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Monoclonal Antibodies in Nanosystems as a Strategy for Cancer Treatment

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Cancer Nanotechnology

Abstract

Monoclonal antibodies (mAbs) are valuable therapeutic tools for targeted therapies to attack tumor cells but preserve healthy tissues, therefore resulting in fewer side effects. With the rise of genetic engineering, recombinant human or humanized mAbs are available in the market for the treatment of cancer, either in monotherapy, in association or conjugated with other drugs. Thus, monovalent or bispecific mAbs find applicability for their antitumor cytotoxic activity, as well as for being able to be used in cancer immunotherapy. Although some antibody-drug conjugates are commercially available, immunoconjugates with nanoparticles are less developed. In this context, nanoparticles play an important role for improving drug delivery, allowing for controlled release and site-specific delivery, both passively, through the enhanced permeation and retention effect, and actively, through the functionalization of nanoparticles with antibodies or antibody fragments with high affinity for receptors overexpressed on tumor cells. The bioconjugation can be performed mainly by adsorption or covalent binding or through the use of adapter molecules. Immobilization of antibodies on the surface of nanoparticles must ensure the desired amount of antibodies per nanoparticle and proper antibody orientation and generate a stable binding in order to preserve its biological activity. In this chapter, the main strategies for conjugating antibodies to nanoparticles through covalent bonds, such as the chemistry of carbodiimide, maleimide, and click, and non-covalent bonds such as adsorption and the biotin-avidin system will be discussed. Herein, we will address the development of monoclonal antibodies, the functionalization strategies, and antibody-receptor-targeted nanoparticles of different compositions, such as lipid, polymeric, and inorganic, focusing on their preparation techniques, physicochemical characterization, and in vitro and in vivo biological activity. Overall, the main bioconjugation technique is provided by the maleimide chemistry, particularly employed in the functionalized of lipid nanoparticles, such as liposomes, the most advanced nanosystem. Cell culture studies have revealed that the functionalized nanoparticle undergoes specific and efficient uptake via receptor-mediated endocytosis. Nanoparticle immunoconjugates have also shown promising for cancer treatment following the success of preclinical studies with cancer xenografts; however, clinical trials have yet to show efficacy and safety.

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Abbreviations

2-MEA:

β-Mercaptoethylamine

5-FU:

5-Fluorouracil

A549:

Adenocarcinomic human basal alveolar epithelial cells

Abs:

Antibodies

Ab-SH:

Antibody with sulfhydryl thiolation reaction

ADC:

Antibody-drug conjugate

ADCC:

Antibody-dependent cellular cytotoxicity

AMF:

Magnetic fields

anti-GPC3:

Anti-glypican-3 antibody

AuNPs:

Inorganic gold nanoparticles

BME:

β-Mercaptoethanol

BsAbs:

Bispecific antibodies

BT474:

Human breast carcinoma with HER2 overexpression

BVZ:

Bevacizumab

C:

Constant

Calcein-AM:

Calcein acetoxymethyl ester

CDC:

Antibody-mediated complement-dependent cytotoxicity

CDR:

Complementarity-determining regions

CET:

Cetuximab

Chi:

Chitosan

CMD:

Carboxymethyl dextran

CNBr:

Cyanogen bromide

CPT:

Camptothecin

CTLA-4:

Cytotoxic T lymphocyte-associated antigen 4

CuAAC:

[3+2] Azide-alkyne cycloaddition reaction catalyzed by copper(I)

DA:

Diels-Alder reaction

DMF:

Dimethylformamide

DMSO:

Dimethyl sulfoxide

DNA:

Deoxyribonucleic acid

DOX:

Doxorubicin

DSPE:

1,2-Distearoyl-sn-glycero-3-phosphorylethanolamine

DSPE-PEG2000:

1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]

DSPS:

1,2-Distearoyl-sn-glycero-3-phosphocholine

DTT:

Dithiothreitol

DTX:

Docetaxel

EDC:

1-Ethyl-3-(-3-dimethylaminopropyl) carbodiimide

EGFR vIII:

Epidermal growth factor receptor variant III

EGFR:

Epidermal growth factor receptor

EPR:

Enhanced permeability and retention

Fab:

Antigen-binding fragments

Fc:

Crystallizable fragment

FDA:

Food and Drug Administration

FITC:

Fluorescein isothiocyanate

FRET:

Fluorescence resonance energy transfer

GPC3:

Glypican-3

H:

Heavy

HACA:

Human anti-chimeric antibodies

HAMA:

Human anti-mouse antibodies

HCC:

Hepatocellular carcinoma

HCC827:

Lung cancer cell line

HCT 116:

Human colon cancer cell line

HepG2:

Hepatocellular carcinoma cell line

HER:

Herceptin

HER2:

Human epidermal growth factor receptor-type 2

HGC-27:

Human gastric carcinoma cell line derived from the metastatic lymph node of gastric cancer (undifferentiated carcinoma)

HKH-2:

Human colon cancer cell line

ICP-MS:

Inductively coupled plasma mass spectrometry

iEDDA:

Inverse electron demand hetero-Diels-Alder reaction

L:

Light

LN:

Lipid nanoparticles

mAb:

Monoclonal antibodies

MAC:

Membrane attack complex

Mal:

Maleimide

MCF-7:

Human breast cancer cell line

MDA-MB-231:

Breast cancer strain isolated from pleural effusion with low expression of HER2

MDA-MB-453:

