Encapsulation Efficiency of a Targeted Drug Delivery System Consisting of Herceptin-Loaded Polymers - Literature review Example

The Encapsulation Efficiency of a Targeted Drug Delivery System Consisting of Herceptin-Loaded Polymers, an Evaluation and Characterization of Student] [Name of Institution] 2773 Words [Date] Literature Review This section contains a review of all relevant literatures, especially studies, conducted to establish the efficacy of trastuzumab for treating early-stage and advanced breast cancer and literatures on encapsulation efficiency of a targeted drug to inhibit proliferation of cancer cell. The Encapsulation Efficacy of Trastuzumab (Targeted Therapy) To Inhibit Proliferation of Cancer Cell and Its Cardiotoxicity Problems Cardiotoxicity of Trastuzumab Trastuzumab therapies have been observed to have cardiac toxicity and drug resistance problems [27]. The cardiotoxicity problems associated with trastuzumab have been addressed by Keefe [23] in an article titled ‘Trastuzumab-associated Cardiotoxicity.’ Keefe [23] defines trastuzumab as a monoclonal antibody that targets HER2 or ErbB2, a human epidermal growth receptor. It has also been established, through studies, that trastuzumab is ideal for treating early and advanced disease for between 15% and 20% of patients with breast cancer whose tumors over-express HER2 [23]. Nonetheless, a small or modest cardiotoxicity risk is associated with the use of trastuzumab [26]. This cardiotoxicity manifests by way of asymptotic drop in the ventricular ejection fraction and clinical heart failure [4]. American Society of Oncology concurs with Keefe [23] on the cardiotoxicity associated with trastuzumab therapy in its report on the study ‘Trastuzumab-Induced Cardiotoxicity: Clinical and Prognostic Implications of Troponin I Evaluation.’ The purpose of this study by the American Society of Clinical Oncology was to address the cardiotoxicity complications associated with the use of trastuzumab to treat breast cancer in about 34% of patients [24]. Although trastuzumab has the cardiotoxicity side effects in some patients, the effect is reversible. The resultant left ventricular ejection improves once the drug is withdrawn. This recovery can also be hastened by starting a heart failure therapy [25]. The trastuzumab-induced cardiotoxicity (TIC) can be reversed cannot be predicted, implying it is of greatly important to identify at-risk patients and the patients not likely to recover from the cardio-dysfunction brought about by trastuzumab [9]. The American Society of Clinical Oncology thus studied the efficacy of troponin I (TNI) in identifying the patients at risk for TIC and predicting LVEF recovery. In the study by the American Society of Clinical Oncology, 251 women participants had their TNI measured before and after each trastuzumab cycle. Their left ventricular ejection fraction (LVEF) was then evaluated at baseline, after every 3 months once the trastuzumab therapy commence then every 6 months afterward. To investigate TIC, the researchers discontinued trastuzumab, replacing it with HF treatment with enalapril and carvedilol. For the purposes of the study, TIC was defined as LVEF decrease of greater 10 units and below 50% while recovery from TIC was defined as LVEF increases above 50% [1]. The findings indicated that TIC occurred in 17%, representing 42 patients, with its highest frequency reported among patients with elevated TNI (TNI+; 62% v 5%; P < .001) [1]. 25 patients (60%) recovered from TIC [1]. It was noted that left ventricular ejection fraction recovery was less frequent in TNI+ patients (35% v 100%; P < .001). Further, multivariate analysis showed that TNI+ was the sole independent predictor of TIC. Hence, it was concluded that TNI+ identifies trastuzumab-treated patients at high risks of cardiotoxicity [1]. These patients are unlikely to fully recover from cardiac dysfunction despite heart failure (HF) therapy. Inhibitory Potential of Nanoparticles In a study published in the 10th volume of the International Journal of Nanomedicine, [28] sought to establish whether nanoparticles inhibit cancer cell invasion and improve antitumor efficiency by targeting drug delivery by cell surface-related GRP78. The background of the study was the idea that nanoparticles targeting specific agents have the ability to effectively identify target cells and boost the stability of chemicals by encapsulation [3]. This ability of nanoparticles forms the basis of their widespread use in the treatment of cancer, especially breast cancer. [28] It has been established that in recent time, nearly more than 90% failures in treating metastatic cancer patients are a consequence of chemotherapy resistance. A study by [28] is among the myriad studies and literatures