Evolution and clinical translation of drug delivery nanomaterials

Background

Nanomaterials are used for drug delivery because targeting can reduce systemic toxicity compared with conventional administration, and they can also improve circulation time, solubility and intracellular delivery. The review notes that degradation rate and biodistribution remain unresolved for many carriers, which makes clinical translation difficult, and that the success rate of nanomaterial-based drugs in gaining FDA approval has not been as high as expected.

How the review is organized

The review is organized by material class. Inorganic nanoparticles (gold, iron oxide, silica and quantum dots) are described through their synthesis, surface modification and diagnostic or therapeutic use. Polymeric nanomaterials are divided into polymer-drug conjugates, polymeric nanoparticles, micelles, nanogels and dendrimers, with emphasis on stimuli-responsive designs, and lipid-based carriers are traced from early liposome synthesis to chemically loaded, long-circulating, targeted and triggered liposomes. Carbon-based nanomaterials are excluded because they were reviewed elsewhere.

Scope of the review

For each class, the authors summarize representative studies and the properties that govern delivery, such as size, surface chemistry, release triggers and clearance. A timeline (Fig. 1) marks milestones from early nanomaterial use to current applications, with the caveat that not all listed materials are approved. Table 1 lists FDA-approved nanomaterial-based drugs with year and indication, material composition and mechanism of delivery, and a separate section groups approved and trial-stage products into inorganic, polymeric and liposomal categories before discussing barriers to approval.

Main points of the review

Among inorganic carriers, the review describes superparamagnetic iron oxide nanoparticles (SPIONs) as a core component of approved inorganic nanomedicine. An iron oxide formulation for epirubicin entered a Phase I trial in 1996 but failed because most particles accumulated in the liver, and the contrast agents Feridex and GastroMARK were withdrawn in 2008 and 2012 because of cytotoxicity. Feraheme (ferumoxytol) was approved in 2009 for anemia in chronic kidney disease; the FDA approval section describes it as dextran-coated, whereas the iron oxide section and Table 1 give a polyglucose sorbitol carboxymethylether coating. Surface chemistry strongly affects protein adsorption: one cited study found 22% protein adsorption on negatively charged polyvinyl alcohol (PVA)-coated SPIONs compared with 36% and 41% on positive and neutral ones. NanoTherm (15-nm aminosilane-coated SPIONs) had been approved in Europe for glioblastoma ablation, gold-silica nanoshells (AuroLase) were in a phase I trial, silica-based Cornell dots had completed a Phase I trial, and quantum dots had not been approved because of heavy-metal content and clearance.

For polymeric carriers, the review traces a progression from sustained-release particles to stimuli-responsive and then multifunctional designs. Representative data include PLGA nanoparticles with lactide-to-glycolide ratios of 90:10 and 70:30 that released 30 and 70 wt.% of mitomycin-C after three months, and doxorubicin-dendrimer conjugates with pH-cleavable bonds that released 5% and 60% of the drug over 96 h at pH 7.4 and 5.5. The authors note that micelles often show burst release and that the in vivo fate of stimuli-responsive micelles is poorly understood, that only a few nanogels (about 100–200 nm) had reached clinical trials, and that dendrimers are rarely used because their synthesis is complex and lacks mass production methods.

Polymeric and liposomal products accounted for most FDA approvals. The review lists Adagen (1990) as the first PEGylated drug, Abraxane (an albumin-paclitaxel nanoconjugate, 2005) and the liposomal drugs Doxil (1995), DaunoXome (1996), DepoCyt (1996), Marqibo (2012) and Onivyde (2015). Some years differ between text and Table 1: DepoCyt is listed in the table as 1999 and 2007, and the pancreatic cancer indication of Abraxane as 2013 in the table but 2014 in the text. The authors identify reliance on passive targeting by the enhanced permeability and retention (EPR) effect as a limiting factor and describe actively targeted and thermosensitive liposomes then in clinical trials.

As barriers to approval, the review names the lack of standardized protocols for efficacy, toxicity and safety testing, and the difficulty of scaling academic formulations to processes that comply with good manufacturing practice (GMP), for which particle replication in non-wetting templates (PRINT) and coaxial turbulent jet mixing had been introduced. It also points to DNA-barcoded nanoparticles, screened simultaneously in mice by sequencing barcodes recovered from tissues, and organ-on-a-chip models as tools for studying biodistribution and toxicity. The authors expect progress from multicomponent nanomaterials, on-demand release, controlled biodegradation, delivery across the blood-brain barrier (BBB) and nanoparticle delivery of gene-editing tools.

Open questions

The review is restricted to materials with clinical potential or FDA approval and excludes carbon-based nanomaterials. The authors note that the in vivo behaviour of stimuli-responsive micelles is still not well understood, and that drug targeting across the BBB has seen little progress over the preceding two decades.

How it connects to other research

The related tumour-delivery analysis pools solid-tumour studies to ask how much of an injected dose reaches tumours, whereas this review follows carrier classes through their development history and regulatory status.