Table 3 Selected preclinical studies with nanotechnology in cancer treatment: applications, nanoparticles, and delivery systems

Li et al. 2013 [137]

Tumor model (KB cells)

Folic acid-targeted Fe3O4 NPs

PEI-mediated synthesis and PEGylation

• PEI-coated Fe3O4 NPs are stable and water-dispersible; cytocompatible and hemocompatible

• Successfully targeted KB cancer cells (FA receptors) in vitro and in vivo MR imaging of xenografted tumors

Li et al., 2014 [214]

Brain metastases of breast cancer

Poly(methacrylic acid)–polysorbate 80-grafted-starch nanoparticles

Multifunctional nanotheranostic system delivering doxorubicin (Dox) and imaging agents

• Confirmed extravasation of gadolinium and dye-loaded nanoparticles across the BBB in healthy mice

• Targetability of Dox-loaded nanoparticles to brain metastases assessed via imaging

• Coexistence of nanoparticles and Dox in tumors confirmed histologically

• Induced apoptosis in cancer cells 24 h post-injection while sparing normal cells

• Significantly inhibited tumor growth compared to free Dox at the same dose

Wei et al. [215]., 2014

Drug-resistant tumors expressing CD44 receptors

Cholesteryl-modified hyaluronic acid (CHA) nanogels

• CHA-drug conjugates with hydrophobic cores, loaded with etoposide, salinomycin, or curcumin

• Nanogels (20–40 nm) with up to 20% drug load

• Sustained drug release via hydrolysis of ester linkage

• 2–7 times higher cytotoxicity in CD44-expressing drug-resistant breast and pancreatic cancer cells compared to free drugs

• Efficient internalization via CD44-mediated endocytosis and membrane interaction

• Enhanced penetration and cytotoxicity in multicellular cancer spheroids

Gao et al., 2014 [138]

HCC

Polymer-lipid hybrid nanoparticles (PLNPs)

• Anti-EGFR antibody conjugated PLNPs loaded with adriamycin

• Improved cytotoxicity, targeted delivery, and tumor suppression in HCC

Goe et al., 2014 [143]

Glioblastoma

VEGF121-conjugated mesoporous silica nanoparticles

• Targeted PET imaging and sunitinib delivery

• Efficient drug delivery and enhanced imaging of glioblastoma tumors

Clark and Davis, 2015 [139]

Brain cancer

80-nm gold nanoparticles with transferrin (Tf) or anti-TfR antibodies

• Acid-cleavable linkage between Tf/Abs and nanoparticles for receptor-mediated transcytosis (RMT) across the BBB

• Tf-containing nanoparticles with cleavable linkages showed increased brain uptake compared to non-cleavable ones

• Antibody-based nanoparticles had lower uptake due to endothelium retention

Obaid et al. 2015 [144]

CRC adenocarcinoma (HT-29 cells) and breast adenocarcinoma (SK-BR-3 cells)

Water-soluble gold nanoparticles (AuNPs) conjugated with zinc phthalocyanine (C11Pc), PEG, and either jacalin (a lectin) or anti-HER-2 antibodies

• AuNPs for enhanced delivery of the photosensitizer

• C11Pc as a photosensitizer for photodynamic therapy (PDT)

• Jacalin to target the Thomsen-Friedenreich (T) antigen

• Anti-HER-2 antibodies to target HER-2 receptors

• Jacalin- and antibody-conjugated nanoparticles exhibited similar singlet oxygen generation and phototoxicity levels

• Targeted nanoparticles had significantly higher phototoxicity than non-conjugated nanoparticles

• Both conjugates are localized in lysosomes, indicating receptor-mediated endocytosis

• Targeting the T antigen with jacalin was as effective as targeting HER-2 with antibodies in PDT

Jørgensen et al., 2016 [145]

Human tumor xenografts in mice

Near-infrared resonant silica-gold nanoshells (AuNSs), solid gold nanoparticles (AuNPs)

• Single particle and PET-based platform

• AuNSs demonstrated superior heat generation and photothermal efficiency compared to AuNPs, both in vitro and in vivo

• PET imaging (using 18 F-FDG) successfully monitored early treatment response, validating the use of the platform for benchmarking plasmonic nanoparticles in cancer therapy