showing the encapsulation efficacy of a targeted drug to inhibit the proliferation of cancer cells. In this study, [28] noted that many tumor cells have glucose-regulated protein of 78 kDa (GRP78) on exposed on their surfaces. This GRP78 is associated with the regulation of invasion and metastasis [13]. The other finding by [28] was that nanoparticles, when conjugated with antibody against GRP78 (mAb GRP78-NPs), have the ability to hamper the adhesion, invasion, and metastasis of hepatocellular carcinoma (HCC). Nanoparticles have also been noted to promote drug delivery of 5-fluorouracil into GRP78 high-expressed human hepatocellular carcinoma cells [11]. The Efficacy of Trastuzumab (Herceptin) Baselga of Medical Oncology Service, Hospital General Universilari Vall dHebron Barcelona conducted Phase I and II clinical trials of trastuzumab and summarized it its findings in a report. The purpose of the report was to summarize the efficacy of trastuzumab (Herceptin), as established during the completed clinical trial program, conducted in patients with HER2-positive metastatic breast cancer for phases I and II studies [5]. In fact, it is the findings of these trials that resulted in the submission and the subsequent approval of trastuzumab for clinical use, in the USA. Phase I of the trials had three small-scale trials conducted to establish the drug’s pharmacokinetics and safety [5]. During this phase, 10–500 mg of trastuzumab was administered in vitro as single or weekly doses. This dosage was then followed by Phase II, which entailed the administration of fixed-dose trastuzumab either as a single-agent or in combination with cisplatin in 46 and 39 patients respectively [5]. The result was an overall response rate of 11.6% and 24.3%, respectively. In a crucial phase II clinical trial, patients were given trastuzumab on a bodyweight-adjusted basis as a single treatment to 222 patients of HER2-positive metastatic breast cancer who had relapsed after prior chemotherapy regimens (Baselga, 2013). The general response rate was 21% under an assessment of participating patients by an investigator and 15% when analyzed on an intent-to-treat basis by an independent committee evaluating the response to the drug [10]. In another study titled “Enhancement of Cancer Therapy Efficacy By Trastuzumab-Conjugated and Ph-Sensitive Nanocapsules with the Simultaneous Encapsulation of Hydrophilic and Hydrophobic Compounds,” Chiang, Hu, Liao, Chang and Chen, [8] studied the use of trastuzumab-conjugated and pH-sensitive nanocapsules with the simultaneous encapsulation of hydrophilic and hydrophobic compounds to enhance the efficacy of cancer therapy. In a double-step process, [7] fabricated and stabilized trastuzumab-conjugated pH-sensitive double emulsion nanocapsules (DENCs) using a single-component Poly (vinyl alcohol) (PVA) with magnetic nanoparticles. The study was based on the notion that the nanoparticles can be effective in the simultaneous encapsulation of the hydrophilic doxorubicin (Dox) and hydrophobic paclitaxel (PTX). Enhanced dual drug release of PTX/Dox was detected; when PMASH was attached to the shell of the DENCs. The enhancement was more pronounced in the intracellular acidic pH environments [8]. The increased targeting efficacy and ability of the Trastuzumab-conjugated DENCs was evidenced by confocal images [8]. The images showed a remarkably improved cellular uptake in HER-2 over-expressing SkBr3 cells. The in vivo suppression of cancer growth was more pronounced following an intravenous injection of the co-delivery system with magnetic targeting (MT) chemotherapy compared to when either PTX or Dox were delivered alone [8]. Catania, Barrajón-Catalán, Nicolosi, Cicirata and Micol [6] also conducted a study entitled ‘Immunoliposome Encapsulation Increases Cytotoxic Activity and Selectivity of Curcumin and Resveratrol against HER2 Over-expressing Human Breast Cancer Cells. The study was published in the 1st issue of the 141st volume of the Breast Cancer Research and Treatment. Such a study is often based on the extensive use of natural compounds to synthesize bioactive compounds, especially phytochemicals, which have been studied and used for their cytotoxic and apoptotic capacities [16]. The studies have been conducted to explain the anticancer capacities of these bioactive compounds, examples of which are curcumin and resveratrol, which have been shown to have cytotoxic activity against a variety of cancer cells. Nonetheless, the clinical use of these bioactive compounds has been hampered by their poor absorption, bioavailability and low selectivity [6]. The study’s aim was to improve the bioavailability and selectivity of these compounds by comparing the anti-proliferative effects of free-, liposomed-, and