Prospects of albumin bound nanoparticles and other chemotherapeutic agents

Prospects of albumin bound nanoparticles and other chemotherapeutic agents (ABRAXANE)
End semester report
Submitted in partial fulfilment of the requirements of study in advance topic
SAT
BITS G513
Submitted by,
Kanchan R. Sonawane (2017H1460158H)
Under the supervision of
Dr. Swati Biswas
Assistant Professor
Department of Pharmacy

BIRLA INSTITUTE OF TECHNOLOGY & SCIENCE, PILANI
HYDERABAD CAMPUS
March 2018
Contents
TOC o “1-3” h z u Abstract PAGEREF _Toc512535431 h 3Introduction PAGEREF _Toc512535432 h 3Structure of albumin: PAGEREF _Toc512535433 h 3Advantages: PAGEREF _Toc512535434 h 3Types of albumin: PAGEREF _Toc512535435 h 4Applications: PAGEREF _Toc512535436 h 4Formulation PAGEREF _Toc512535437 h 4Method of preparation: PAGEREF _Toc512535438 h 4Formulations in research: PAGEREF _Toc512535439 h 5Formulation in clinical trial: PAGEREF _Toc512535440 h 5Paclitaxel(Abraxane) PAGEREF _Toc512535441 h 5Introduction PAGEREF _Toc512535442 h 5Mechanism of action PAGEREF _Toc512535443 h 6Formulation PAGEREF _Toc512535444 h 7Treatment PAGEREF _Toc512535445 h 7Result PAGEREF _Toc512535446 h 8conclusion PAGEREF _Toc512535447 h 9
TOC h z c “Figure” Figure 1:Structure of albumin PAGEREF _Toc512536982 h 3Figure 2:Desolvation method PAGEREF _Toc512536983 h 5Figure 3: curcumin paclitaxel nanoparticles PAGEREF _Toc512536984 h 6Figure 4:Doxsorubisin and surface modified nanoparticle PAGEREF _Toc512536985 h 6
TOC h z c “Table” Table 1:Site on albumin with drugs PAGEREF _Toc512536997 h 3
Prospects of Albumin bound nanoparticles and other chemotherapeutic agents (ABRAXANE)
AbstractIn this report, an attempt has been made to study the overall importance and strategies employed in research to use albumin as a novel drug delivery carrier. Albumin, a component of the human blood, has been widely used as a clinical excipient in many formulations which is evident by its successful application in Abraxane- nanoparticles made of albumin and drug paclitaxel, it is one of the most attractive material for the development of novel drug delivery system.

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IntroductionIn cancer therapy during the past decades, precise diagnosis and effective drug delivery have been major interest in nanoparticle-based systems. Albumin demonstrated promising potential for precise diagnosis and effective drug delivery by active and passive targeting or prolonging the blood circulation time. Scientists are inspired mainly due to potential side effects of nanocarrier materials to explore biocompatible materials to construct nanoparticles.
13398512001500Structure of albumin:The three-dimensional structure of human serum albumin (HSA), is heart-shaped. Structurally, albumin consists of three homologous domains I, II, and III. Each domain contains two sub-domains (A and B), which contains 4 and 6 ?-helices, respectively. There are two main drug binding sites namely Sudlow site I and Sudlow site II. Below table gives idea about the type of drugs that bind specifically to a particular site on albumin.

Figure SEQ Figure * ARABIC 1:Structure of albuminTable SEQ Table * ARABIC 1:Site on albumin with drugsSite Type of drugs Examples
Sudlow’s site I (located in subdomain IIA), Bulky heterocyclic bilirubin, anticoagulants like warfarin, nonsteroidal anti-inflammatory drugs like azapropazone, phenylbutazone and salicylate
Sudlow’s site II (located in subdomain IIIA) Aromatic carboxylates profens like ibuprofen, fenoprofen, ketoprofen and benzodiazepines like diazepam
Advantages:Albumin has many advantages such as 1) It shows no immunogenicity as it is a endogenous protein (35-50 g/L human serum). 2) The half-life of albumin in human blood is 19 days. 3) Albumin presents a long half-life that helps improve the plasma area under curve (AUC) value, thereby maintaining a high blood drug concentration for a relatively long time.5) The most abundant protein found in the human body with a molecular weight of 66.5 kDa. 6) HSA can bind to metabolic substrates, as well as therapeutic drugs, which include hydrophobic as well as hydrophilic drugs.

