Biomaterials Research2019ReviewDrug Delivery

Therapeutic efficacy of nanoparticles and routes of administration

Dhrisya Chenthamara, Sadhasivam Subramaniam, Sankar Ganesh Ramakrishnan, Swaminathan Krishnaswamy, Musthafa Mohamed Essa, Feng-Huei Lin, And M. Walid Qoronfleh29 September 2026DOI 10.1186/s40824-019-0166-x

Summary

Despite enormous strides in nanotechnology research and development, it is often confusing for beginners to make an informed choice regarding the nanocarrier system and its potential applications. There is a need to provide a comprehensive overview of commonly used nanomaterials, their core properties, surface functionalization strategies, and the impact of different administration routes on drug delivery efficacy and biological barriers. PEGylated L-asparaginase: Circulation lifetime of 5.7 days in humans compared to 1.2 days for the original enzyme. - Albumin-bound paclitaxel (Abraxane): 4.5-fold increase in paclitaxel transport across endothelial.

Keywords

Nanoparticles Nanocarriers Drug delivery Polymeric Hydrogels Peptides Lipid nanoparticle

Purpose: Despite enormous strides in nanotechnology research and development, it is often confusing for beginners to make an informed choice regarding the nanocarrier system and its potential applications. There is a need to provide a comprehensive overview of commonly used nanomaterials, their core properties, surface functionalization strategies, and the impact of different administration routes on drug delivery efficacy and biological barriers.

Hypothesis: As a review article, this work does not test a single hypothesis. Its central thesis is:

If the unique physicochemical properties of nanoparticles (size, shape, surface charge, morphology, and surface functionalization) are appropriately matched with the optimal route of administration (transdermal, blood-brain barrier, oral, inhalation, intravenous), then targeted drug delivery, controlled release, and improved therapeutic efficacy can be achieved while minimizing off-target toxicity and overcoming biological barriers.

Aims: Primary Aim: To briefly explain the most commonly used nanomaterials, their core properties, and how surface functionalization facilitates competent delivery of drugs or therapeutic molecules.

Secondary Aims:
To discuss the suitability of carbon-based nanomaterials (CNTs, QDs) for targeted drug delivery and siRNA therapy.
To describe different mechanisms of drug targeting (passive and active), the role of drug-laden nanocarrier fabrication, and methods to augment drug solubility and bioavailability.
To discuss different routes of nanocarrier administration and the biological barriers associated with each.
To facilitate straightforward perception of nanocarrier design, routes of nanoparticle administration, and challenges associated with each drug delivery method.

Delivery system:

Category: Polymeric Nanoparticles; Examples Discussed: Natural polymers (chitosan, alginate, dextran, pectin, guar gum, chondroitin); Synthetic polymers (PLGA, PLA, PCL, polyacrylates, PEI); PEGylated polymers

Category: Lipid-Based Nanoparticles; Examples Discussed: Liposomes (cationic, PEGylated), solid lipid nanoparticles (SLNPs), transferosomes, ethosomes, niosomes, nanoemulsions

Category: Dendrimers; Examples Discussed: PAMAM, PPI, PLL dendrimers; PEGylated dendrimers; multifunctional theranostic dendrimers (Gd₂O₃, Fe₃O₄)

Category: Hydrogels; Examples Discussed: Chitosan-based, hyaluronic acid-based, pNIPA (temperature-sensitive), pH-sensitive (HC/SA), nanohydrogels

Category: Inorganic Nanoparticles; Examples Discussed: Gold (Au), silver (Ag), iron oxide (Fe₃O₄), silica, quantum dots (QDs), magnetic nanoparticles (MNPs), carbon nanotubes (CNTs)

Category: Payloads; Examples Discussed: Chemotherapeutics (doxorubicin, paclitaxel, docetaxel, 5-fluorouracil, cisplatin, curcumin), siRNA, pDNA, proteins/peptides (insulin, interferons), vaccines

Category: Targeting Ligands; Examples Discussed: Folate, transferrin, hyaluronic acid (CD44), aptamers, antibodies (anti-HER2, cetuximab), RGD peptides, lactoferrin

Category: Routes of Administration; Examples Discussed: Transdermal, oral, inhalation/pulmonary, intravenous, intranasal (nose-to-brain), blood-brain barrier crossing

Category: Stimuli-Responsive Systems; Examples Discussed: pH-sensitive, temperature-sensitive, redox-responsive, magnetic field-guided, NIR light-responsive

Approach: This is a narrative review synthesizing preclinical and clinical literature. No primary experimental data are presented. The review covers:

In vitro studies (Caco-2 cell monolayers, MDA-MB-231, MCF-7, SCC-7, U87 glioblastoma cells, HeLa, SK-BR-3, MCF7-C18).
In vivo animal models (mice, rats, pigs, non-human primates).
Disease contexts: cancer (breast, colon, liver, brain, head and neck), diabetes, multiple sclerosis, tuberculosis, hypertension, chronic kidney disease, CNS disorders.
Clinical trials and FDA-approved nanomedicines (Doxil, Abraxane).

