Aug 2026· Small· pp.
e74919
· 1 citation· 65 references
Medicine
TL;DR
All-atom molecular dynamics simulations are used to investigate drug-loaded ABA-type triblock copolymer micelles with a hydrophobic poly(2-n-butyl-2-oxazine) core and hydrophilic coronas composed of poly(ethylene glycol) (pEG), poly(N,N-dimethylacrylamide) (pDMAA), and poly(sarcosine) (pSAR).
Abstract
Polymeric micelles are established delivery platforms for hydrophobic drugs. The molecular interactions governing their structure and function remain, however, poorly understood. All-atom molecular dynamics simulations are used to investigate drug-loaded ABA-type triblock copolymer micelles with a hydrophobic poly(2-n-butyl-2-oxazine) core and hydrophilic coronas composed of poly(ethylene glycol) (pEG), poly(N,N-dimethylacrylamide) (pDMAA), and poly(sarcosine) (pSAR). Here, pDMAA and pSAR are considered as alternative polymers to address emerging pEG immunogenicity. Three micellar formulations are examined at moderate (20%) and high (60%) loadings of curcumin as a model hydrophobic drug. The simulations reveal that pEG-based micelles exhibit higher hydration and looser corona structures compared to pDMAA and pSAR micelles. In pEG micelles, curcumin localizes primarily within the hydrophobic core, whereas in pDMAA and pSAR micelles it is more uniformly distributed. At both drug loadings, curcumin preferentially aggregates into a single stable cluster, not densely packed, and interpenetrated by polymer chains. Micelles with pDMAA and pSAR coronas exhibit enhanced stability, reflecting higher internal density and tighter curcumin packing. Hydrogen bond analysis reveals the strongest curcumin-hydrophilic A-block interactions in pDMAA micelles, moderate loading-dependent interactions in pSAR micelles, and minimal hydrogen-bonding in pEG micelles due to corona hydration.
Conventional chemotherapy with doxorubicin (Dox) is limited by poor selectivity and systemic toxicity. Polymeric micelles based on Pluronic F127 offer a versatile platform for drug delivery, but their stability and responsiveness to tumor-specific stimuli remain critical challenges. To address these issues, two pH-sensitive F127-Dox conjugates were synthesized using cis-aconitic (Cis) and succinic (Suc) linkers. The conjugates were structurally characterized by FTIR and 1H NMR, and their micellization behavior was studied via pyrene fluorescence. Dynamic light scattering was employed to analyze micelle size and pH responsiveness, while UV-Vis spectrophotometry was used to quantify drug loading (DL%) and encapsulation efficiency (EE%). Drug release kinetics were evaluated using the dialysis method at pH 7.4 and 5.5. Conjugation reduced the CMC of F127 from 112 μg/mL to 89 μg/mL (Cis-Dox) and 75 μg/mL (Suc-Dox), enhancing micellar stability. F127-Cis-Dox achieved higher drug loading (5.54%) and encapsulation efficiency (61.8%) compared to F127-Suc-Dox (3.42%, 37.0%) and physically loaded F127-Dox micelles (4.94%, 60.3%). In vitro release showed pronounced pH sensitivity: F127-Cis-Dox released 80.7% of Dox at pH 5.5, compared with 25.2% at pH 7.4, whereas F127-Suc-Dox released 65.0% versus 33.9%, respectively. By contrast, F127-Dox exhibited rapid, nonspecific release (∼85% at pH 7.4, 144 h). These results highlight the importance of linker chemistry in tuning micelle stability and drug release. F127-Cis-Dox, in particular, demonstrates superior pH-responsiveness and drug-loading capacity, making it a promising candidate for tumor-targeted doxorubicin delivery.