Kim MS et al., 2016 [147]

MDR cancer

Exosome-encapsulated paclitaxel (exoPTX)

• Natural exosome-based drug delivery

• Increased cytotoxicity and improved targeting in MDR cancer models

Sambade et al., 2016 [140]

NSCLC (brain metastases)

PRINT® PLGA nanoparticles of docetaxel and acid-labile C2-dimethyl-Si-docetaxel

• Intravenous injection of nanoparticle formulations of docetaxel and C2-dimethyl-Si-docetaxel (acid-labile)

• Intracranial tumor concentrations of PRINT-docetaxel were 13-fold higher and PRINT-C2-docetaxel sevenfold higher than small molecule (SM)-docetaxel

• C2-docetaxel conversion to docetaxel was threefold higher in tumor tissues compared to non-tumor tissues

• PRINT-C2-docetaxel increased median survival by 35% with reduced toxicity compared to other treatments

Yao et al., 2016 [216]

Breast cancer (4 T1 cells as model system)

Graphene Quantum Dots (GQDs)-Capped Magnetic Mesoporous Silica Nanoparticles (MMSN)

• MMSN nanoparticles loaded with doxorubicin (DOX) for chemotherapy, magnetic hyperthermia, and photothermal therapy

• MMSN/GQDs nanoparticles (100 nm) efficiently loaded DOX and triggered its release in a low pH environment

• MMSN/GQDs generated heat under an alternating magnetic field or near-infrared irradiation, achieving hyperthermia temperature

• Combined chemo-magnetic hyperthermia or chemo-photothermal therapy with DOX-loaded MMSN/GQDs significantly enhanced the therapeutic efficiency, killing more cancer cells compared to individual therapies

Xu et al., 2016 [149]

Breast cancer (MCF-7 cells)

Amine functionalized hydroxyapatite (NHAP) nanoparticles

• NHAP nanoparticles combined with anti-angiogenesis (ANG) plasmid for gene therapy

• ANG/NHAP nanoparticles were around 50 nm in diameter and showed effective plasmid condensation

• Cellular assays confirmed high transfection efficiency, low cytotoxicity, and significant anti-angiogenesis activity

• ANG/NHAP nanoparticles are suggested as a safe and effective drug delivery system for potential breast cancer gene therapy

Wen L et al., 2016 [157]

Deep-seated liver tumors

Single-wall carbon nanotubes

• Microwave-pumped thermoacoustic tumor therapy

• Selective targeting and destruction of tumor mitochondria; effective in deep-seated tumors

Prava and Raj 2016 [156]

Not specified (in vitro cytotoxicity tested)

Iron oxide nanoparticles (Fe3O4) coated with β-cyclodextrin (β-CD), PEG, and PEI, loaded with 5-fluorouracil (5-FU)

• Fe3O4 as the core for potential magnetic targeting

• β-CD, PEG, and PEI as coating agents for stability and drug loading

• 5-FU as the anticancer drug

• 5-FU-loaded nanoparticles exhibited toxicity towards cancer cells but not normal cells

• Released 5-FU more rapidly and at higher levels at pH 6.8 compared to acidic pH 1.2

Wadajkar et al., 2017 [148]

GBM

Poly(lactic-co-glycolic acid) (PLGA) and PLGA-polyethylene glycol (PLGA-PEG)

• DART therapeutics with decreased non-specific adhesivity and receptor targeting

• Minimized non-specific binding in the brain microenvironment

• Enhanced binding to Fn14 receptor

• Preserved nanoparticle diffusivity in brain tissue

• Increased cellular uptake in tumor cells

• Longer retention in orthotopic tumors compared to non-targeted versions

Gu L et al., 2017 [217]

NSCLC with KRAS mutation and p53 loss

Layer-by-layer nanoparticles

• Core liposomes encapsulating cisplatin, layered with polyelectrolytes including siKRAS and miR-34a, and an outer hyaluronic acid layer for targeting

• Enhanced toxicity against lung adenocarcinoma cells

• Preferential uptake in lungs of tumor-bearing mice

• Prolonged survival in treated mice

• Potential for clinical application in NSCLC therapy

Penon et al. 2017 [218]

Human breast cancer (SK-BR-3 cells)

