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


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Figure 1

Various processes for the preparation of albumin nanoparticles.
Various processes for the preparation of albumin nanoparticles.

Figure 2

Desolvation process for preparation of albumin nanoparticles.
Desolvation process for preparation of albumin nanoparticles.

Figure 3

Chemical cross-linking of albumin nanoparticles.
Chemical cross-linking of albumin nanoparticles.

Figure 4

Preparation of drug-loaded albumin nanoparticles using desolvation process.
Preparation of drug-loaded albumin nanoparticles using desolvation process.

Figure 5

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

Figure 6

Preparation of drug-loaded albumin nanoparticles using emulsification.
Preparation of drug-loaded albumin nanoparticles using emulsification.

Figure 7

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

Figure 8

Preparation of drug-loaded albumin nanoparticles using nab technology.
Preparation of drug-loaded albumin nanoparticles using nab technology.

Figure 9

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

Figure 10

Spray-drying process for the preparation of albumin nanoparticles.
Spray-drying process for the preparation of albumin nanoparticles.

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

Albumin usedFunctionalizing or conjugating agentDrug or antioxidant loadedTarget indicationOutcome or applicationReference
Egg albuminCurcumin (CUR)

Particle diameter: 232 nm, DLC: 4.125%, DEE: 55%

Enhanced solubility of CUR

RSM was used for process optimization

[32]
HSADoxorubicinNeuroblastoma (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]
BSAGinsenoside CKLung, 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]
BSASalicylic 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]
BSAFolic acidTamoxifen (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]
BSAFolic acidBexarotene (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]
HSAFolic acid and magnetic nanoparticlesCisplatin

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]
BSAFolic acidChrysin (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]
HSAPEIGallic 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]
HSAPEIDoxorubicinBreast 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]
HSAPEGTamoxifen (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]
BSALactobionic acidOridonin (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]
BSAGalactosamineDoxorubicin (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]
HSAPaclitaxel and gold nanorodsBreast 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]
BSAPolycaprolactone (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]
HSASP and PEGPaclitaxel (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]
BSAMagnetic 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]
BSAMagnetic nanoparticlesCurcumin (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]
BSACurcumin (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 albuminGallic 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]
BSASulfasalazine (SSZ)

Particle diameter: 208–381 nm, ZP: −24.6 to −36.3 mV, DLC: 0.5%, DEE: 28%

Enhanced solubility of SSZ

[64]
BSACurcumin (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]
HSADoxorubicin (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]
HSAPyrazolo[3,4-d] pyrimidineNeuroblastoma (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]
BSAFolic acidCurcumin 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]

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

Albumin usedOrganic phaseFunctionalizing or conjugating agentDrug or antioxidant loadedTarget indicationOutcome or applicationReference
HSA in waterChloroform + ethanol mixtureTacrolimus (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 waterChloroformGem-C14Pancreatic 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 waterMixed organic phaseGambogic 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 waterChloroform + ethanol mixtureLactobionic acidDoxorubicin (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]

Process parameters for production of albumin nanoparticles by desolvation

Albumin usedPreparation conditionsParticle diameter (nm), approximateZeta potentialReference
HSAHSA: 100 mg/mL in 10 mM NaCl, pH: 8.2; ethanol addition rate: 1 mL/min; cross-linker: 8% glutaraldehyde; stirring rate: 500 rpm150–44 mV[18]
BSA + HSAProtein: 250 mg/4 mL; stirring rate: 1,250 rpm; desolvating agent: ethanol; cross-linker: 5 mg EDC; stirring time: 3 h100BSA: −35 mVHSA: −29.6 mV[35]
BSABSA: 50 mg/mL in 10 mM NaCl, pH: 7; cross-linker: 8% glutaraldehyde; desolvating agent: ethanol100[36]
BSABSA: 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 min100–300[37]
BSABSA: 1% solution, pH: 6.0; ethanol addition rate: 1 mL/min; cross-linker: glutaraldehyde; stirring rate: 700 rpm100[38]
BSABSA: 100 mg/mL, desolvating agent: ethanol; stirring rate: 500 rpm; pH: 8.2; cross-linker: 8% glutaraldehyde139–50 mV[39]
Egg whiteEgg white: 10%, pH 7.0; desolvating agent: ethanol; stirring rate: 550 rpm; cross-linker: 8% glutaraldehyde100–28 mV[40]

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

Albumin usedOrganic phase and surfactantFunctionalizing or coating agentDrug or antioxidant loadedTarget indicationOutcome or applicationReference
HSA in waterChloroform + ethanolPaclitaxel (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 NaOHCastor oil + Span 8010-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 waterChloroform + acetone + cholesterolChitosan, PLG-PEGTeniposide (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 waterBmimPF6 + Tween 20Folic acid

Particle size: 100 nm.

Enhanced cellular uptake • Folate receptors are overexpressed in cancer cells • Exhibit high cell viability

[77]
BSA in watern-Butanol + toluene + coconut oil

Particle diameter: 269 nm.

Green method of synthesis

[78]
HSA in waterEthanol + Tween 80CarvacrolGastric 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]

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

Albumin usedTemperature, time, pHFunctionalizing or conjugating agentDrug or antioxidant loadedTarget indicationOutcome or applicationReference
Egg albumin in water80 °C, 30 min, 5.4Chitosan, PEG400Alprazolam (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 water80 °C, 30 min, 5.4Chitosan, Carbopol 940Aceclofenac (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 water90 °C, 2 h, 4.2Chitosan (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]

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

Albumin usedConjugating or disulfide reducing agentDrug or antioxidant loadedSelf-assembly strategyTarget indicationOutcome or applicationsReference
HSAβ-Mercaptoethanol (β-ME)Paclitaxel (PTX)Disulfide bond breakingBreast 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]
HSADithiothreitol (DTT)Curcumin (CUR)Disulfide bond breakingH22 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]
BSACholesterolPaclitaxel (PTX)Covalent conjugateBreast 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]
BSAAptamer AS1411Doxorubicin (DOX)Hydrophobic drug interactionBreast 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]
BSACurcumin (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]
HSAPEGPaclitaxel (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]
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