) and amplified the number of patients achieving an objective response. In a population with few treatment options, this drug combination was tolerable and did not have a negative effect on quality of life, which are important factors for this population. Nanoliposomal irinotecan in combination with fluorouracil and folinic acid represents a potential treatment option for patients with metastatic PC that progressed after a gemcitabine-based regimen. Future research will assess its use in frontline therapy[151].

Arsenic trioxide (As2O3) is a hopeful anticancer agent for solid tumors. The mal-PEG-PDLLA was synthesized and assembled to vesicles with arsenite ion (As) encapsulated in their cores (As-NPs).Conjugation of scFvCD44v6 (anti-CD44v6 single chain variable fragment) with mal-PEG-PDLLA (scFv-As- NPs) enabled delivery that is more efficient and exhibited higher cytotoxic activity than nontargeted ones (As-NPs) in human PC cells PANC-1. Also,the targeted delivery of as induced more significant gene suppression regarding the expression of the anti-apoptotic Bcl-2 protein. Therefore,the expression level of cleaved caspase-3, which is a little indicator of cell apoptosis, was remarkably elevated. In animal tests, scFv-As-NPs found to increase accumulation of the drug in tumor site greatly and have an efficacy as in inhibiting tumor growth owing to the enhanced cell apoptosis. These results imply that our tumor specific nanocarriers provide a highly efficient and safe platform for PC therapy[152].

Antibody-mediated therapies containing antibody-drug conjugates (ADCs) have displayed much potential in cancer treatment by tumor-targeted delivery of cytotoxic drugs. The combination of antibodies with drug-loaded nanocarriers expands the application of antibodies to a broad range of therapeutics. Antibody fragment installed polymeric micelles developed by maleimide-thiol conjugation for selectively delivering platinum drugs to pancreatic tumors. By modifying the surface density of maleimide on the micelles, one tissue factor (TF)- targeting Fab’ conjugated to each carrier.Fab’-installed platinum-loaded micelles showed more than 15-fold increased cellular binding within 1 h and rapid cellular internalization compared to nontargeted micelles, leading to superior in vitro cytotoxicity. In vivo, Fab’-installed micelles significantly suppressed the growth of pancreatic tumor xenografts for more than 40 days, outperforming nontargeted micelles and free drugs [153]. The other example in this field is silicon nanocarriers with a Ly6C antibody designed as targeted nanocarriers. Anti-phagocytosis CD59 and CD47 expression on PC cells increased related endothelial cells as well as infiltrating cells in the stroma as compared to the uninvolved pancreas. Due to silicon has porous and then Ly6C antibody can trap on them.  At 4 h after administration, much more of injected dose/g tumor of the Ly6C targeting nanocarriers accumulated in the pancreatic tumors than non-targeted nanocarriers [154]. However, CD47 inhibition effectively slowed tumor growth only in combination with Gemcitabine or Abraxane. For this reason generation of the multi-functionalized iron oxide magnetic NPs (MNPs) that contain the anti-CD47 antibody and the chemotherapeutic drug Gemcitabine in a single formulation. The in vitro efficacy of the formulation against CD47-positive PC cells demonstrated [155].

The other medication that it used in cancer therapy is Paclitaxel (PTX). Although it is therapeutically very effective, its poor biopharmaceutical properties severely limit its clinical usage. PTX, being a poorly soluble and poorly permeable drug, classified under class IV of Biopharmaceutics Classification System (BCS). When PTX formulated in various NPs delivery system; the aqueous solubility of it greatly enhanced; they are small in size (several to several hundred nm), which enables the special delivery of PTX into the tumor site due to the EPR effect. They can escape the recognition of reticuloendothelial system (RES) in healthy tissues and therefore reduce the side effects of the drug. For example, PEGylated cationic (PCat)-siRNA lipoplexes used as in the intraperitoneal study to treat mice bearing subcutaneous human pancreatic tumors. The results showed that single agent PTX postponed tumor development but also considerably induced the survivin protein level in residual tumors, while the addition of PCat-si surviving reversed the paclitaxel-induced surviving and increased the PTX activity (p<0.05) [156, 157]. Albumin NPs considered an effective way to load water-insoluble anticancer drugs and target tumors via the gp60-mediated pathway. The albumin NP formulates for co-loading paclitaxel (PTX) and curcumin (CCM), both of which have prominent anticancer efficacy, by using NPalbumin-bound (NabTM) technology using high-pressure homogenization. The PTX/CCM co-bound albumin NPs (PTX/CCM Alb-NPs) had a slightly greater particle size of ~250 nm than that of plain PTX Alb- NPs and CCM Alb-NPswith sphere shape. PTX/CCM Alb-NPs appeared to be efficiently internalized into Mia Paca-2 cells and exhibited a 71% increased IC50 versus PTX Alb-NPs regarding cytotoxicity to Mia Paca-2 cells. These results recommend that PTX/CCM Alb-NPs are a new promising anticancer agent for combination therapy [158]. One-pot/step formulation of PTX-bound albumin NPs with embedded tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/PTX HSA- NP) used for the treatment of PC. The loading efficiencies of PTX were in the range of 86.4% and significantly low at 2.0% TRAIL (60.4%). Specifically, the IC50 of TRAIL (1.0 or 2.0%)/PTX HSA-NPs were >20-fold lower than that of plain PTX-HSA NP in pancreatic Mia Paca-2 cells [159].