Water-soluble porphyrin-gold nanoparticle conjugates with anti-erbB2 antibody

• Gold nanoparticles (AuNPs) for enhanced delivery

• Porphyrin as a photosensitizer for PDT

• Anti-erbB2 antibody for targeted delivery to erbB2-positive cancer cells

• Successful synthesis of water-soluble antibody-porphyrin-AuNP conjugates

• Monophasic synthesis method produced nanoparticles with higher singlet oxygen generation

• Antibody-porphyrin-AuNP conjugates effectively targeted and killed erbB2-positive breast cancer cells via PDT

Amreddy et al., 2018 [219]

Lung cancer (H1299 cells)

Folate receptor-targeted polyamidoamine dendrimer nanoparticles (Den-based)

• Folic acid (FA)-conjugated Den nanoparticles for co-delivery of HuR siRNA and cis-diamine platinum (CDDP) to folate receptor-α (FRA)-overexpressing lung cancer cells

• FRA-targeted NP showed significantly higher therapeutic efficacy in co-delivery of HuR siRNA and CDDP than individual therapies

• FRA-targeted NP exhibited enhanced cytotoxicity compared to non-targeted NP

• The system showed negligible toxicity towards normal lung fibroblasts (MRC9 cells)

Sun Y et al., 2018 [190]

NSCLC

Cysteine-modified iron-platinum (FePt-Cys) nanoparticles

• FePt-Cys NPs inducing reactive oxygen species (ROS) generation

• Induced ROS burst leading to apoptosis in NSCLC cells

• Suppressed antioxidant protein expression

• Inhibited migration and invasion of H1975 and A549 cells

• Decreased MMP-2/9 expression and enhanced cellular attachment

• Enhanced effects of cisplatin and radiation therapy by activating caspase system and impairing DNA damage repair

• Demonstrated good solubility, stability, biocompatibility, and safety in vivo

Moghimipour et al., 2018 [135]

CRC

Folic acid-modified liposomes

Targeted delivery of 5-fluorouracil (5-FU)

• Enhanced cytotoxicity, targeted drug delivery, and reduced tumor volume compared to free 5-FU

Kim JS et al., 2018 [220]

GBM

Dual-targeting immunoliposomes

Liposomes conjugated with angiopep-2 and anti-CD133 monoclonal antibody, encapsulating temozolomide (TMZ)

• Dual-targeting liposomes effectively crossed the blood–brain barrier and targeted glioblastoma stem cells (GSCs)

• In vitro, Dual-LP-TMZ increased cytotoxicity against U87MG GSCs by 425-fold compared to free TMZ

• In vivo, treatment with Dual-LP-TMZ significantly reduced tumor size and prolonged survival in orthotopic brain tumor mouse models

Abazari et al. 2018 [155]

Breast cancer (MCF-7)

Bio-metal–organic framework (Bio-MOF) coated with chitosan (CS)

• pH-responsive, target-selective delivery system for doxorubicin (DOX)

• Drug release assessed at different pH levels (PBS, pH 7.4 and 6.8)

• Slow, continuous release profile at pH 7.4, and significant release (93%) at pH 6.8

• Enhanced cellular uptake and apoptosis in MCF-7 cells

• Biocompatible with high drug loading capacity (21.7% at pH 7.4)

Lang FM et al., 2018 [154]

Gliomas

Exosomes derived from mesenchymal stem cells (MSCs)

• MSCs engineered to overexpress miR-124a, producing exosomes (Exo-miR124) containing high levels of miR-124a

• miR-124a identified as a potent antiglioma microRNA

• Exo-miR124 significantly reduced viability and clonogenicity of glioma stem cells (GSCs) in vitro

• Systemic delivery of Exo-miR124 in mice with intracranial GSCs led to long-term survival in 50% of treated animals

• Mechanistic studies showed miR-124a silences FOXA2, causing aberrant lipid accumulation in GSCs

Kakali De et al., 2021 [134]

Prostate and breast cancer (PC3 and SKBR3)

Decapeptide-modified solid lipid nanoparticles (SLNs)

• Targeted delivery of doxorubicin using LHRH-receptor binding SLNs

• Enhanced targeting and cytotoxicity in prostate cancer cells; improved apoptosis and reduced side effects

Liu et al., 2019 [221]