Parisa Mostafapour Golezani, Mahrokh Sadat Alaei, Ebrahim Vasheghani-Farahani et al.· Journal of Pharmacy and Scie...· 0 citations
The clinical translation of small interfering RNA (siRNA) therapeutics critically depends on delivery systems capable of protecting nucleic acids, enabling efficient cellular uptake, and promoting cytosolic release. Liquid crystalline nanoparticles (LCNs) are promising carriers due to tunable internal nanostructure and biocompatibility, yet how composition controls membrane affinity and biological performance remains limited. Here, we compared two cationic reverse-hexagonal LCNs formulated from monoolein, oleic acid, poly(allylamine hydrochloride) and either poloxamer 407 (P407) or poloxamer 188 (P188). Both LCN-P407 and LCN-P188 shared reverse-hexagonal organization, mean diameters of 150–185 nm, low polydispersity (0.09–0.18), positive zeta potentials (10–20 mV), and protection of siRNA from RNase A. Langmuir isotherms and Brewster angle microscopy revealed pronounced adsorption and expansion of DPPC monolayers, with LCN-P188 inducing stronger perturbations, consistent with its higher cytotoxicity (∼20% increase in cell death) relative to LCN-P407. Crucially, siRNA delivered by LCN-P407 showed significantly greater uptake (> 1.7-fold) than that administered by LCN-P188. Functionally, as a proof of concept, we showed that LCN-P407-siTNFα induced robust gene silencing in LPS-stimulated macrophages, reducing TNFα secretion by 1.2–3.5-fold depending on particle concentration and incubation time. LCN-P188-siTNFα produced only delayed and modest reductions (1.3–1.6-fold). In addition, in dermatomized porcine skin, LCN-P407 also exhibited superior cutaneous penetration, delivering siRNA efficiently into the viable epidermis and dermis. Collectively, these results reveal a direct relationship between LCN composition, membrane affinity, and functional performance, providing mechanistic insight for the rational design of LCN-based carriers in RNA therapeutics.
Ana Vitória Pupo Silvestrini, Márcia Carvalho de Abreu Fantini, Ana Paula Ramos et al.· International Journal of Pha...· 0 citations
This study investigates the formation and characterization of nanocarriers derived from the self-assembly of amphiphilic lipid-polymer hybrids (LPHs) engineered with a symmetric ABA block copolymer architecture. In this design, the terminal A-blocks comprise branched hydrophobic fatty acid (FA) moieties, while the central B-block consists of a hydrophilic polymer segment, either polyethylene glycol (PEG) or a polypeptide-based glycine–lysine (GK) construct. By systematically varying the degree of branching within the hydrophobic blocks and the chemical identity of the hydrophilic segments, this work elucidates how architectural and compositional features govern the physicochemical behavior of the resulting nanoparticles (NPs). Comprehensive characterization, including 1D and 2D NMR spectroscopy, differential scanning calorimetry (DSC), dynamic light scattering (DLS), transmission electron microscopy (TEM), and in vitro cellular assays, revealed that both the morphology and mechanical properties of the NPs could be finely tuned through precise molecular design. Results indicate that NPs within the therapeutic size window (<200 nm) and with near-neutral surface charges meet key criteria for systemic delivery. Encapsulation efficiencies (EE%) for small-molecule therapeutics (doxorubicin and curcumin) ranged from 11–33%. Notably, modulation of hydrophilic block identity produced distinct NP surface chemistries that appear to influence cellular uptake behavior, while variations in hydrophobic block branching affected particle size distributions and nanostructural integrity. Substitution of inert PEG with the cationic, biofunctional GK polypeptide was associated with increased cellular uptake and enhanced doxorubicin delivery efficacy in breast cancer cell models. Additionally, increasing hydrophobic branching density (4FA versus 2FA) was correlated with improved colloidal stability and the formation of larger internal hydrophobic domains, supporting higher drug loading capacity. Collectively, these results provide an initial in vitro proof of concept and begin to establish structure–property–function relationships that expand the design space of amphiphilic LPH nanocarriers. While promising as an exploratory study, the work lays the groundwork for future studies needed to evaluate biological performance, safety, and translational potential.
