Overview of Preclinical and Clinical Trials of Nanoparticles for the Treatment of Brain Metastases
Abstract
1. Introduction
2. Structure of Nanoparticles
3. Factors Affecting the Biodistribution of Nanoparticles
4. Overview of Pre-Clinical Trials Using Nanoparticles for Brain Metastases
4.1. Overview of Nanoparticles Carrying Chemotherapeutic Agents
4.2. Overview of Nanoparticles Carrying Immunotherapeutic Agents
4.3. Overview of Nanoparticles Carrying Small-Molecule Inhibitors
4.4. Overview of Nanoparticles Carrying Therapeutic Genes
4.5. Overview of Nanoparticles Carrying Radiotherapeutic/Radiosensitizer
4.6. Overview of Nanoparticles Carrying Tumor Microenvironment Modulators
5. Overview of Clinical Trials
6. Discussion
7. Limitations
8. Clinical Perspectives
9. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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S.No. | Nanomaterial | Structure | Targeting Moiety | Molecular/Cellular Target | Cargo | Mechanism of Action | Animal Model/Cell Line | Outcomes | Adverse Events | Reference |
---|---|---|---|---|---|---|---|---|---|---|
1 | LANP |
|
|
| Dox | LANP are activated by NE, allowing them to shrink in size. Lexiscan helps them pass the BBB, and AMD3100 target the tumor specifically via binding to CXCR4. |
|
| None | [26] |
2 | PMAA-PS 80-g-St terpolymer (PPT) |
| PS 80-bound Apo-E | LDL-R/BBB/tumor cells | Dox | PS 80 adsorb Apo-E from plasma onto the surface of NPs facilitating the NP uptake by BCECs and tumor cells through interaction with LDL-R. |
|
| None | [53] |
3 | iRGD-PPT |
|
|
| Dox & MMC |
|
|
| None | [54] |
4 | MM-302 |
| Anti-HER2 antibody | HER2-overexpressing cells | Dox |
|
|
| None | [55] |
5 | PRINT-C2-docetaxel | PLGA | None specified | Acidic TME (pH-triggered activation) | C2-DTX (prodrug of DTX) | NPs accumulate in tumors; prodrug converts to active DTX in acidic TME, enhancing delivery and minimizing systemic toxicity. |
|
| None | [56] |
6 | T7-DSNP/9291 |
| T7 peptide | TfR, and high GSH in tumor cells | Osimertinib (AZD9291) & Dox | BBB penetration via TfR-mediated transcytosis, GSH-triggered drug release within tumor cells for EGFR inhibition (AZD9291) and DNA damage-induced apoptosis (Dox) |
|
| None | [57] |
7 | HER3-HBP-Dox |
| anti-HER3 abs | HER3 receptors/tumor cells | Dox |
|
|
| None | [58] |
8 | M@H-NP/Dox | PLGA-PLL polymer; surface-modified with PEG and hyaluronic acid (HA) | HA targets CD44 on tumor cells |
|
|
|
|
| None | [59] |
9 | NP (TM@TTP)/(Dox@TTP-HA; drug-loaded NP) | PLGA-PLL polymer- Surface: PEGylated and functionalized with TTP and HA |
|
| Tunicamycin & Dox |
|
|
| None | [60] |
10 | hDOX@NP—dual-targeting PLGA-based NP | PLGA-PLL NPs functionalized with transcytosis-targeting peptide (TTP) |
|
| hDOX -a prodrug of Dox conjugated to HA |
|
|
| None | [61] |
11 | S@A-NP/Dox: Simvastatin (SIM)-loaded Angiopep-2-anchored NP Dox | PLGA anchored with Angiopep-2 peptide |
|
| SIM and Dox |
|
|
| None | [62] |
12 | ACUPA and cyclic TT1 (cTT1) functionalized NP (A-NP-cT) | PLGA-PLL Surface: modified with ACUPA and cTT1 peptide via PEG linker |
|
|
|
|
|
| None | [63] |
13 | TAT-Au-Dox NP | PEGylated gold HIV-derived TAT peptide (YGRKKRRQRRR) | TAT | BBB/tumor cells | Dox |
|
|
| None | [64] |
14 | cFd-Lip/PTX | PEGylated liposomes PTX |
| Folate receptors/Tumor cells | PTX |
|
|
| None | [65] |
15 | PTX-OA NP | Oleanolic acid (OA) | Oleanolic acid (OA) | Cannabinoid receptor 1 (CB1) | PTX |
|
|
| None | [66] |
