Albumin and functionalized albumin nanoparticles: production strategies, characterization, and target indications

Abhishek Srivastava; Anjali Prajapati

doi:10.1515/abm-2020-0032

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Albumin and functionalized albumin nanoparticles: production strategies, characterization, and target indications

Asian Biomedicine

Volume 14 (2020): Issue 6 (December 2020)

By: Abhishek Srivastava and Anjali Prajapati

Open Access

|Dec 2020

Figures & Tables

Various processes for the preparation of albumin nanoparticles.

Desolvation process for preparation of albumin nanoparticles.

Chemical cross-linking of albumin nanoparticles.

Table 1

Process parameters for production of albumin nanoparticles by desolvation

Albumin used	Preparation conditions	Particle diameter (nm), approximate	Zeta potential	Reference
HSA	HSA: 100 mg/mL in 10 mM NaCl, pH: 8.2; ethanol addition rate: 1 mL/min; cross-linker: 8% glutaraldehyde; stirring rate: 500 rpm	150	–44 mV	[18]
BSA + HSA	Protein: 250 mg/4 mL; stirring rate: 1,250 rpm; desolvating agent: ethanol; cross-linker: 5 mg EDC; stirring time: 3 h	100	BSA: −35 mV HSA: −29.6 mV	[35]
BSA	BSA: 50 mg/mL in 10 mM NaCl, pH: 7; cross-linker: 8% glutaraldehyde; desolvating agent: ethanol	100	–	[36]
BSA	BSA: 100 mg in 10 mM NaCl, pH: 7.0; ethanol addition rate: 1 mL/min; cross-linker: 8% glutaraldehyde; stirring rate: 500 rpm; stirring time: 30 min	100–300	–	[37]
BSA	BSA: 1% solution, pH: 6.0; ethanol addition rate: 1 mL/min; cross-linker: glutaraldehyde; stirring rate: 700 rpm	100	–	[38]
BSA	BSA: 100 mg/mL, desolvating agent: ethanol; stirring rate: 500 rpm; pH: 8.2; cross-linker: 8% glutaraldehyde	139	–50 mV	[39]
Egg white	Egg white: 10%, pH 7.0; desolvating agent: ethanol; stirring rate: 550 rpm; cross-linker: 8% glutaraldehyde	100	–28 mV	[40]

[i] BSA, bovine serum albumin; EDC, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; Egg white = crude ovalbumin; HSA, human serum albumin.

Preparation of drug-loaded albumin nanoparticles using desolvation process.

Preparation of drug-loaded folic acid-decorated albumin nanoparticles.

Table 2

Characterization, target indications, drug release pattern, and cytotoxicity of albumin and functionalized albumin nanoparticles prepared by desolvation process