immunoliposomed-curcumin and resveratrol formulations in two human breast cancer cell lines with different HER2 expression levels. Many studies have established that whenever HER2-targeted immunoliposomes were joined to trastuzumab, there was a remarkable boost in the anti-proliferative effects of curcumin and resveratrol in HER2 positive human breast cancer cells, compared to regular liposomed or free forms [19]. For [6], this finding showed an increase in the therapeutic effects. The improvement on the cytotoxic effects of the bioactive compounds was correlated to the uptake of curcumin at intracellular level. This finding was confirmed using the Image Stream technique. The conspicuous efficacy of the immune-liposomed formulation containing combined resveratrol and curcumin suggested that a multi-targeted mechanism of action should be studied further [6]. The findings of this study by [6] showed the high potential of HER2-targeted nano-vesicles in developing new drug delivery systems for cancer therapy, built on these bioactive compounds, thus justifying further preclinical trials. The other important study that touched on the efficacy and use of Herceptin as successful target therapy for treatment and overcoming trastuzumab’s resistance and cardiotoxicity by encapsulating the Herceptin loaded polymer nanoparticler (alginate) was conducted by Fernández, M. A., Gozalbo, F., Carrascosa, M., Camps, J., Guillem, V., Ruiz, A., Gavilá, J., and Guerrero, A. in 2014. The study, entitled “Efficacy and Safety of Neoadjuvant Chemotherapy with Concurrent Liposomal-Encapsulated Doxorubicin, Paclitaxel and Trastuzumab for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in Clinical Practice,” was published in the 2nd issue of the 4th volume of the International Journal of Clinical Oncology. This study was based on the findings of other past studies on non-pegylated liposomal-encapsulated doxorubicin (TLC-D99) with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (BC) [22]. In the study, a schedule comparable to non-pegylated liposomal-encapsulated doxorubicin (TLC-D99) with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (BC) was evaluated in the neo-adjuvant setting in a prospective series of consecutive patients of clinical stage II-III BC [12]. The main goals of the study were to establish the rate of pathological complete response and its safety and predictive factors. In this study, pathological complete response was defined as the nonexistence of invasive cancerous cells in the breast and the axilla. The participating patients were given six cycles of TLC-D99 (50 mg/m (2) every 3 weeks, paclitaxel (80 mg/m (2) every week and trastuzumab (4 mg/kg initial dose and 2 mg/kg) every week. All the participants underwent surgery after treatment. The results of the study indicated that of the 62 patients with a median age of 46.6 years analyzed, stage IIIA was diagnosed in 43.5 % of them while14.5 % had inflammatory BC. Conservative surgery was performed in 46.8 % of the patients and pathological complete response achieved in 63 % of them (95 % CI 50.5-75.5). On the other hand, patients with estrogen receptor (ER)-negative tumors had a significantly higher pathological complete response rate compared to patients with ER-positive tumors, (74.4 versus 43.5 %; P = 0.028). 45 of the patients, representing 72.6 %, completed the study treatment with 80.6 % of them receiving at least five treatment cycles. Notably, no patient developed congestive heart failure whereas 14.5 % of the participants had higher than 10 % drop in the left ventricular ejection fraction. Fernández et al [12] concluded that the triple combination therapy investigated in the study was effective and safe and offered quite high pathological complete response rate in patients with HER2-positive BC. In the 4 Issue of the 4th volume of the Journal Nanomedicine is published the findings of a study by Bingfeng Sun & Si-Shen Feng. In the study, titled “Trastuzumab-Functionalized Nanoparticles of Biodegradable Copolymers for Targeted Delivery of Docetaxel,” the researcher sought to synthesize a novel system of docetaxel-loaded, trastuzumab-functionalized nanoparticles (NPs) of biodegradable copolymers for targeted and synergistic cancer chemotherapy [2]. The study entailed the modified solvent extraction and evaporation of nanoparticles of two component biodegradable co-polymers using D-α-tocopheryl polyethylene glycol succinate (TPGS) as emulsifier [29]. One of the component copolymers was poly(lactide)-TPGS of the desired hydrophobic–lipophilic balance, for cellular adhesion (Bingfeng & Si-Shen, 2013). The others was carboxyl group-terminated TPGS. The latter’s function was to facilitate the conjugation of trastuzumab on the NP surface for targeting. The