The Necessity to Investigate In Vivo Fate of Nanoparticle-Loaded Dissolving Microneedles

Transdermal drug delivery systems are rapidly gaining prominence and have found widespread application in the treatment of numerous diseases. However, they encounter the challenge of a low transdermal absorption rate. Microneedles can overcome the stratum corneum barrier to enhance the transdermal absorption rate. Among various types of microneedles, nanoparticle-loaded dissolving microneedles (DMNs) present a unique combination of advantages, leveraging the strengths of DMNs (high payload, good mechanical properties, and easy fabrication) and nanocarriers (satisfactory solubilization capacity and a controlled release profile). Consequently, they hold considerable clinical application potential in the precision medicine era. Despite this promise, no nanoparticle-loaded DMN products have been approved thus far. The lack of understanding regarding their in vivo fate represents a critical bottleneck impeding the clinical translation of relevant products. This review aims to elucidate the current research status of the in vivo fate of nanoparticle-loaded DMNs and elaborate the necessity to investigate the in vivo fate of nanoparticle-loaded DMNs from diverse aspects. Furthermore, it offers insights into potential entry points for research into the in vivo fate of nanoparticle-loaded DMNs, aiming to foster further advancements in this field

Mesoporous silica nanoparticles for drug and gene delivery

Mesoporous silica nanoparticles (MSNs) are attracting increasing interest for potential biomedical applications. With tailored mesoporous structure, huge surface area and pore volume, selective surface functionality, as well as morphology control, MSNs exhibit high loading capacity for therapeutic agents and controlled release properties if modified with stimuli-responsive groups, polymers or proteins. In this review article, the applications of MSNs in pharmaceutics to improve drug bioavailability, reduce drug toxicity, and deliver with cellular targetability are summarized. Particularly, the exciting progress in the development of MSNs-based effective delivery systems for poorly soluble drugs, anticancer agents, and therapeutic genes are highlighted. KEY WORDS: Mesoporous silica nanoparticles, Poorly soluble drug, Cancer therapy, Multidrug resistance, Gene deliver

Supersaturable organic-inorganic hybrid matrix based on well-ordered mesoporous silica to improve the bioavailability of water insoluble drugs

Mesoporous silica with uniform 2-D hexagonal pores has been newly employed as facile reservoir to impove the dissolution rate of water insoluble drugs. However, rapid drug release from mesoporous silica is usually accompanied by the generation of supersaturated solution, which leads to the drug precipitation and compromised absorption. To address this issue, a supersaturated ternary hybrid system was constructed in this study by utilizing inorganic mesoporous silica and organic precipitation inhibitor. Vinylprrolidone-vinylacetate copolymer (PVP VA64) with similar solubility parameter to model drug fenofibrate (FNB) was expected to well inhibit the precipitation. Mesoporous silica Santa Barbara amorphous-15 (SBA-15) was synthesized in acidic media and hybrid matrix was produced by hot melt extrusion technique. The results of in vitro supersaturation dissolution test obviously revealed that the presence of PVP VA64 could effectively sustain a higher apparent concentration. PVP VA64 was suggested to simultaneously reduce the rate of nucleation and crystal growth and subsequently maintain a metastable supersaturated state. The absorption of FNB delivered by the organic-inorganic hybrid matrix was remarkably enhanced in beagle dogs, and its AUC value was 1.92-fold higher than that of FNB loaded mesoporous silica without PVP VA 64. In conclusion, the supersaturated organic-inorganic hybrid matrix can serve as a modular strategy to enhance the oral availability of water insoluble drugs

Superparamagnetic Nanocrystals Clustered Using Poly(ethylene glycol)-Crosslinked Amphiphilic Copolymers for the Diagnosis of Liver Cancer

Superparamagnetic iron oxide (SPIO) nanocrystals have been extensively studied as theranostic nanoparticles to increase transverse (T2) relaxivity and enhance contrast in magnetic resonance imaging (MRI). To improve the blood circulation time and enhance the diagnostic sensitivity of MRI contrast agents, we developed an amphiphilic copolymer, PCPZL, to effectively encapsulate SPIO nanocrystals. PCPZL was synthesized by crosslinking a polyethylene glycol (PEG)-based homobifunctional linker with a hydrophobic star-like poly(ε-benzyloxycarbonyl-L-lysine) segment. Consequently, it could self-assemble into shell-crosslinked micelles with enhanced colloidal stability in bloodstream circulation. Notably, PCPZL could effectively load SPIO nanocrystals with a high loading capacity of 66.0 ± 0.9%, forming SPIO nanoclusters with a diameter of approximately 100 nm, a high cluster density, and an impressive T2 relaxivity value 5.5 times higher than that of Resovist®. In vivo MRI measurements highlighted the rapid accumulation and contrast effects of SPIO-loaded PCPZL micelles in the livers of both healthy mice and nude mice with an orthotopic hepatocellular carcinoma tumor model. Moreover, the magnetic micelles remarkably enhanced the relative MRI signal difference between the tumor and normal liver tissues. Overall, our findings demonstrate that PCPZL significantly improves the stability and magnetic properties of SPIO nanocrystals, making SPIO-loaded PCPZL micelles promising MRI contrast agents for diagnosing liver diseases and cancers