Angel M. Weather, Penelope E. Jankoski, Allison Rattay et al.· ACS Omega· 0 citations
The development of efficient and targeted drug delivery systems remains a significant challenge, particularly for active pharmaceutical ingredients with poor aqueous solubility. Among various nanocarrier systems, Mesoporous Silica Nanoparticles (MSNs) have emerged as promising candidates due to their high surface area, tunable pore size (2-50 nm), thermal stability, and chemical modifiability. This review comprehensively discusses the rationale behind the utilization of MSN as drug delivery systems, focusing on how the type and concentration of surfactants, along with surface functionalization strategies, influence their physicochemical characteristics and pharmacokinetic performance. The synthesis of MSNs typically involves sol-gel processes using silica precursors (e.g., tetraethyl orthosilicate) and surfactants (e.g., cetyl trimethyl ammonium bromide, Pluronic F127), which dictate the morphology, particle size, and pore architecture of the resulting nanoparticles. Furthermore, surface modifications employing functional groups such as polyethylene glycol or pH-responsive polymers enhance biocompatibility, prolong systemic circulation, and enable controlled and site-specific drug release. Evidence from recent studies demonstrates that MSNs significantly improve drug loading efficiency, enhance solubility and bioavailability, and reduce off-target toxicity. Consequently, MSNs represent a highly versatile and modifiable platform with considerable potential for addressing the limitations of conventional drug delivery systems, particularly in oncology and the treatment of chronic diseases.
Ahmad Ainurofiq, Y. Ramadhana, Salma Aqilah Rachmadani et al.· Recent Advances in Drug Deli...· 0 citations
The role of vesicular systems in the field of drug delivery has led to increased research in the optimization of these novel delivery methods. Niosomes are bilayer structures that are capable of encapsulating lipophilic and hydrophilic compounds. In this study, niosomal systems formed from either Span 60 or Tween 60 non-ionic surfactants were investigated through experimental work and molecular dynamics simulations. Niosomes were prepared using thin-film hydration (TFH) and organic phase injection (OPI) methods and characterized in terms of particle size, polydispersity index, zeta potential, morphology, and encapsulation efficiency. A low-molecular-weight active pharmaceutical ingredient, tetracaine, and its water-soluble form, tetracaine HCl, were employed to understand the effect of pH on the encapsulation efficiency (EE) of the process. The molecular dynamics simulation of the niosomal system provided information on the distribution of Span 60 or Tween 60 surfactant molecules within the bilayer and the behavior of the tetracaine molecule.
Martina Ježková, A. H. George, Mario Vazdar et al.· Nanoscale Advances· 0 citations
ABSTRACT Lipid nanoparticles (LNPs) have rapidly emerged as the leading delivery platform for nucleic acid therapeutics due to their high encapsulation efficiency, scalable manufacturing, and clinical success in siRNA and mRNA medicines. Poly(ethylene glycol)‐lipids ((PEG)–lipids) have been central to this progress by providing steric stabilization, size control, and tunable biodistribution. However, PEGylation also introduces important limitations, including complement activation, pre‐existing and treatment‐induced anti‐PEG antibodies, and accelerated blood clearance, which increasingly constrain repeated and long‐term dosing strategies. This review focuses on recent advances in PEG‐alternative LNP designs, including non‐PEG polymers, zwitterionic and biomimetic lipids, polypeptides, and structurally modified PEG analogues. We compare how polymer chemistry, anchor geometry, and grafting architecture influence LNP formation, physicochemical properties, biodistribution, cellular uptake, and immunological outcomes. Moreover, we discuss key challenges that remain in translating PEG‐free and PEG‐modified LNPs toward clinical application and propose future directions to better understand in vivo behavior and enable rational design of next‐generation stealth LNPs. Overall, PEG lipid alternatives should not be viewed as simple PEG mimics, but as distinct surface‐engineering materials that create new nano‐bio interfaces and reshape LNP behavior in biological systems.
Zihnil A I Mazrad, Yi Ju, S. J. Kent et al.· Advancement of science· 0 citations