Albumin used	Functionalizing or conjugating agent	Drug or antioxidant loaded	Target indication	Outcome or application^†	Reference
Egg albumin	–	Curcumin (CUR)	–	Particle diameter: 232 nm, DLC: 4.125%, DEE: 55% Enhanced solubility of CUR RSM was used for process optimization	[32]
HSA	–	Doxorubicin	Neuroblastoma (UKF-NB3 and IMR-32 cell lines)	Particle diameter: 158.5 nm, ZP: −31.9 mV, DEE: 95% Stable up to 6 months at 4 °C Increased inhibition of UKF-NB3 and IMR-32 cell lines, compared with free doxorubicin	[43]
BSA	–	Ginsenoside CK	Lung, skin, colon cancer, and hepatocarcinoma (A549, HaCaT, HT29, and HepG2 cell lines)	Particle diameter: 30–50 nm, ZP: −70.8 mV. Nanoparticles were stable at biological pH and were readily degraded in acidic conditions, enhanced water solubility of ginsenoside CK. Increased antiproliferative activity toward HT29, A546, HepG2, and HaCaT cancer cell lines.	[44]
BSA	–	Salicylic acid (SA)	–	Particle diameter: 110 nm, ZP: −33.2 mV, DEE: 55% at pH 7.4 Increases the bioavailability of SA Instant release, progressive up to 120 min, then constant release of SA up to 400 min	[33]
BSA	Folic acid	Tamoxifen (TMX)	Breast cancer	Particle diameter: 76–417 nm, ZP: −10 to −43 mV Folic acid: for selective delivery of TMX Rapid in the first 2 h, followed by sustained release of TMX up to 24 h. Enhanced release in acidic conditions • Enhanced cellular uptake and effective in reducing carcinoma cell survival	[46]
BSA	Folic acid	Bexarotene (BXT)	Breast cancer (MCF-7 cell line)	Particle diameter: 195.3 nm, ZP: −33.64 mV, DEE: 65%, DLC: 1.7% Folate receptors are overexpressed in MCF-7 Initial burst release (39% in 12 h), followed by up to 69% of slow release of BXT in 48 h, then sustained release up to 72 h • Greater antiproliferative effect on MCF-7 cells	[47]
HSA	Folic acid and magnetic nanoparticles	Cisplatin	–	Particle diameter: 9 nm, DLC: 5.3%, DEE: 90% Folate receptors are overexpressed in cancer cells • Sustained release of cisplatin for 24 h without burst release • The nanocarrier has selective chemotherapy action, along with thermotherapy	[48]
BSA	Folic acid	Chrysin (CHA)	Breast cancer (MCF-7 cell line)	Particle diameter: 97.5 nm, ZP: −11.0 mV Folate receptors are overexpressed in cancer cells • Initial burst (20%) in 10 h, followed by cumulative 57% sustained release of CHA up to 96 h • Enhanced cellular uptake and cytotoxicity toward MCF-7 cell line	[49]
HSA	PEI	Gallic acid (GA)	Parkinson disease (PC-12 neuroendocrine cell line)	Particle diameter: 117 nm and 180 nm, ZP: +35.2 mV and +34.2 mV, respectively • DLC and DEE depend on GA-to-PEI-HSA ratio, Initial burst (30%) in 1.5 h, followed by sustained release of GA up to 48 h. No significant toxicity toward PC-12 cells	[50]
HSA	PEI	Doxorubicin	Breast cancer (MCF-7 cell line)	Particle diameter: 137 nm, ZP: +15 mV 80% of cells were transfected due to positive surface charge • Exhibited greater cytotoxic effect against MCF-7 cancer cell lines	[51]
HSA	PEG	Tamoxifen (TMX)	Tumor target	Particle diameter: 195 nm, ZP: −21 mV, DEE: 74%, DLC: 7% Only a slight increase in particle size after 3 months of storage • Ultrasonication of TMX-HSA mixture was done before desolvation	[52]
BSA	Lactobionic acid	Oridonin (ORI)	Liver cancer	Particle diameter: 200 nm, ZP: −30 mV, DLC: 5%, DEE: 63% Galactosylated BSA: for selective liver targeting • Initial burst, followed by sustained release of ORI up to 70 h.	[53]
BSA	Galactosamine	Doxorubicin (DOX)	Hepatocarcinoma (HepG2 cell line)	Particle diameter: 200 nm, ZP: −16.1 mV, DEE: 58%, DLC: 2% Asialoglycoprotein receptors are overexpressed in HepG2 cells • Slow release (5% in 5 h), followed by 12% sustained release of DOX up to 160 h • Increased cellular uptake causes more cytotoxicity toward HepG2 cells.	[54]
HSA	–	Paclitaxel and gold nanorods	Breast cancer (4T1 cell line in mouse)	Particle diameter: 221 nm, ZP: −45 mV, DEE: 92% combined (chemo + photothermal) therapy • 94% of 4T1 cell death on 15-min exposure to near-infrared light	[57]
BSA	Polycaprolactone (PCL)	Albendazole (ABZ)	Pancreatic cancer	Particle diameter: 10 and 200 nm, DEE: 68% (10 nm) and 81% (100 nm) BSA-PCL nanoparticles of 200 nm effectively deliver ABZ to pancreatic cells and show a greater antiproliferative effect on cancer cells	[58]
HSA	SP and PEG	Paclitaxel (PTX)	Brain cancer	Particle diameter: 150 nm, ZP: −12.0 mV, DLC: 8%, DEE: 86% Substance P (SP) receptors are overexpressed in glioma sites • Initial burst (40%), followed by the sustained release of PTX up to 48 h • The targeting effect of SP increases the cellular uptake and nanoparticles exhibit strong antitumor effect toward U87 cells	[59]
BSA	Magnetic nanoparticles	–	–	Particle diameter: 70–95 nm, ZP: −9.38 mV Biocompatible and do not show a toxic effect on HFF2 cell lines • Can be used in MRI technique and chemothermotherapy	[60]
BSA	Magnetic nanoparticles	Curcumin (CUR)	Breast cancer (MCF-7 cell line)	Particle diameter: 56 nm, ZP: −10.1 mV, DLC: 7% Initial burst, followed by sustained release of CUR up to 160 h. Enhanced release in acidic conditions • Biocompatible and showed a significant cytotoxic effect on MCF-7 cells	[61]
BSA	–	Curcumin (CUR)	Breast cancer (MDA-MB-231 cell line)	Particle diameter: 223.5 nm, ZP: −31.7 mV, at drug polymer ratio of 1:2, DEE: 91%. Enhancement in the solubility of CUR Initial burst (23%) in 24 h, followed by the sustained release of CUR up to 30 days • Enhanced antiproliferative effect toward MDA-MB-231	[62]
Egg albumin	–	Gallic acid (GA)	Brain cancer	Particle diameter: 150 nm, ZP: −30 mV, DLC: 28%, DEE: 91% A good candidate for brain-targeted drug delivery system	[63]
BSA	–	Sulfasalazine (SSZ)	–	Particle diameter: 208–381 nm, ZP: −24.6 to −36.3 mV, DLC: 0.5%, DEE: 28% Enhanced solubility of SSZ	[64]
BSA	–	Curcumin (CUR)	Breast cancer (MCF-7 cell line)	Particle diameter: 92.6 nm, ZP: −9.2 mV, DLC: 2.2%, DEE: 78% Rapid in 10 h (20%), followed by controlled release of 30% of CUR up to 96 h • Cytotoxic toward MCF-7, inhibitory effect increases with time	[65]
HSA	–	Doxorubicin (DXR), daunorubicin (DNR), pirarubicin (THP), and aclarubicin (ACR)	Breast cancer (MCF-7 cell line)	DXR-HSA-NPs: particle diameter: 108 nm, ZP: −35 mV, DLC: 4%, DEE: 96% DNR-HSA-NPs: particle diameter: 109 nm, ZP: −33 mV, DLC: 6%, DEE: 97% THP-HSA-NPs: particle diameter: 121 nm, ZP: −43 mV, DLC: 2.6%, DEE: 88% ACR-HSA-NPs: particle diameter: 119 nm, ZP: −45 mV, DLC: 1%, DEE: 30% All anthracycline-HSA-NPs exhibit cytotoxicity toward MCF-7 and HepG2 cells	[66]
HSA	–	Pyrazolo[3,4-d] pyrimidine	Neuroblastoma (SH-SY5Y cell line)	Particle diameter: 50–115 nm, ZP: −29.9 mV, DEE: 40%–99.5%., DLC: 39%–95% Improved drug solubility • Enhanced antiproliferative effect on SH-SY5Y.	[67]
BSA	Folic acid	Curcumin difluorinated (CDF)	Ovarian cancer (SKOV 3 cell line)	Particle diameter: 279 nm, ZP: −45.9 mV, DEE: 78%, DLC: 38% Higher cellular uptake causes enhanced cytotoxicity	[68]