16 | PEGylated liposomal Dox (PLD) vs. Doxorubicin (NonL-Dox) | Dox encapsulated in PEGylated liposomes | None | None | Dox +ABT-888 (inhibitor of a PARP) | Passive targeting via enhanced permeability and retention effect; prolonged circulation due to PEGylation allows accumulation in TME and enhanced drug delivery across BBB |
|
| None | [67] |
17 | DTX-NP |
| PS 80-bound Apo-E | LDL-R/BBB/tumor cells | DTX | PS 80 adsorb Apo-E from plasma onto the surface of NP. Apo-E facilitates the uptake of the NPs by BCEC and tumor cells through interaction with LDL-R family members expressed on these cells. |
|
| None | [68] |
18 | Ang-MIC-PTX/LP |
| Angiopep-2 peptide | LRP1 | PTX and LAP | Angiopep-2 facilitates LRP1-mediated transcytosis across BBB and endocytosis in BM. |
|
| None | [69] |
S.No. | Nanomaterial | Structure | Targeting Moiety | Molecular/Cellular Target | Cargo | Mechanism of Action | Animal Model/Cell Line | Outcomes | Adverse Events | Reference |
---|---|---|---|---|---|---|---|---|---|---|
1 | H-TZ | Human ferritin NPs covalently conjugated with TRZ via PEG linker | Ferritin | TfR1/BBB | TRZ (anti-HER2 antibody) | Crosses BBB via TfR1, targets HER2+ tumor cells, enhances antibody delivery and retention, activates macrophage-mediated killing, modulates neuroinflammation |
|
| None | [76] |
2 | TRZ terpolymer NP (TRZ-TNP) |
| PS 80-bound Apo-E | LDL-R/BBB/tumor cells | TRZ | PS 80-bound Apo-E-LDLR-mediated transcytosis. TRZ target HER2+ cells. |
|
| None | [77] |
3 | Transferrin receptor (TfR)-targeted mucic acid polymer (MAP) NP |
|
| TfR/BBB HER2/tumor cells |
|
|
|
| None | [78] |
4 |
| Zwitterionic polymer shell made of 2-methacryloyloxyethyl phosphoryl-choline (MPC; monomer), PLA-PEG-PLA and/or GDMA (crosslinkers), conjugation to CXCL13 | CXCL13 |
| Rituximab (anti-CD20 mAbs) |
|
|
| None | [74] |
5 | SIL@T NP |
| CSKC peptide (analog of IGF-1) | IGF-1R on brain endothelial cells and metastatic cells | Silybin (SIL) and Oxaliplatin (OXA) |
|
|
| None | [86] |
S.No. | Nanomaterial | Structure | Targeting Moiety | Molecular/Cellular Target | Cargo | Mechanism of Action | Animal Model/Cell Line | Outcomes | Adverse Events | Reference |
---|---|---|---|---|---|---|---|---|---|---|
1 * | Lipid-polymeric NP |
| FD7 and CCD peptides | TJ proteins/BBB | Afatinib | The peptides FD7 and CCD of LPN disrupt tight junction proteins, helping LNP primarily traverse the BBB via a paracellular route. They also undergo partial transcellular transport. |
|
| NA | [89] |
2 | NP-K-s-A |
|
|
|
| K-s-A binds to LRP1 on BBB and mediate endocytosis of NP-K-s-A. MMP1 then cleaves K-s-A into angiopep-2 and KAAYSL. Angiopep-2 inhibits LRP1, reducing NP clearance and KAAYSL, targets HER2 on tumor cells |
|
| None | [93] |
3 | T12/PD-L1-Nb-modified liposomes (T12/P-Lipo) |
|
| PD-L1 on TAM and tumor cells; TfR on endothelial and tumor cells | Simvastatin (SV), Gefitinib (Gef) | BBB penetration via T12-TfR interaction. TAM repolarization (M2→M1), ROS elevation, inhibition of EGFR/Akt/Erk signaling pathway, reversal of EGFR T790M-associated drug resistance. |
|
| None. | [98] |
4 | T12 peptide-modified bovine serum albumin nanoparticles (T12-BSA NP) | <135 nm nanoparticles with negative ζ-potential, formed via albumin denaturation and conjugated with T12 peptide | T12 peptide (targets transferrin receptor), albumin (binds SPARC protein) | TfR & SPARC/BBB/TAM | Disulfiram/copper ion chelate (DSF/Cu) and regorafenib (Rego) |
|
|
| None | [100] |
