Frontiers in Pharmacology2018ReviewDrug Delivery

PLGA-Based Nanoparticles in Cancer Treatment

Sima Rezvantalab, Natascha Ingrid Drude, Mostafa Keshavarz Moraveji, Nihan Güvener, Emily Kate Koons, Yang Shi, Twan Lammers, Fabian Kiessling29 September 2026DOI 10.3389/fphar.2018.01260

Summary

PLGA-based nanoparticles are widely investigated for cancer therapy, but their clinical translation remains limited. A consolidated overview was needed of how PLGA NP physicochemical properties, biological behavior, targeting strategies, and combination therapies interact—and why promising preclinical results have rarely translated into approved cancer nanomedicines. PLGA molecular weight controls release: At day 18, payload release was 95%, 66%, 50%, and 23% for PLGA Mw of 14.5, 45, 85, and 213 kDa, respectively. PTX-loaded NP sizes increased with Mw: 122 ± 3, 133 ± 2, and 160 ± 2.

Keywords

PLGA Nanoparticles CRISPR siRNA DNA Cellular uptake Biodistribution

Purpose: PLGA-based nanoparticles are widely investigated for cancer therapy, but their clinical translation remains limited. A consolidated overview was needed of how PLGA NP physicochemical properties, biological behavior, targeting strategies, and combination therapies interact—and why promising preclinical results have rarely translated into approved cancer nanomedicines.

Hypothesis: As a review, there is no formal testable hypothesis. The central thesis is:

> If PLGA NPs are rationally designed with appropriate size, surface chemistry, targeting ligands, and combination treatment modalities, then tumor accumulation, therapeutic efficacy, and safety can be improved—but clinical translation requires reproducibility, GMP manufacturing, and clinically relevant preclinical models.

Aims: Provide an overview of previously reported PLGA NPs, their properties, and behavior in biological systems. - Summarize PLGA NP use for cancer therapy, including passive and active targeting strategies. - Introduce combination therapies that enhance NP accumulation and therapeutic efficacy. - Highlight the potential of PLGA NPs as cancer drug carriers and encourage further translational research.

Delivery system:

Feature: Polymer; Description: Poly(lactic-co-glycolic acid) (PLGA); LA/GA ratio and molecular weight tune degradation, release, and hydrophobicity

Feature: Particle types; Description: PLGA nanoparticles (NPs); also PLGA microspheres, gels, and implants in clinical use

Feature: Shapes; Description: Spherical, rod-, needle-, and cylindrical-shaped PLGA NPs

Feature: Surface modifications; Description: PEGylation, chitosan, poly(dopamine), TPGS, poly(vinyl alcohol), d-α-tocopheryl PEG 1000 succinate

Feature: Targeting ligands; Description: Folate, biotin, aptamers (AS1411, A10), antibodies/antibody fragments, RGD peptides, transferrin, PSMA ligands, hyaluronic acid, EGFR-targeting peptides, VEGF-R

Feature: Payloads; Description: Chemotherapeutics (DOX, PTX, DTX, cisplatin, CUR, tamoxifen, 5-FU), nucleic acids (siRNA, shRNA, pDNA, CRISPR/Cas9 plasmid), imaging agents (SPIONs, ICG, magnetic NPs), immunotherapeutics/adjuvants

Feature: Combination modalities; Description: Chemotherapy + radiotherapy, magnetic hyperthermia, photodynamic therapy (PDT), photothermal therapy (PTT), gene therapy, cancer immunotherapy

Approach: This is a narrative review synthesizing preclinical and clinical literature.

In vitro models: MCF-7, MCF-7/ADR, HeLa, HT-29, CT26, LNCaP, H1299, K562, 4T1, and others; drug-resistant and sensitive cancer cell lines.
In vivo models: Mouse xenografts and orthotopic models (breast, colon, prostate, glioma, CML); tumor-bearing mice; CT26 colon carcinoma; MCF-7/ADR breast cancer; orthotopic glioma.
Clinical context: FDA-approved PLGA microsphere/gel/implant formulations (Lupron Depot, Trelstar, Eligard, Zoladex); BIND-014 (PLA-PEG NP, not PLGA NP) phase II failure.
Group structure / controls: From cited studies; typically free drug vs. NP, passive vs. active targeting, with/without magnetic field, with/without laser irradiation, combination vs. monotherapy.