The other drug is docetaxel, the same reasons that said about Gem and PTX, the DTX formulation in nano-platform affected on its functions. Cellax-DTX polymer is a conjugate of docetaxel (DTX), polyethylene glycol (PEG), and acetylated carboxymethyl cellulose, a construct that condenses into well-defined 120 nm particles in an aqueous solution, and is suitable for intravenous injection. Cellax-DTX treatment effects examined in highly stromal primary patient-derived PC xenografts and a metastatic PAN02mouse model of PC,focusing on specific cellular interactions in the stroma, pancreatic tumor growth, and metastasis. Greater than 90% of Cellax-DTX particles accumulate in smooth muscle actin (SMA) positive cancer-associated fibroblasts that result in long-term depletion of this stromal cell population, an effect not observed with Nab-paclitaxel (Nab-PTX). The reduction in stromal density leads to a 10-fold increase in tumor perfusion, reduced tumor weight and a decrease in metastasis. Consentingly, Cellax-DTX treatment increased survival when compared to treatment with gemcitabine or Nab-PTX in a metastatic PAN02 mouse model. Cellax-DTX NPs interact with the tumor-associated stroma, selectively interacting with and depleting SMA positive cells and macrophage, effects of which associated with significant changes in tumor progression and metastasis[160].

Quercetin and 5-fluorouracil were loaded in chitosan NPs, individually as well as in combination as drug delivery vehicles. The dual drug-loaded carrier demonstrated good entrapment efficiency (quercetin 95% and 5-fluorouracil 75%) with chitosan: quercetin: 5-fluorouracil in the ratio 3:1:2, David et al. claimed. The release profiles suggest that 5-fluorouracil preferentially localized in the periphery while quercetin located towards the core of chitosan NPs. Both drugs showed significant association with the chitosan matrix. The dual drug-loaded carrier system exhibited significant toxicity towards PC cells both in the 2D as well as in the 3D cultures. The results from these studies can open up interesting options in the treatment of PC [161].

Debotton and co-worker developed a monoclonal antibody, AMB8LK; specifically recognizing H-ferritin was thiolated and conjugated to maleimide-activated polylactide NPs that result in the formation of Immuno NPS (Immuno NPS). A lipophilic PTX derivative, paclitaxel palmitate (pcpl), encapsulated within the various NP formulations, and their cytotoxic effect evaluated on A-549 cells using MTT assay. Pcpl-loaded AMB8LK Immuno NPS showed a significantly increased cytotoxic effect when compared to pcpl solution and pcpl NPs [162].

Dextran-coated SPIO NP ferrofluid, functionalized with the red auto fluorescing doxorubicin and the green-fluorescent dye fluorescein isothiocyanate as a reporter, enables tracking the intracellular NP transport and drug release Arachchige and co-worker said. They showed that their engineered NP enables to 20-fold rapid entry and release of the drug in human PC cells. The low extracellular pH of most tumors stopping the entry of some weakly basic drugs, for example, doxorubicin, conferring drug resistance, can now be overcome[163].

Verma et al. demonstrated anthothecol-encapsulated PLGA-NPs (Antho-NPs) prevented cellproliferation and colony formation. It causedapoptosis in pancreatic CSCs and cancer cell lines but had noeffects on humannormal pancreatic cells. Antho-NPs preventedself-renewal capacity of pancreatic CSCsisolated fromhuman and KrasG12D mice. Also, Antho-NPs inhibited pluripotency maintaining factors and stem cell markers, suggesting their inhibitory role on CSC population [164].