Optimization of a doxycycline hydroxypropyl-β-cyclodextrin inclusion complex based on computational modeling

To prepare a stable complex of doxycycline (Doxy) and hydroxypropy-β-cyclodextrin (HP-β-CD) for ophthalmic delivery, the optimum formulation and preparation conditions were investigated using response surface methodology (RSM), artificial neural network (ANN) and support vector machine (SVM) modeling. The molar ratios of HP-β-CD/Doxy and Mg2+/Doxy, inclusion time and temperature were selected as independent variables (X1–X4) and inclusion efficiency and stability of the Doxy-HP-β-CD complex were selected as dependent (response) variables (Y1 and Y2). The optimal formulation predicted by genetic algorithm (GA) combined with the models was characterized by microscopy and nuclear magnetic resonance spectrometry, and the stability of Doxy in the complex was evaluated. The highest values of Y1 and Y2 were obtained using an ANN model combined with GA which predicted the values of X1–X4 to be 4, 10.8, 12 h and 25 °C, respectively. The modeling and optimization results indicated that a feed-forward back-propagation ANN with one hidden layer and 10 hidden units showed better fitting to both responses compared to the RSM and SVM models. GA proved to be an efficient tool in multi-objective optimization of a pharmaceutical formulation

Synergistic immunoreaction of acupuncture-like dissolving microneedles containing thymopentin at acupoints in immune-suppressed rats

Dissolving microneedles carried drug molecules can effectively penetrate the stratum corneum of skin to improve the transdermal drug delivery. The traditional Chinese medicine acupuncture is based on the needle stimulation at a specific location (acupoint) to generate and transmit biochemical and physiological signals which alter the pathophysiological state of patients. However, the pain associated with conventional acupuncture needles and the requirement of highly trained professionals limit the development of acupuncture in non-Asian countries. The purpose of this study is to investigate whether the dissolving microneedles can be utilized as a self-administered painless replacement for acupuncture and locally released drug molecules can achieve expected therapeutic outcomes. Immunosuppressive rats were treated with acupuncture at Zusanli (ST36) acupoint using microneedles containing thymopentin. The immune functions and psychological mood of the immunosuppressed animals were examined. The proliferation of splenocytes was examined by CCK-8 assay. CD4 and CD8 expression patterns in spleen cells were detected by flow cytometry. The current study showed that use of either microneedles containing thymopentin or conventional acupuncture both resulted in immune cell proliferation, which was confirmed by flow cytometry. Furthermore, either conventional acupuncture or microneedles were able to effectively mitigate the anxiety caused by immune-suppression when applied on the ST36. KEY WORDS: Dissolving microneedles, Acupoint, Thymopentin (TP5), Immune-modulating effects, transdermal drug delivery, Acupunctur

Anhydrous reverse micelle nanoparticles: new strategy to overcome sedimentation instability of peptide-containing pressurized metered-dose inhalers

The objective of this study was to develop a novel anhydrous reverse micelle nanoparticles (ARM-NPs) system to overcome the sedimentation instability of peptide-containing pressurized metered-dose inhalers (pMDIs). A bottom-up method was utilized to fabricate ARM-NPs. Tertiary butyl alcohol (TBA)/water system, freeze-drying and lipid inversion method were successively used to produce the ARM-NPs for pMDI. Various characteristics of ARM-NPs were investigated including particle size, morphology, secondary structure of the peptide drug, aerosolization properties and storage stability. As revealed by the results, ARM-NPs with spherical shape possessed 147.7 ± 2.0 nm of particle size with 0.152 ± 0.021 PdI. The ARM-NPs for pMDI had satisfactory fine particle fraction (FPF) value of 46.99 ± 1.33%, while the secondary structure of the peptide drug was unchanged. Stability tests showed no pronounced sedimentation instability for over 12 weeks at 4–6 °C. Furthermore, a hypothesis was raised to explain the formation mechanism of ARM-NPs, which was verified by the differential scanning calorimetry analysis. The lecithin employed in the reverse micelle vesicles could serve as a steric barrier between peptide drugs and bulk propellant, which prevented the instability of peptide drugs in hydrophobic environment. Homogenous particle size could avoid Ostwald ripening phenomenon of particles in pMDIs. It was concluded that the ARM-NPs for pMDI could successfully overcome sedimentation instability by the steric barrier effect and homogeneous particle size