Types of albumin:There are generally two types of albumin used in constructing nanoparticles: human serum albumin (HSA) and bovine serum albumin (BSA). Both of these albumins are serum albumin proteins from human serum and cow serum, respectively. They share a lot of properties, including high solubility in water, long half-life in blood, similar molecular weight (65-70 kDa), similar number of amino acid residues i.e. 585 amino acids for HSA and 583 amino acids for BSA. There are no observable differences in properties in constructing nanomedicine. Thus, both kinds of albumin have been widely used in designing multifunctional nanoparticles.

Applications:Applications include:1) Albumin nanoparticles are suitable for drug and gene carriers. 2) Suitable carrier systems for protection of antisense oligonucleotides (ASOs) from nuclease digestion and thus enabled a sustained release. 3) it enabled the delivery of a variety of drugs across the BBB into the brain. As a brain targetor, apolipoproteinE (Apo E) was covalently bound to HAS nanoparticles to enhance the delivery of drugs across the blood–brain barrier.

FormulationFrom Formulation point of view, the retention of these colloidal drug delivery systems(nanoparticles) within the body is highly influenced by the 1) particle’s size 2) physical stability 3) surface characteristics. 10 to 100 nm size particles enter the lymphatic capillaries and undergo clearance, whereas 250 nm to 1 µm size particles are identified by macrophages and removed by the reticuloendothelial system (RES) by the process of opsonization. HSA is a negatively-charged molecule, thus, increasing the amount of HSA in the starting solution leads to greater formation of intermolecular disulphide bonds. This further causes higher protein aggregation and the formation of larger-sized HSA-NPs with a more negative zeta potential Thus, it is essential to control the particle size and zeta potentials of HSA-NPs to prevent their removal and ensure maximum efficacy.
Method of preparation:The preparation techniques used so far in research for albumin nanoparticles can be classified
as
1. Desolvation
2. Emulsification
3. Thermal gelation and recently
4. Nano spray drying
5. Nab-technology
6. Self-assembly
50245024
Figure 2:Desolvation methodSome of the articles suggest the use of desolvation method and scientist are trying to incorporate different drugs into albumin nanoparticulate system. Abraxane was prepared by nab technology, American Bioscience, Inc. has developed a unique albumin-based nanoparticle technology (nab-technology) that is ideal for encapsulating lipophilic drugs into nanoparticles. The drug was mixed with HAS in an aqueous solvent and passed under high pressure through a jet to form drug albumin nanoparticles in the size range of 100–200 nm. Finally, the particles were lyophilized and supplied in powder form for injection.

Formulations in research:Two drugs are in research to develop as an albumin bound nanoparticles.1) Curcumin + paclitaxel. Here two drugs are incorporated together to get synergistic effect as showen in figure 3.

left32639000
2)Doxorubicin as core drug and surface coated with TNF related apoptosis-inducing ligand.

Human serum albumin (HSA) nanoparticles (NPs) surface modified with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and transferrin, and containing doxorubicin were designed to get multiple site targeting actions. This is depicted in figure 4 below.

Figure 3: curcumin paclitaxel nanoparticles349256096000
Figure SEQ Figure * ARABIC 4: Doxorubicin and surface modified nanoparticleFormulation in clinical trial:Other than that, 1) Nanoparticle Albumin-Bound Rapamycin in treating Patient with Advanced Cancer With mTOR Mutations, 2) Gemcitabine Hydrochloride, Paclitaxel Albumin-Stabilized Nanoparticle Formulation, Metformin Hydrochloride, and a Standardized Dietary Supplement in Treating Patients with Pancreatic Cancer that Cannot be Removed by Surgery. 3) Nanoparticle Albumin-Bound (Nab) Paclitaxel/Cyclophosphamide in Early-Stage Breast Cancer studies are under clinical trials which includes albumin as a carrier system for drug release.

Paclitaxel(Abraxane)Introduction
Paclitaxel is an anti-cancer drug, commercially available as Taxol®, and has been widely used as a chemo-therapeutic agent for the treatment of different cancer types, such as breast, ovarian and lung cancer .Due to toxic effects of formulations on normal cells, Paclitaxel was used in combination with HSA-NPs (Abraxane®) for site-specific delivery .This has led to improved tumor targeting by enhancement of the permeability and retention effect which was opposed to administration of free drugs.