5 | LHNP | Core-shell made from HSA and phosphatidylcholine | Albumin | HER2/EGFR on tumor cells and P-gp/BCRP at BBB | Lapatinib (Lap) | Inhibits HER2 and EGFR signaling, albumin NP bypass P-gp efflux, increase BBB penetration, and enhance tumor accumulation via EPR and gp60/SPARC |
|
| None | [101] |
S.No. | Nanomaterial | Structure | Targeting Moiety | Molecular/Cellular Target | Cargo | Mechanism of Action | Animal Model/Cell Line | Outcomes | Adverse Events | Reference |
---|---|---|---|---|---|---|---|---|---|---|
1 | T-M/siRNA micelle (CSKC-PEG-pArg-pLys-SS-PTX) |
| CSKC peptide | IGF-1R/BBB/tumor cells |
|
|
|
| None | [105] |
2 | Modified MN (MN-anti–miR-10b) |
| cyclic RGDfK (cRGD) | αvβ3/αvβ5 integrins/BBB/tumor cells | anti–miR-10b | cRGD-integrin mediated endocytosis of MN-anti–miR-10b. anti–miR-10b targets upregulated miRNA-10b in BM, disrupting its role in BM. |
|
| None | [109] |
3 | Engineered exosome (ExoscFv) | Same as exosome
| anti-EGFR scFv-lamp2b | EGFR/tumor cells | LPCAT1-targeting siRNA | Exosomes are biological NP, so they passively cross the BBB. But the anti-EGFR scFv-lamp2b selectively bind to EGFR on the surface of BM. |
| Reduced BM burden in mice treated | Weight loss in treated mice | [114] |
4 | T-siHER2-NP(DTX) |
| TRZ | HER2 Receptors |
|
|
|
| None | [115] |
5 | AP30NP Poly(lactone-co-β-amino ester) |
| AMD3100 | CXCR4/tumor cells | proMel gene | AMD3100-CXCR4 interaction based tumor target. proMel Gene synthesize secretory promelittin, which is converted to melittin by MMP in TME. Melittin is tumor cytolytic. |
|
| None | [118] |
S.No. | Nanomaterial | Structure | Targeting Moiety | Molecular/Cellular Target | Cargo | Mechanism of Action | Animal Model/Cell Line | Outcomes | Adverse Events | Reference |
---|---|---|---|---|---|---|---|---|---|---|
1 | AGuIX |
| None | BBB/Tumor cells | Gd | AGuIX accumulate passively and preferentially in brain tumors due to blood–brain barrier is damaged |
|
| None | [119] |
2 | Iodine NP (INP) |
| None | Tumor cells (via EPR effect) | Iodine | Passive targeting via EPR effect. Iodine absorbs X-rays during RT, effectively boosting RT dose at the tumor, creating free radicals leading to increased DNA damage in cancer cells. |
|
| None | [120] |
3 | LRRC31 NP |
|
|
| LRRC31 DNA plasmid | Lexiscan helps NPs pass the BBB, and CTX enables them to target the tumor cells specifically. LRRC31inhibits DNA DSB repair sensitizing tumor cells to radiation. |
|
| None | [121] |
S.No. | Nanomaterial | Structure | Targeting Moiety | Molecular/Cellular Target | Cargo | Mechanism of Action | Animal Model/Cell Line | Outcomes | Adverse Events | Reference |
---|---|---|---|---|---|---|---|---|---|---|
1 | Lasomes |
| Portion of CM of RA and/or BM cells | CM of RA and/or BM cells | carbenoxolone | Las, being biomimetic, use homotypic CM recognition mechanism to carry CBX to astrocytes and BM cells, blocking GJs between them, enhancing DNP chemosensitivity. |
|
| None | [127] |
2 | P5091@RMPs-R4F |
| R4F peptide | SR-B1 receptor/BBB/TAM | P5091 (USP7 inhibitor) | R4F peptide binds SR-B1 receptor, mediating P5091@RMPs-R4F cross the BBB and targeting M2. P5091 reverses immune-suppressive TME. |
|
| NS | [135] |
3 | R&B/NP | PLGA core coated with erythrocyte and MDA-MB-231Br hybrid cell membranes | Hybrid membrane (erythrocyte + 231Br cell membrane) | CM of Inflammatory BBB/tumor cells | Dexamethasone (Dex), Embelin (Emb) | Hybrid membrane, being biomimetic, use homotypic CM recognition to target the BBB and tumor cells. Inhibits secretion of serpin B2 and neuroserpin to restore plasmin activity, plasmin cleaves L1CAM and converts FasL to sFasL, leading to apoptosis and blocking vessel-associated spread |