Plant mediated green synthesis of Platinum NPs is an eco-friendly and efficacious approach which finds broad application in the field of medicine. The cytotoxic effect of platinum NPs (ptNPs) on human lung adenocarcinoma (A549), ovarian teratocarcinoma (PA-1), PC (Mia-Pa-Ca-2) and normal peripheral blood mononucleocyte (PBMC) cells and assess anti-cancer potential via induction of apoptosis in PA-1 cells. Cytotoxicity was appraised using MTT assay, trypan blue dye exclusion assay and anticancer potential evaluated using clonogenic assay, apoptosis assay, and cell cycle analysis. The results showed that ptNPs had potent anticancer activities against PA-1 cell line via induction of apoptosis and cell cycle arrest because of ptNPs exerted a cytotoxic effect on cancer cell lines, whereas no cytotoxic effect observed at highest dose on normal cells [165].

Adrenocortical carcinoma (ACC) is one of the deadliest of human cancers. Although rare, with a worldwide incidence of 1 to 2 per million. The prognosis is poor with a 5-year survival rate of 10% to 20%, due to the usual late presentation and the restricted efficiency of broad-spectrum chemotherapy [166]. At present, the only realistic opportunity for cure is complete surgical removal, but unfortunately, the metastatic spread is already present in 40% to 70% of patients at the time of diagnosis. First, approved in 1960, mitotane (Bristol-Myers Squibb Company, New York) remains the standard chemotherapeutic treatment for this disease. Mitotane is a derivative of the pesticide DDT and an adrenolytic [166, 167].

Paclitaxel showed promise in the laboratory setting but did not study in patients with ACC. Paclitaxel reported inhibiting in vitro growth of H295R, an adrenocortical cancer cell line. However, there have been no subsequent investigations regarding the use of this agent for ACC[168]. Abraxane, or nab-paclitaxel, is a novel albumin stabilized NP formulation of paclitaxel [169]. The drug nab-paclitaxel is bound to NPs of albumin, a protein that the body uses to transport water-insoluble compounds. It postulated that increased levels of the drug might get into tumor cells through transendocytosis via active transport by gp60 on the endothelial cell surface into the interior of the tumor [170, 171].

TKM-PLK1 is another lipid NP that encapsulating siRNA and preventsthe protein productpolo-likekinase 1 (PLK1). PLK1 phosphorylates Cdc25C, controls DNA damage,microtubule nucleation, chromosomal condensation, and segregation, and is an important target fortreatment [172]. This “nanoformulation” is important because it does not depend on accumulation in the organs such as the liver to deliver its payload. TKM-PLK1 depend mainly on the EPR effect to localize NPs into solid tumors [173]. In phase I trialsassessedthe effects of doseincreaseon solid tumors in advanced cancer patients with promising safety and efficacy results, culminating in an ongoing phase II clinical trial for patients with advanced Gastrointestinal Neuroendocrine Tumors (GI-NET) or Adrenocortical Carcinoma (ACC)[45].

Ovarian cancer relates to any cancerous growth that happens in the ovaries. The common of ovarian cancers arise from the epithelium (outer lining) of the ovaries.According to the American Cancer Society, it is the 8th most majority cancer among women in the US (excluding non-melanoma skin cancers). But, it is the 5th most common cause of cancer deaths in women. Among the gynecologic cancers (uterine, cervical, and ovarian), ovarian cancer has the maximum rate of deaths. More than 22,000 women in the U.S. diagnosed with ovarian cancer, and around 14,000 will die each year. Unfortunately, the overall 5-year survival rate is only 46% in most advanced countries. However, according to the National Cancer Institute, if diagnosis made early before the tumor has spread, the 5-year survival rate is 94 %. Nanotechnology has a capability to enhance the existing imaging techniques as well as developing novel approaches for tumor-specific imaging that also can apply to ovarian cancer (table 4). For instance, single-walled carbon nanotubes proposed for in vivo fluorescence imaging [74] as well as tumor-targeted responsive NP based systems recently developed for enhancing magnetic resonance imaging and simultaneous therapy of ovarian cancer [103, 104]. It showed that uniform, stable cancer targeted NPs (PEGylated water-soluble manganese oxide NPs, modified with LHRH targeting peptide) exhibited a notable ability of substantially enhancing the detection of ovarian tumor and intraperitoneal metastases. In in vitro findings on human ovarian carcinoma cell (SKOV-3) and healthy cell (HOMEC) lines displayed that PTX loaded on 30 nm CoFe2O4@BaTiO3 MENs (magneto electric NPs), drug penetrated through the membrane and completely eradicated the tumor within 24 hours without affecting the normal cells[174].