† All particle diameters are approximate; BSA, bovine serum albumin; DEE, drug entrapment efficiency (approximate); DLC, drug-loading capacity (approximate); Egg albumin = ovalbumin; HSA, human serum albumin; MRI, magnetic resonance imaging; PEG, polyethylene glycol; PEI, polyethylenimine; RSM, response surface methodology; ZP, zeta potential.

Preparation of drug-loaded albumin nanoparticles using emulsification.

Table 3

Characterization, target indications, drug release pattern, and cytotoxicity of albumin and functionalized albumin nanoparticles prepared by emulsification

Albumin used	Organic phase and surfactant	Functionalizing or coating agent	Drug or antioxidant loaded	Target indication	Outcome or application^†	Reference
HSA in water	Chloroform + ethanol	–	Paclitaxel (PTX)	Breast cancer (MCF-7 cell line)	Particle diameter: 170.2 nm, ZP: −17.4 mV, DEE: 82% 64% of PTX release in 48 h • Concentration-dependent cell viability for MCF-7 cells • IC₅₀ for PTX-HSA-NPs is 4.9 μm	[19]
BSA in NaOH	Castor oil + Span 80	–	10-Hydroxycamptothecin (HCPT)	Liver cancer	Particle diameter: 600 nm, DEE: 58%, DLC: 2.2% Sustained release of 90% HCPT at pH 7.4 in trypsin medium • Higher concentration of HCPT in liver than in heart and kidney • 95% of HCPT was present in the lactone form	[74]
HSA in water	Chloroform + acetone + cholesterol	Chitosan, PLG-PEG	Teniposide (TS)	Lung cancer (A549 cell line)	Particle diameter: 180 nm, ZP: −4 mV, DEE: 61%., DLC: 2.2% Lower concentration of TS in heart and kidney • 80% of TS release in 72 h • Lower cellular uptake and antitumor efficacy toward A-549.	[75]
BSA in PBS (w₁)	Tween 80 (o) Aqueous solution of PLGA (w₂)	–	–	–	Double emulsion technique was used. Addition of NaCl and glucose increases entrapment efficiency and delays the release of BSA Tween 80 increases BSA entrapment	[76]
BSA in water	B_mimPF₆ + Tween 20	Folic acid	–	–	Particle size: 100 nm. Enhanced cellular uptake • Folate receptors are overexpressed in cancer cells • Exhibit high cell viability	[77]
BSA in water	n-Butanol + toluene + coconut oil	–	–	–	Particle diameter: 269 nm. Green method of synthesis	[78]
HSA in water	Ethanol + Tween 80	–	Carvacrol	Gastric cancer (AGS cell line)	Particle diameter: 230 nm, ZP: −33.7 mV, DEE: 32%, DLC: 32% Initial fast release (27% in 3 h), followed by sustained release of carvacrol (80%) up to 240 h • Reduces cell viability (AGS cell line) to 50%.	[79]