Key methods: Techniques from cited primary studies include:

Physicochemical characterization: dynamic light scattering (DLS), zeta potential, SEM/TEM, drug loading and encapsulation efficiency.
Release kinetics: in vitro drug release profiles.
Cellular uptake/internalization: flow cytometry, confocal microscopy.
Targeting/biodistribution: MRI, magnetic particle imaging (MPI), ultrasound, fluorescence imaging, gamma scintigraphy.
Therapeutic efficacy: tumor volume, survival rate, IC50, apoptosis assays.
Gene editing/silencing: CRISPR/Cas9 knockout, siRNA/shRNA knockdown, mRNA/protein expression.
Immune response: CD8+ T cell priming, cytokine profiles, checkpoint blockade combination.

Key results: PLGA molecular weight controls release: At day 18, payload release was 95%, 66%, 50%, and 23% for PLGA Mw of 14.5, 45, 85, and 213 kDa, respectively. PTX-loaded NP sizes increased with Mw: 122 ± 3, 133 ± 2, and 160 ± 2 nm for 6, 14.5, and 63.6 kDa. - PEG density threshold: Above 20 PEG chains (5 kDa) per 100 nm², circulation time depended on PEG density rather than PLGA NP size. - Nanoprecipitation improved DNA encapsulation: Modified nanoprecipitation achieved >95% DNA encapsulation efficiency vs. ~65% for conventional emulsion-evaporation. - Active + magnetic targeting: RGD + magnetic targeting produced up to 8-fold increase in tumor accumulation and prolonged survival in CT26 colon carcinoma. Transferrin + magnetic targeting gave >10-fold tumor accumulation and 5-fold improved BBB crossing in orthotopic glioma. - Hyperthermia + chemotherapy: Herceptin-targeted tamoxifen/Fe₃O₄ PLGA-PVP NPs reduced tumor size by 90% vs. 60% for passively targeted NPs at 14 days. - PDT/PTT combination: DOX + ICG co-loaded PLGA-lecithin-PEG NPs (~90 nm) synergistically promoted cell death in MCF-7/ADR and MCF-7 models after laser irradiation. - CRISPR/Cas9 delivery: PEG-PLGA cationic lipid-assisted NPs delivering Cas9/gRNA knocked out BCR-ABL, reduced K562 cells in blood and bone marrow, and significantly prolonged survival in a CML mouse model. - Clinical translation: BIND-014 (PLA-PEG NP targeting PSMA) failed phase II due to low response rates.

Interpretation: The authors conclude that PLGA NPs remain highly promising for cancer therapy, but their clinical translation has been limited. They argue that rational design—optimizing size, drug loading, release, surface properties, and targeting—combined with clinically relevant preclinical testing and GMP-compatible manufacturing is necessary to close the gap between material research, preclinical experimentation, and clinical reality. The heterogeneity of the EPR effect and the complexity of external stimuli–based targeting are major barriers.

Limitations: Stated by authors: - EPR effect is highly heterogeneous across patients, tumor types, and over time; this limits passive targeting. - Batch-to-batch consistency of PLGA NP synthesis is challenging due to heterogeneous mixing conditions. - Obtaining particle sizes below 100 nm in an up-scalable process remains difficult. - Additional purification steps impede GMP manufacturing. - Surface modifications (e.g., PEGylation) can increase size, hide targeting ligands, reduce cellular uptake, and alter biodistribution. - External stimuli (magnetic fields, light) can only be applied to accessible tumor regions; deep tumors are problematic. - Magnetic hyperthermia is limited by clinical SPION dose limits; PDT is limited by light penetration (max 1–2 cm). - Active targeting can decrease circulation time due to increased opsonization and MPS recognition. - BIND-014, the only NP formulation that reached clinical trials in this family, failed in phase II. - No PLGA NP is currently approved for cancer treatment; approved PLGA formulations are microspheres, gels, or implants.

Implicit limitations: - Review is not systematic and provides no meta-analysis. - Most cited studies are preclinical; long-term toxicity and clinical efficacy data are sparse. - Regulatory and cost-effectiveness considerations are not deeply addressed.

Biochemical Pharmacology*, Volume 173, 2020, Article 113648 DOI/