Orthotopic CRC

Silicasomes

• Silica-based nanoparticles encapsulating irinotecan

• Enhanced therapeutic efficacy in orthotopic colon cancer models

• Reduced systemic toxicity compared to free irinotecan

• Improved drug delivery and retention at tumor sites

• Potential for clinical translation in colon cancer treatment

Ebadi et al., 2019 [222]

Liver cancer (HepG2 cells)

Iron oxide nanoparticles (Fe3O4) coated with PEG and co-coated with 5-fluorouracil/Mg/Al-LDH or 5-fluorouracil/Zn/Al-LDH

• Fe3O4 as the core for magnetic properties; PEG as a stabilizing agent; LDH as the drug carrier; 5-fluorouracil (5-FU) as the anticancer drug

• Demonstrated enhanced anticancer activity against HepG2 cells compared to free 5-FU

• Exhibited reduced toxicity towards normal fibroblast 3 T3 cells

Kadiyala O et al., 2019 [223]

GBM

HDL-mimicking nanodiscs

• Nanodiscs loaded with doxorubicin (DOX) and Toll-like receptor 9 (TLR9) agonist CpG

• Nanodiscs effectively delivered DOX and CpG to GBM tumors

• Combination therapy induced immunogenic cell death

• Enhanced activation of dendritic cells and T cells

• Significant inhibition of tumor growth and prolonged survival in mouse models

Hu M et al., 2019 [158]

Liver metastasis from colorectal, pancreatic, and breast cancers

Aminoethyl anisamide-conjugated lipid-calcium-phosphate (LCP) nanoparticles

• LCP nanoparticles delivering plasmid DNA encoding relaxin (pRLN)

• Targeted delivery to metastatic tumor cells and activated hepatic stellate cells

• Reversed stromal microenvironment, inhibiting metastatic progression

• Prolonged survival in mouse models

• Reactivated intra-metastasis immune milieu

• Synergistic effect with PD-L1 blockade immunotherapy, enhancing anti-metastatic efficacy

Chen et al., 2019 [141]

Pancreatic cancer

TR peptide-modified liposomes

• Co-delivery of paclitaxel and hydroxychloroquine

• Synergistic anti-cancer and anti-stromal effects in pancreatic ductal adenocarcinoma

Zhang et al., 2019 [224]

ATC

131I-labeled anti-VEGFR2 mesoporous silica nanoparticles

• 131I-labeled anti-VEGFR2 mesoporous silica nanoparticles

• Enhanced targeting, increased tumor retention, and prolonged survival in mouse models of ATC

Ebadi et al., 2020 [225]

Liver cancer (HepG2 cells)

FeNPs coated with PVA/LDH or PEG/LDH and loaded with sorafenib

• FeNPs as the core for magnetic properties PVA or PEG as coating agents

• Magnesium–aluminum layered double hydroxide (MLDH) as the drug carrier

• Sorafenib as the anticancer drug

• Approximately 85% of sorafenib was released from the nanoparticles within 72 h, following pseudo-second-order kinetics

• The coated nanoparticles loaded with sorafenib demonstrated anticancer activity against HepG2 cells

• Lower toxicity was observed in fibroblast-type 3 T3 cells compared to the pure drug

Tsakiris et al., 2020 [226]

CRC

SN38 and salinomycin nanoparticles

• Solid lipid nanocapsules

• Tested on colorectal cancer cell lines and in vivo murine models. Targeted proliferating cancer cells (via SN38) and therapy-resistant cancer stem cells (via salinomycin), improving survival and reducing systemic toxicity

Khan and Sahu, 2020 [227]

Breast cancer (MCF-7 cells)

Polyethylene glycol-diamine functionalized mesoporous SPION

• SPIONs prepared via a solvothermal method

• Folic acid (FA) attached for targeting via carbodiimide chemistry

• High drug-loading efficiency (~ 96%) due to mesoporous structure

• NPs achieved hyperthermic temperature of 43 °C within 223 s under alternating magnetic field

• Non-appreciable toxicity in MCF-7 cells until loaded with doxorubicin

Asghar et al., 2020 [228]

Tumor cells (RAW 264.7 cells)

Thermoresponsive polymer-coated, superparamagnetic Fe3O4 embedded hollow mesoporous silica nanoparticles (HmSiO2-F-P(NIPAM-MAm))