† Particle diameters are approximate; B_mimPF₆, 1-butyl-3-methylimidazolium hexafluorophosphate, BSA, bovine serum albumin; DEE, drug entrapment efficiency (approximate); DLC, drug-loading capacity (approximate); HSA, human serum albumin; IC₅₀, half-maximal inhibitory concentration; o, organic phase; PBS, phosphate-buffered saline; PEG, polyethylene glycol; PLG, poly(l-glutamic acid)-g-methoxy; PLGA, poly(d,l-lactic-co-glycolic acid); W1, internal aqueous phase; W2, external aqueous phase; ZP, zeta potential.

Thermal gelation process for the preparation of drug-loaded albumin nanoparticles.

Table 4

Characterization, target indications, drug release pattern, and cytotoxicity of albumin and functionalized albumin nanoparticles prepared by thermal gelation

Albumin used	Temperature, time, pH	Functionalizing or conjugating agent	Drug or antioxidant loaded	Target indication	Outcome or application^†	Reference
Egg albumin in water	80 °C, 30 min, 5.4	Chitosan, PEG400	Alprazolam (ALP)	–	Particle diameter: 260 nm, ZP: −9.0 mV, DEE: 99.4%. Initial burst, then sustained release of ALP (85%) up to 24 h • Excellent carrier for sustained delivery of lipophilic drugs	[81]
Egg albumin in water	80 °C, 30 min, 5.4	Chitosan, Carbopol 940	Aceclofenac (ACA)	–	Particle diameter: 353 nm, ZP: −22.1 mV DEE: 96%. Initial burst, then slow release of ACA (54%–88%) in 8 h • Carbopol 940 gel containing NPs exhibited faster permeation of ACA	[82]
BSA in water	90 °C, 2 h, 4.2	Chitosan (CS)	β-Carotene (CRT)	–	DEE: 46%, DLC: 9.3% Hydrodynamic radius: 70–100 nm. CS-BSA NPs were prepared by electrostatic adsorption, followed by thermal treatment	[83]

† Particle diameters are approximate; BSA, bovine serum albumin; Egg albumin = ovalbumin; DEE, drug entrapment efficiency (approximate); DLC, drug-loading capacity (approximate); PEG, polyethylene glycol; ZP, zeta potential.

Preparation of drug-loaded albumin nanoparticles using nab technology.

Table 5

Characterization, target indications, drug release pattern, and cytotoxicity of albumin and functionalized albumin nanoparticles prepared by nab technology

Albumin used	Organic phase	Functionalizing or conjugating agent	Drug or antioxidant loaded	Target indication	Outcome or application	Reference
HSA in water	Chloroform + ethanol mixture	–	Tacrolimus (TAC)	Rheumatoid arthritis	Particle diameter: 186 nm, ZP: −30.5 mV, DEE: 79%, DLC: 1.5% Increased solubility (46 times) in water than free TAC 94% release of TAC in 24 h • Excellent tumor targeting and antiarthritic activity	[84]
HSA in water	Chloroform	–	Gem-C14	Pancreatic cancer	Particle diameter: 150 nm, ZP: −10.2 mV, DEE: 83%., DLC: 10% 82% of slow GEM release in 90 h • An excellent inhibitory effect on tumor growth in the BxPc-3 cell line	[85]
HSA in water	Mixed organic phase	–	Gambogic acid (GmA)	Lung cancer	Particle diameter: 135 nm, ZP: −21.81 mV, DEE: 99.3%, DLC: 11% Nanopowder is stable for up to 12 months • 69% of slow GmA release in 72 h • Increased TGI than GmA and GmA-Arg in A549-bearing mice.	[86]
BSA in water	Chloroform + ethanol mixture	Lactobionic acid	Doxorubicin (DOX) and paclitaxel (PTX)	Liver cancer	Particle diameter: 148 nm, ZP: −54.1 mV 84% PAC and 73% DOX release in 24 h • Lactose residue exhibits high receptor affinity toward ASGPR 62% internalization in HepG2 cells • Improved therapeutic efficacy against HepG2 cells	[87]

† Particle diameters are approximate; ASGPR, asialoglycoprotein receptor; BSA, bovine serum albumin; DEE, drug entrapment efficiency (approximate); DLC, drug-loading capacity (approximate); Gem-C14, 4-N-myristoyl-gemcitabine; HSA, human serum albumin; TGI, tumor growth inhibition rate; ZP, zeta potential.