|
| None | [130] |
4 | NI@I-NP: Physical combination of two ICAM-1-targeted NP: NTZ@I-NP and IBR@I-NP | PLGA-PLL NP functionalized with ICAM-1-targeting γ3 peptide via PEGylation | ICAM-1-targeting γ3 peptide | ICAM-1 on BTB endothelial cells and tumor pericytes | NTZ@I-NP loaded with Nitazoxanide I@I-NP loaded with Ibrutinib |
|
|
| None | [136] |
ID | Country | Phase | Status | Nanoparticle | Therapeutic | Mechanism | Primary Outcome | Published Results | Adverse Events (AEs) | PI | Reference to Results |
---|---|---|---|---|---|---|---|---|---|---|---|
NCT02820454 | France | I | Completed | AGuIX | Gd/WBRT |
| To determine the maximum tolerated dose (MTD) |
|
| Camille VERRY, MD | [137] |
NCT03818386 | France | II | Active, not recruiting | AGuIX | Gd/WBRT |
| Evaluation of BM response, according to RECIST v1.1 criteria (or modified RECIST) by MRI at 6th week and 3rd month | NA | NA | Camille VERRY, MD | NA |
NCT04094077 | France | II | Terminated | AGuIX | Gd/stereotactic radiation |
| Rate of local control of BM | NA | NA | NA | NA |
NCT04899908 | US | II | Recruiting | AGuIX | Gd/stereotactic radiation |
| Local Recurrence (RANO criteria) | NA | NA | Ayal Aizer, MD, MHS | NA |
NCT03328884 | Spain | II | Completed | Nal-IRI | Irinotecan/naI-IRI monotherapy |
| Efficacy in term of overall response rate | NA | NA | Javier Cortes | NA |
EUCTR2018-003994-80-FR | France | II | unknown | AGuIX | Gd/stereotactic radiation |
| rate of local control | NA | NA | Ronan TANGUY, MD | NA |
NCT05255666 | US | II | withdrawn | Nal-IRI | Nal-IRI/Pembrolizumab |
| CNS disease control rate (RANO) for 6 months | NA | NA | Ashley Frith, MD | NA |
NCT01770353 | US | I | Completed | Ferumoxytol/MM-398 (liposomal Irinotecan) | Ferumoxytol followed by MM-398 |
|
|
| Grade 3 AEs | NA | [138] |
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Izhar, M.; Al Gharyani, M.; Kattaa, A.H.; Cardona, J.J.; Jain, R.P.; Shaghaghian, E.; Hori, Y.S.; Lam, F.C.; Abu Reesh, D.; Emrich, S.C.; et al. Overview of Preclinical and Clinical Trials of Nanoparticles for the Treatment of Brain Metastases. Pharmaceutics 2025, 17, 899. https://doi.org/10.3390/pharmaceutics17070899
Izhar M, Al Gharyani M, Kattaa AH, Cardona JJ, Jain RP, Shaghaghian E, Hori YS, Lam FC, Abu Reesh D, Emrich SC, et al. Overview of Preclinical and Clinical Trials of Nanoparticles for the Treatment of Brain Metastases. Pharmaceutics. 2025; 17(7):899. https://doi.org/10.3390/pharmaceutics17070899
Chicago/Turabian StyleIzhar, Muhammad, Mohamed Al Gharyani, Ahed H. Kattaa, Juan J. Cardona, Ruchit P. Jain, Elaheh Shaghaghian, Yusuke S. Hori, Fred C. Lam, Deyaaldeen Abu Reesh, Sara C. Emrich, and et al. 2025. "Overview of Preclinical and Clinical Trials of Nanoparticles for the Treatment of Brain Metastases" Pharmaceutics 17, no. 7: 899. https://doi.org/10.3390/pharmaceutics17070899
APA StyleIzhar, M., Al Gharyani, M., Kattaa, A. H., Cardona, J. J., Jain, R. P., Shaghaghian, E., Hori, Y. S., Lam, F. C., Abu Reesh, D., Emrich, S. C., Ustrzynski, L., Tayag, A., Lesniak, M. S., Chang, S. D., & Park, D. J. (2025). Overview of Preclinical and Clinical Trials of Nanoparticles for the Treatment of Brain Metastases. Pharmaceutics, 17(7), 899. https://doi.org/10.3390/pharmaceutics17070899