• HmSiO2-F-P(NIPAM-MAm)-Dox (doxorubicin-loaded)

• Synthesis and characterization of nanocarriers with high loading capacity (95% encapsulation efficiency)

• Biocompatibility confirmed

• Significant anticancer activity against HeLa cells

• pH and temperature-dependent drug release profile

Ou et al., 2020 [229]

OSCC

Graphene oxide-polyethylenimine

• miRNA inhibitor delivery for gene therapy

• Reduced tumor growth, increased apoptosis, and suppression of metastasis in OSCC

Chowdhury et al., 2020 [230]

Her-2 + breast cancer (MCF-7 and SKBR-3 cells)

Aptamer-labeled liposomes loaded with doxorubicin (DOX)

• Liposomes composed of various saturated and unsaturated lipids (HSPC, DPPC, POPC, DOPC)

• Aptamer A6 for targeted delivery to HER2 + cells

• Liposomal formulations had small particle sizes (< 200 nm) and high drug encapsulation efficiency (≈ 88 ± 5%)

• Aptamer-labeled liposomes (F5) demonstrated over 60% increased uptake in HER2 + cells compared to non-targeted liposomes

• F5 achieved approximately 1.79-fold higher DOX uptake in HER2 + cells than in HER2- cells

Crous and Abrahamse et al., 2020 [231]

Lung cancer stem cells

Gold nanoparticles (AuNPs) conjugated with photosensitizer (AlPcS4 Cl) and antibody (Ab)

• AuNPs for drug delivery and retention

• Antibody for targeted delivery to lung CSCs

• AlPcS4 Cl as a photosensitizer for PDT

• Successful conjugation of the nanobioconjugate (NBC) confirmed

• NBC localized in integral organelles of lung CSCs

• AlPcS4 Cl-AuNP-Ab induced significant cell toxicity and death compared to free AlPcS4 Cl

• Enhanced PDT effect observed with the NBC, leading to significant lung CSC destruction

Yin J. et al., 2021 [150]

General cancer immunotherapy

Polyethylenimine-functionalized graphene oxide hydrogel

• In situ transforming RNA nanovaccine delivery for immunotherapy

• Improved tumor antigen presentation, increased CD8 + T-cell activation, long-term antigen-specific immunity, and efficient prevention of metastasis

Nunes et al., 2021 [232]

CRC cells

Folate-coated pH-sensitive liposomes

• Encapsulation of irinotecan for controlled release

• Improved antitumor activity with reduced systemic toxicity in murine colorectal cancer model

Mulens-Arias V. et al., 2021 [177]

Colon peritoneal metastasis

Gold nanoparticles (AuNPs) conjugated with fluorouracil (5-FU)

• Systemic administration of 5-FU-AuNPs followed by near-infrared (NIR) laser irradiation to induce mild hyperthermia

• Selective accumulation of 5-FU-AuNPs in tumor tissues

• NIR laser irradiation induced mild hyperthermia (40–42 °C) in tumor sites

• Combined treatment enhanced antitumor efficacy compared to chemotherapy alone

• Increased infiltration of immune cells, including cytotoxic T lymphocytes, into tumor microenvironment

• Induction of immunogenic cell death markers, such as calreticulin exposure and HMGB1 release

• Reduced tumor growth and prolonged survival in mouse models

Luiz et al., 2022 [233]

Breast cancer

Folic acid-modified curcumin-loaded liposomes

• Targeted drug delivery to folate receptors

• Enhanced cytotoxicity, increased cellular uptake, and improved penetration in 3D tumor models

Honarvari et al. 2022 [234]

Breast cancer

Folate-targeted curcumin-loaded biosomes

• Site-specific delivery to breast cancer cells

• Improved curcumin efficacy in breast cancer; reduced side effects

Tunç C.Ü et al., 2022 [134]

TNBC & MCF7

AuNPs

siRNA-functionalized AuNPs with intercalated doxorubicin (Dox)

• Efficient co-delivery of Bcl-2 siRNA and Dox

• Significant downregulation of Bcl-2 gene expression (40% reduction)

• Increased apoptosis (~ 35% vs. 24% with free Dox)