Table 4. Various nanocarriers to targeted ovarian cancer

One of the most common endocrine malignancy is thyroid cancer. It approximated that 96% of all new endocrine organ cancers will initiate from the thyroid gland, resulting in about 64,300 new cases in the US in 2016 [188]. Papillary thyroid cancer (PTC) is the most commonkinds of thyroid cancers withmore than 90% of all thyroid cancers. The incidence of PTC has beengrowingin recent years, largely because of advances in early detection with ultrasonography and fine-needle aspiration biopsy [188-191]. The most effective treatment for PTC is the complete removal of the primary tumor and the metastatic regional lymph nodes, which is also a prerequisite for other adjuvant therapies. Cervical lymph node metastases are common in PTC and reported to occur in 12–81% of patients with PTC [192]. The most usualsite of PTC nodal metastases is the central neck, with reported rate of lymph node metastases as high as 50–70% [192]. Lymph node metastases in this region are difficult to identify preoperatively because the lymph nodes typically do not appear abnormal on preoperative imaging. The One study was to investigate the use and clinical utility of carbon NPs as a lymph node tracer in the central neck lymph node dissection in patients withPTC.One hundred forty consecutive patients were divided into a carbon NP group (n = 70) and a control group (n = 70). All patients experiencedtotal or near-total thyroidectomy with bilateral central neck dissection. The carbon NP and control groups had various rates of metastatic lymph nodes; total detected numbers of lymph nodes, total numbers of dissected lymph nodes and numbers of metastatic lymph nodes.Of the 682 lymph nodes dissected in the carbon NP group,85% were stained black, and of these, 25% were metastatic lymph nodes. Of the total number of metastatic lymph nodes, 76% were stained black. Moreover, pathologic results revealed that 5 accidental parathyroid resections occurred in the carbon NP group, compared with 14 in the control group. Carbon NPs might help to find lymph nodes and enhance the number of metastatic lymph nodes visualized and preserved. Therefore, use of carbon NPs may reflect the metastatic condition of the central neck and have the potential to protect parathyroid glands [193].

Various tissue-specific antibodies attached to NPs to obtain targeted delivery. In particular, nanodelivery systems with selectivity for breast, prostate, thyroid and cancer tissue developed. Nanoliposomes bind to TSH viabinds to the TSH receptor (TSHr) on the surface of thyrocytes. The results show that the intracellular uptake of TSH nanoliposomes enhancedin cells expressing the TSHr. The aggregationof targeted nanoliposomes in the thyroid gland following intravenous injection was 3.5-fold higher in comparison to untargeted nanoliposomes. Also, TSH-nanoliposomes encapsulated with Gemshowed improved anticancer efficacy in vitro and a tumor model of follicular thyroid carcinoma. This drug delivery system could beutilizedfor the treatment of a broad spectrum of thyroid diseases todecreaseside effects and improve therapeutic efficacy[194].

Although thymomas are rare neoplasms, they are the most common tumor of the anterior mediastinum in adults. Usual therapy for these neoplasms is complete surgical resection. If a thymoma cannot be completely resected, postoperative radiotherapy may produce satisfactory results in controlling the tumor. Significant 5-10 years survival rates recorded for patients with advanced thymomas who treated by radiation therapy alone. Chemotherapy employed in patients with unresectable thymomas but the results are less hopeful than with radiotherapy. Combinations of radiotherapy and chemotherapy used on patients with unresectable thymomas produced encouraging results. Surveillance of patients with thymoma prolonged because late recurrence (more than 5 years after initial therapy) expected in a significant minority of patients. Aggressive therapy for late recurrence, including resection of new tumor masses and pleural metastases, yielded successive disease-free intervals that validate persistent treatment[195].

Cisplatin and doxorubicin-based combination chemotherapy regimens produce overall major response rates between 50 and 90% in chemotherapy-naive patients. However, in patients with recurrent disease previously treated with chemotherapy, response rates to chemotherapy are lower [196-199].

Table 5 showed the some of nanomedicines that they used for ET cancer therapy. The some of them approved by FDA and used as commercial medications. A

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