This formulation is already in market with Trade Name: Abraxane, Generic Name: paclitaxel protein-bound particles for injectable Suspension, Sponsor: Abraxis BioSciences, Approval Date: October 11, 2012
Paclitaxel is widely used for the treatment of solid tumors, it is the solvent used in the commercial formulation of solvent-based (sb)-paclitaxel, polyoxyethylated castor oil (Kolliphor® EL, formerly known as Cremophor EL is associated with severe, sometimes fatal hypersensitivity reactions. To reduce the risk of hypersensitivity reactions with sb-paclitaxel, patients were pretreated with corticosteroids and antihistamines. some of the studies have shown that Kolliphor EL can entrap paclitaxel in solvent micelles, due to which less drug is available to enter tumors, thereby limiting its clinical efficacy.

Abraxane® (ABI-007) is albumin-bound, solvent-free, paclitaxel nanoparticle was approved for metastasis breast cancer. After a while supplemental New Drug Application (sNDA), application was seeking a regulatory approval of the use of abraxane® in combination with carboplatin to get synergistic effect in non-small cell lung cancer in 2014 potentially for candidates who are not undergoing curative surgery or radiation therapy.

Mechanism of actionFigure 5: formulation release mechanism
left698500nab-paclitaxel over sb-paclitaxel include enhanced transport of paclitaxel across endothelial cells and greater delivery of paclitaxel to tumors. As nab-paclitaxel is formulated with albumin, it is assumed that the drug uses endogenous albumin transport pathways, including receptor mediated transcytosis, to cross endothelial cell monolayers and enter tumors. In a preclinical study, fourfold more nab-paclitaxel was transported across endothelial cells than sb-paclitaxel. Nab-paclitaxel, finds a way into the tumor microenvironment via the enhanced permeation and retention effect, which proposes that molecules are able to escape the circulation through gaps between endothelial cells resulting from leaky vasculature around tumors, as showen in figure 5. Here glycoprotein (gp60) is highly expressed in endothelial cells around tumors, and albumin bind to gp60, forming caveolae of albumin–gp60 complex. This complex traverse to the tumor interstitium via gp60-mediated active transcytosis pathway.

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Figure 6: Marketed product Figure 7: albumin bound to paclitaxil
Formulation
Abraxane, albumin-bound nanoparticles had mean particle size of approximately 130 nanometres. It exists in the particles in a non-crystalline, amorphous state and supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 ml of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-use vial contains 100 mg of paclitaxel and 900 mg of human albumin (containing sodium caprylate and sodium acetyltryptophanate as protein stabilizers. Each (ml) of reconstituted suspension contains 5 mg paclitaxel.

Treatment
Std Taxol (175 mg/m2 IV over 3 h with premedication) with steroid or antihistamine premedication, granulocyte colony-stimulating factor (G-CSF) support, special IV infusion sets, or in-line filters was given to different set of people. It was repeated every 3 weeks until disease progression or unacceptable toxicity occurred. Dose reductions (from 260 to 200 mg/m²) were permitted for grade 4 hematologic toxicity, neutropenic fever or sepsis and grade 3 or 4 non-hematologic toxicity. If any of these adverse events (AEs) recurred after the initial resolution and reinitiation of Abraxane dosing, a second dose reduction (to 130 mg/m²) was recommended for all subsequent cycles. Patients who experienced a further recurrence of the dose-limiting AEs were withdrawn from the study.

Disease Dose Frequency
Metastatic Breast Cancer 260 mg/m² intravenously
over 30 minutes. every 3 weeks
Non-Small Cell Lung Cancer 100 mg/m² intravenously over 30 minutes Days 1, 8, and 15 of
each 21-day cycle
Adverse reaction
The most common adverse reactions (? 20%) in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea.
The most common adverse reactions (? 20%) in NSCLC when used in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, and nausea.

Result

conclusionIn this large, international phase III study, ABI-007, a novel 130 nanometer albumin-bound paclitaxel particle, was superior to standard paclitaxel for both ORR and TTP in all
patients with MBC. 50% higher than the dose delivered with solvent-based Paclitaxel.

Paclitaxel particles were well tolerated, requiring minimal dose modification for AEs, and no
severe hypersensitivity reactions to ABI-007 occurred despite the absence of corticosteroid
premedication
Preclinical models demonstrated increased antitumor activity and higher intratumor paclitaxel concentrations for ABI-007 compared with equal doses of standard paclitaxel. In addition, ABI-007 was less toxic than standard paclitaxel.

Abraxane is a novel, albumin-stabilized, 130-nanometer particle form of paclitaxel, as it does not utilize Cremophor for drug delivery.

Pharmacokinetic parameters were linear over the clinically relevant dose range.

use of a second-generation paclitaxel formulation in patients with advanced NSCLC showed good performance status.

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