• Enhanced inhibition of cancer cell proliferation (70–82% reduction in TNBC cells)

• Decreased cancer cell migration and colony formation

• Biocompatible and scalable approach with no need for cationic polymers

Radzi MRM, 2022 [235]

Breast cancer

Oxidized multiwalled carbon nanotubes (O-MWCNTs)

• O-MWCNTs administered intravenously, followed by near-infrared (NIR) laser irradiation to induce hyperthermia

• O-MWCNTs demonstrated efficient photothermal conversion upon NIR laser exposure

• In vivo studies showed significant tumor growth inhibition in treated mice

• Histopathological analysis revealed increased tumor cell apoptosis and necrosis

• Minimal adverse effects observed in vital organs, indicating biocompatibility of O-MWCNTs

Mkhobongo et al. 2023 [236]

Metastatic melanoma stem cells (CD133 + A375 cell line)

Aluminum phthalocyanine conjugated to gold nanoparticles (AlPcS4 Cl-AuNP)

• Gold nanoparticles (AuNPs) for enhanced delivery of the photosensitizer

• AlPcS4 Cl as a photosensitizer for photodynamic therapy (PDT)

• The AlPcS₄Cl-AuNP conjugate mediated PDT that promoted apoptotic cell death in melanoma stem cells

• Increased expression of p53 and caspase-3 indicated apoptosis

• Enhanced PDT effects were observed with the AlPcS₄Cl-AuNP conjugate compared to AlPcS₄Cl alone

Ilangovan SS, Mahanty et al., 2023 [237]

Breast cancer (MCF-7 cells), liver cancer (HepG2 cells), lung cancer (NCIH460 cells)

Superparamagnetic iron oxide nanoparticles (SPIONs) conjugated with β-sitosterol (BS) and coated with PEG and/or PNIPAM

• SPIONs, PEG, and PNIPAM as modifiers to enhance BS delivery

• Various conjugates: BS-S, BS-SP, BS-SPP

• Increased size, stability, and monodispersity observed in the order of BS-S, BS-SP, BS-SPP

• Highest drug encapsulation efficiency in BS-SPP (82.5%)

• Sustained drug release in BS-SP (82.6%) and BS-SPP (83%)

• IC50 values indicate highest inhibition towards NCIH 460 cells (164 µg/mL)

Potential for targeted therapy against EGFR and MET receptor-expressing cancer cells

Taghikhani et al., 2024 [238]

Breast cancer (MCF-7)

Magnetic layered double hydroxides/Cu metal–organic framework-chitosan crosslinked к-carrageenan

pH-sensitive biocompatible hydrogel nanoparticles (LDH-Fe3O4/Cu MOF-DOX-CS@CAR) for controlled doxorubicin delivery

• High encapsulation efficiency (96.1%) and drug loading capacity (9.6%)

• Controlled release: 60.3% at pH 5.5 vs. 22.6% at pH 7.4 after 72 h

• Enhanced cytotoxicity toward MCF-7 cells with biocompatibility for L929 cells

• Exhibited excellent antioxidant activity (71.81%) and blood compatibility (< 5%)

Simelane and Abrahams, 2024 [239]

CRC (Caco-2 cells in 3D MCTS)

PEGylated gold nanoparticles (PEG-AuNPs) conjugated with photosensitizer (ZnPcS₄) and anti-guanylate cyclase monoclonal antibodies (mAb)

• PEG-AuNPs for enhanced delivery of the photosensitizer

• Anti-guanylate cyclase mAb for targeted delivery to CRC cells

• ZnPcS₄ as a photosensitizer for PDT

• Enhanced anticancer effects observed in Caco-2 3D MCTS after PDT using the BNC nanoconjugate

• Targeted BNC nanoconjugates improved PDT efficacy in a 3D tumor model

Ji D, et al., 2024 [240]

Lung cancer

Chimeric antigenic peptide influenza virus (CAP-Flu)

• Attenuated influenza A virus conjugated with CpG and covalently linked to tumor antigens

• Intranasal administration led to increased immune cell infiltration in tumors

• Enhanced antigen uptake by dendritic cells

• Specific immune cell response with increased tumor-infiltrating lymphocytes

• Engineered virus expressing anti-PD-L1 nanobodies further enhanced tumor regression and prolonged survival in mouse models