Human breast cancer cell line

MEA:

2-Mercaptoethylamine

MES:

2-(N-Morpholino)ethanesulfonic acid

MGC-803:

Human gastric cancer cell line

MKN-45:

Gastric adenocarcinoma cells

MMAE:

Monomethyl auristatin E

MRI:

Magnetic resonance imaging

MSNPs:

Mesoporous silica nanoparticles

MTT:

Bromide of (4,5-dimetilltiazol-2-il)-2,5-difeniltetrazolium

mV:

Millivolts

NB:

Nanobubble

NHS:

N-Hydroxysuccinimide

NK:

Natural killer cell

NLC:

Nanostructured lipid carriers

nm:

Nanometer

NP:

Nanoparticle

P123:

Pluronic

PANC-1:

Human pancreatic cancer cell line isolated from pancreatic carcinoma of ductal cell origin

PCL:

Poly(ε-caprolactone)

PD-1:

Programmed cell death receptor 1

PD-L1:

Programmed death ligand 1

PDLA:

Poly(D-lactic acid)

PDLLA:

Poly(D,L-lactic acid)

PEG:

Polyethylene glycol

PGA:

Poly(glycolic acid)

pH:

Hydrogen potential

pI:

Isoelectric point

PLA:

Poly(lactic acid)

PLGA:

Poly(lactide-co-glycolide)

PLLA:

Poly(L-lactic acid)

PTT:

Photothermal therapy

PTX:

Paclitaxel

QD:

Quantum dots

RAPA:

Rapamycin

RES:

Reticuloendothelial system

SAMSA:

S-Acetylmercaptosuccinic anhydride

SATA:

N-Succinimidyl S-acetylthioacetate

SATP:

N-Succinimidyl S-acetylthiopropionate

scFv:

Single-chain variable fragment

SFB:

Sorafenib

SIA:

N-Succinimidyl iodoacetate

SKBR-3:

Human breast cancer cell lines that overexpress HER2

SLNs:

Solid lipid nanoparticles

SMCC:

Succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate

SMPT:

4-Succinimidyloxycarbonyl-α-methyl-α-[2-pyridyldithio]toluene

SPAAC:

Strain-promoted [3+2] azide-alkyne cycloaddition reaction

SPDP:

N-Succinimidyl 3-(2-pyridyldithio)propionate

SPIONs:

Superparamagnetic nanoparticles

Sulfo-LC-SMPT:

Sulfosuccinimidyl 6-[α-methyl-α-(2-pyridyldithio)toluamido]hexanoate

Sulfo-LC-SPDP:

Sulfosuccinimidyl 6-[3′-(2-pyridyldithio)propionamido]hexanoate

Sulfo-NHS:

N-Hydroxysulfosuccinimide

Sulfo-SMCC:

Sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate

TCEP:

Tris-(2-carboxyethyl)phosphine

TCO:

Trans-cyclooctene

THF:

Tetrahydrofuran

THPP:

Tris-(3-hydroxypropyl)phosphine

Tmab:

Trastuzumab

TMZ:

Temozolomide

TPGS:

D-α-Tocopheryl polyethylene glycol succinate

TPGS-COOH:

Carboxyl-terminated TPGS

Tz:

Tetrazine diene

U87MG vIII:

Glioblastoma cells expressing mutant epidermal growth factor VIII receptor

U87MG:

Cell line with epithelial morphology isolated from malignant gliomas

US:

Ultrasound

V:

Variable

VEFGA:

Vascular endothelial growth factor A

VEGF:

Vascular endothelial growth factor

WHO:

World Health Organization

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Acknowledgments

This work was supported by the National Council for Scientific and Technological Development (CNPq) (grants # 409362/2018-2; #409352/2018-7).

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Authors and Affiliations

  1. Federal University of Ceará, Faculty of Pharmacy, Dentistry and Nursing, Department of Pharmacy, Fortaleza, Brazil

    João Vito Barroso de Freitas, Alice Vitoria Frota Reis, Alan Denis Olivindo Silva, Ana Carolina Cruz de Sousa, Thais da Silva Moreira & Josimar O. Eloy

  2. Federal University of Ceará, Northeast Network in Biotechnology – Renorbio, Fortaleza, Brazil

    Jéssica Roberta Pereira Martins

  3. Federal University of Ceará, Center of Technology, Department of Chemical Engineering, Fortaleza, Brazil

    Karina Alexandre Barros Nogueira

  4. University for International Integration of the Afro-Brazilian Lusophony, Institute of Health Sciences, Redenção, Brazil

    Raquel Petrilli

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  1. João Vito Barroso de Freitas
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Correspondence to Josimar O. Eloy .

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  1. University of Beira Interior, CICS-UBI – Health Sciences Research Centre, Covilhã, Portugal

    Ângela Maria Almeida de Sousa

  2. School of Pharmaceutical Sciences, São Paulo State University, São Paulo, Brazil

    Christiane Pienna Soares

  3. School of Pharmaceutical Sciences, São Paulo State University, São Paulo, Brazil

    Marlus Chorilli

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de Freitas, J.V.B. et al. (2023). Monoclonal Antibodies in Nanosystems as a Strategy for Cancer Treatment. In: Almeida de Sousa, Â.M., Pienna Soares, C., Chorilli, M. (eds) Cancer Nanotechnology. Springer, Cham. https://doi.org/10.1007/978-3-031-17831-3_5

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