Key methods: As a review, the "methods" are literature synthesis and comparative analysis. Headline data cited from primary studies were generated using:

Physicochemical characterization: Particle size, zeta potential, morphology (TEM, SEM), DLS.
Drug loading and release: Encapsulation efficiency, in vitro release profiles (burst vs. sustained).
Cellular uptake: Flow cytometry, confocal laser scanning microscopy (CLSM), fluorescence microscopy.
Biodistribution and pharmacokinetics: Area under the curve (AUC), half-life (T½), tissue distribution.
Efficacy assessments: Tumor volume reduction, blood pressure reduction, blood glucose control, survival.
Toxicity assessments: Hemolysis, ROS generation, inflammatory cytokines (TNF-α, IL-1β, MIP-2), micronuclei formation.
Imaging: MRI, NIR fluorescence, photoacoustic imaging.

Key results: PEGylated L-asparaginase: Circulation lifetime of 5.7 days in humans compared to 1.2 days for the original enzyme. - Albumin-bound paclitaxel (Abraxane): 4.5-fold increase in paclitaxel transport across endothelial cells compared to standard paclitaxel; higher response rate in metastatic breast cancer patients. - Paclitaxel-LDE (cholesterol-rich nanoemulsion): Mean half-life of 14.51 ± 3.23 h vs. 6.62 ± 2.05 h for paclitaxel-cremophor; 3.5-fold higher tumor targeting than normal tissues. - DXM-SLNP (intravenous): Area under the drug concentration-time curve in the lung was 17.8-fold larger compared to free DXM solution. - HIH nanocomplex (HA-IONP/HCPT): 3 mg/kg with magnetic field showed complete disappearance of tumor after 14 days in mice, with no systemic toxicity. - Paclitaxel in PEG-β-poly(4-phenyl-1-butanoate)-L-aspartamide micelles: ~100-fold increase in AUC, 15-fold decrease in volume of distribution, 25-fold improvement in drug accumulation in C-26 tumors. - Anti-HER2 antibody-conjugated GMO-MNPs: 24 times more effective anticancer activity than free drug. - MTA-loaded SLN (oral): Increased half-life from 28 min to 1.25 h; improved locomotor activity from 49% to 79%. - YF4-loaded lipid nanoparticles (oral): Blood pressure decreased by 43.5 mmHg in ~2 h post-administration vs. 15.6 mmHg for free YF4. - Budesonide-loaded SLNPs (pulmonary): 80% pulmonary deposition in Sprague-Dawley rats. - Paclitaxel-LDE in gynecological cancers: T½ of 14.51 ± 3.23 h vs. 6.62 ± 2.05 h for paclitaxel-cremophor.

Interpretation: The authors conclude that nanoparticles offer higher drug loading, better bioavailability, and improved therapeutic efficacy, but nanoparticle-mediated toxicity remains to be resolved. The successful delivery of a drug to the target region requires not only an ideal nanocarrier but also an effective route of drug administration that enables crossing biological barriers (e.g., blood-brain barrier). Each route of administration has advantages and disadvantages for targeted drug delivery. To overcome limitations, superior understanding of intercellular, transcellular, and carrier-mediated transporting pathways is essential to develop next-generation futuristic nanocarriers. The creation of such advanced nanotherapeutic systems will mark the beginning of a new era in nanotechnology-based drug delivery.

Limitations: Limitations inherent to the review:

No primary experimental data; conclusions are synthesized from existing literature.
No systematic search strategy or meta-analysis.
Focus is primarily on preclinical studies; limited clinical translation data.
Heterogeneity of nanoparticle designs, drug payloads, and administration routes makes direct comparisons difficult.

Limitations of the field highlighted by the authors:

Nanotoxicity: Cationic nanoparticles (gold, polystyrene) can cause hemolysis and clotting; anionic nanoparticles are less toxic. Silver nanoparticles and quantum dots induce ROS, inflammatory mediators (TNF-α, MIP-2, IL-1β), and micronuclei formation.
Clearance by RES: Nanoparticles are rapidly cleared by the mononuclear phagocyte system, liver, and spleen unless surface-modified (e.g., PEGylation).
Protein corona formation: The protein corona occupies the nanoparticle surface, blocking chemical functionality and affecting circulation time, intracellular trafficking, and clearance.
Route-specific barriers:
Transdermal: Only low molecular weight drugs (<500 Da) can penetrate the stratum corneum passively.
Oral: Acidic environment and enzymatic system of the GIT degrade proteins/peptides; poor solubility and permeability limit oral availability.
Inhalation: Rapid particle clearance via mucociliary escalator; alveolar macrophages; cytochrome P450 detoxification.
Intravenous: Risk of opsonization, RES uptake, and systemic toxicity; painful, expensive, requires healthcare personnel.
BBB: Tight junctions restrict paracellular transport; efflux pumps (P-gp) extrude drugs; only small, lipophilic molecules (<500 Da) can passively diffuse.
Drug loading limitations: Most nanoparticles exhibit relatively low drug-loading efficiencies; PLGA's acidic nature does not favor release of acid-labile drugs.
Long-term safety: Inorganic nanoparticles (gold, iron oxide, silica) have not been sufficiently evaluated for long-term toxicity and clearance.
Dendrimer toxicity: Cationic dendrimers can display cytotoxic and hemolytic properties; non-degradable dendrimers accumulate in cells/tissues.
Scale-up and manufacturing: Complex formulations (e.g., liposomes, hydrogels) can be challenging to scale up reproducibly.
Regulatory challenges: Nanoparticle versions of existing drugs are usually regarded as new drugs requiring an Investigational New Drug application; vehicle components may be considered separately.