Preparation of drug-loaded albumin nanoparticles using self-assembly.

Table 6

Characterization, target indications, drug release pattern, and cytotoxicity of albumin and functionalized albumin nanoparticles prepared by self-assembly

Albumin used	Conjugating or disulfide reducing agent	Drug or antioxidant loaded	Self-assembly strategy	Target indication	Outcome or applications	Reference
HSA	β-Mercaptoethanol (β-ME)	Paclitaxel (PTX)	Disulfide bond breaking	Breast cancer (MCF-7 and A549 cell lines)	Particle diameter: 120 nm, ZP: −30.0 mV, DEE: 100%, DLC: 20% More stability and enhanced cytotoxicity toward MCF-7 and A549 cells • Longer survival of H22-bearing mice	[90]
HSA	Dithiothreitol (DTT)	Curcumin (CUR)	Disulfide bond breaking	H22 tumor-bearing mice	Particle diameter: 100 nm, DEE: 92%, DLC: 4% Initial 45% burst, followed by 100% release of CUR in >24 h • Enhanced accumulation of NPs in the cytoplasm of tumor cells • Accumulation of NPs in H22-bearing mice (at tumor sites), reaches the peak level after 28 h	[91]
BSA	Cholesterol	Paclitaxel (PTX)	Covalent conjugate	Breast cancer (B16F10 and MCF-7 cell lines)	Particle diameter: 146 nm, ZP: −20.0 mV, DEE: 95%, DLC: 38% Enhanced cellular uptake and cytotoxicity toward B16F10 and MCF-7 cancer cell lines • Much slower and prolonged release of PTX Longer survival of tumor-bearing mine	[92]
BSA	Aptamer AS1411	Doxorubicin (DOX)	Hydrophobic drug interaction	Breast cancer (MCF-7 cell line)	Particle diameter: 163 nm, ZP: −20.7 mV DEE: 78%, DLC: 4.4% Aptamer AS1411: for specific targeting as receptors are overexpressed on tumor cells • Increased cytotoxicity due to enhanced cellular uptake in MCF-7 cells	[93]
BSA	–	Curcumin (CUR)	Hydrophobic drug interaction	–	Particle diameter: 110 nm, DEE: 89%, DLC: 7% Ionic strength is the key parameter for nanoparticle production • Strong antioxidant activity and effective and neuroprotective effects on neuronal HT22 cells	[94]
HSA	PEG	Paclitaxel (PTX)	Covalent conjugation (film casting method)	Human breast cancer cell lines (SK-BR-3, MDA-MB-453 and MCF-7), SK-BR-3 tumor-bearing mice	Particle diameter: 280 nm, DEE: 86%, DLC: 8.7% Enhanced solubility and sustained release of PTX Prolonged and systemic circulation of nanoparticles after intravenous injection • Higher cytotoxicity in human breast cancer cell lines (SK-BR-3, MDA-MB-453, and MCF-7)	[95]

† Particle diameters are approximate; BSA, bovine serum albumin; DEE, drug entrapment efficiency (approximate); DLC, drug-loading capacity (approximate); HSA, human serum albumin; NPs, nanoparticles; PEG, polyethylene glycol; ZP, zeta potential.

Spray-drying process for the preparation of albumin nanoparticles.

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DOI: https://doi.org/10.1515/abm-2020-0032 | Journal eISSN: 1875-855X | Journal ISSN: 1905-7415

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Language: English

Page range: 217 - 242

Published on: Dec 31, 2020

Published by: Chulalongkorn University

In partnership with: Paradigm Publishing Services

Keywords:

albumin,

drug delivery systems,

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Assistive professions, nursing,

Basic medical science,

Basic medical science, other,

Clinical medicine,

Clinical medicine, other

© 2020 Abhishek Srivastava, Anjali Prajapati, published by Chulalongkorn University
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

Volume 14 (2020): Issue 6 (December 2020)

Albumin and functionalized albumin nanoparticles: production strategies, characterization, and target indications

Figures & Tables

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