study established that in vitro examination with SK-BR-3 breast cancer cells of HER2 over-expression indicated that the trastuzumab-functionalized nanoparticles have more advantages over exposed nanoparticles in cellular uptake and cytotoxicity [18]. Bingfeng and Si-Shen (2013) concluded that trastuzumab conjugated onto the nanoparticles surface has two functions. First, it targets HER2-overexpressing cancer cells. Second, it enhances the cytotoxicity of docetaxel by its synergistic effects. Bingfeng and Si-Shen (2013) also observed that trastuzumab-functionalized, docetaxel-loaded nanoparticles bear improved capacity for targeted chemotherapy to treat HER2-overexpressing cancer. The other important study on the encapsulation efficiency of a targeted drug delivery system consisting of Herceptin-loaded polymers, in particular, the use and efficacy of trastuzumab was the ‘Multicenter Randomised Phase II Study of Neo-adjuvant Trastuzumab+Docetaxel+NPLD+/-Bevacizumab in Her2-pos: Early Breast Cancer (ABCSG 32).’ This study was sponsored by the Austrian Breast and Colorectal Cancer Study Group, Hoffmann-La Roche and Cephalon. A multiple center randomised study of neo-adjuvant therapy in HER2-positive early breast cancer, its core aim was the evaluation of the cardiac toxicity of the combined treatment using trastuzumab, docetaxel, bevacizumab and NPLD) then comparing these treatments with standard therapy. Studies of this nature are normally interventional with the design or allocation being randomised [17]. The endpoint classification was safety or efficacy study while the intervention model was parallel assignment. Its primary purpose was treatment. The study was located in Austria’s Medical University of Graz-Oncology; Coop., State Hospital-Leoben, Gynaegological Medical University-Innsbruck, District Hospital-Kufstein, Hospital BHS Linz, Coop., Medical University Vienna, General Hospital, Med. Univ. Vienna; General Hospital Vienna. It started in June 2011 and ended in April 2014, enrolling 100 participants. The target population had pre- and post-menopausal males and females with HER2-positive, adenocarcinoma of the breast (except inflammatory breast cancer, T4d). All participants had to be 18 years or older. All the participants were scheduled to receive neo-adjuvant cytotoxic treatment. The other condition for participating in the study was that a patient must have been pathologically confirmed to have breast cancer with histologically confirmed HER2 over-expression with an adequate left ventricular ejection fraction. The participants also had to have sufficient liver, renal and bone marrow function and must have been free from other serious conditions that might have jeopardized the implementation of the study and compliance with protocols of the study and the interpretation of results. The participants of such studies should also have reduced risks of contracting gastrointestinal perforation, hypertension, proteinuria, wound healing complications and haemorrhage or other primary malignancies that would have interfered with compliance with the protocols or interpretation of the findings [14]. Also, often excluded from such a study are patients of central nervous system (CNS) metastases, pregnant or lactating females, hypertensive people with >150 mmHG systolic or >100 mmHG diastolic as well as those with history of abdominal fistula or intra-abdominal abscess within 6 months of the study. The results of the study indicated that cardiac toxicity time frame ranged from day 1 of cycle 1 and day 28 after the day of final surgery. The secondary finding of the study was that the time frame for pathological complete responses was up to 22 weeks [20]. The complete pathological response was defined as the absence of invasive tumor at final surgery. 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(2008) “Cardiac Management during Adjuvant Trastuzumab Therapy: Recommendations of the Canadian Trastuzumab Working Group.”  Current Oncology, 15:35. 26. Perez, E. A. (2004) “Cardiac Issues Related To Trastuzumab.” Breast 13:171–172. 27. Perik, P. J., de Korte, M. A., and van Veldhuisen, D. J., (2007) “Cardiotoxicity associated with the Use of Trastuzumab in Breast Cancer Patients.” Expert Rev Anticancer Ther7:1763–1771. 28. Zhao, L., Li, H., Shi, Y., Wang, G., Liu, L., Su, C., and Su, R. (2015) “Nanoparticles Inhibit Cancer Cell Invasion and Enhance Antitumor Efficiency by Targeted Drug Delivery via Cell Surface-Related GRP78.” International Journal of Nanomedicine, 10: 245–256. 29. Zhao, Z., and Feng, S. (2014) “Effects of PEG Tethering Chain Length of Vitamin E TPGS with a Herceptin-Functionalized Nanoparticle Formulation for Targeted Delivery of Anticancer Drugs.” Biomaterials, 35, 3340-3347.    Read More