Correction: Microneedle-mediated delivery of MIL-100(Fe) as a tumor microenvironment-responsive biodegradable nanoplatform for O2-evolving chemophototherapy.

Correction for 'Microneedle-mediated delivery of MIL-100(Fe) as a tumor microenvironment-responsive biodegradable nanoplatform for O2-evolving chemophototherapy' by Sulan Luo et al., Biomater. Sci., 2021, DOI: 10.1039/d1bm00888a.

Bioresponsive Nanoarchitectonics-Integrated Microneedles for Amplified Chemo-Photodynamic Therapy against Acne Vulgaris.

The excessive colonization of Propionibacterium acnes (P. acnes) is responsible for the genesis of acne vulgaris, a common inflammatory disease of skin. However, the conventional anti-acne therapies are always limited by various side effects, drug resistance, and poor skin permeability. Microneedles (MNs) are emerging topical drug delivery systems capable of noninvasively breaking through the skin stratum corneum barrier to efficiently enhance the transdermal drug penetration. Herein, MNs loaded with intelligent pH-sensitive nanoplatforms were constructed for amplified chemo-photodynamic therapy against acne vulgaris, jointly exerting antimicrobial and anti-inflammatory effects. The photosensitizer indocyanine green (ICG) was loaded into the zeolitic imidazolate framework-8 (ZIF-8) to improve its photostability, which would be triggered by 808 nm laser irradiation to generate cytotoxic reactive oxygen species (ROS) to result in oxidative damage and disturbed metabolic activities of P. acnes. In addition to the efficient drug delivery, the ZIF-8 carrier could selectively degrade in response to the acidic microenvironment of acne lesions, and the released Zn2+ also exhibited a potent antimicrobial activity. The fabricated ZIF-8-ICG@MNs presented an outstanding synergistic anti-acne efficiency both in vitro and in vivo. This bioresponsive microneedle patch is expected to be readily adapted as a generalized, modular strategy for noninvasive therapeutics delivery against superficial skin diseases.

Microneedle-mediated delivery of MIL-100(Fe) as a tumor microenvironment-responsive biodegradable nanoplatform for O2-evolving chemophototherapy.

The low oxygen level in tumors significantly reduces the antitumor efficacy of photodynamic therapy (PDT). The provision of O2 and monomeric hydrophobic photosensitizers (PSs) under physiological conditions would greatly help to shrink malignant tumors. We take advantage of the high porosity and multifunctionality of metal-organic frameworks (MOFs) to fabricate a simple all-in-one nanoplatform mediated by microneedle delivery to achieve synergistic O2 evolution and chemophototherapy. An iron(III)-based MOF (MIL-100(Fe)) acted not only as a vehicle for the concurrent delivery of zinc phthalocyanine (ZnPc) and doxorubicin hydrochloride (Dox), but also to supply O2 by decomposing hydrogen peroxide (H2O2) in the tumor microenvironment via a Fenton-like reaction. In vitro and in vivo experiments indicated that the nanoplatform had excellent biocompatibility and exerted enhanced anticancer effects. The encapsulated drug was sustainably released from the nanoplatform skeleton in response to acidic tumor microenvironments. Moreover, upon 660 nm light irradiation, ZnPc effectively produced reactive oxygen species (ROS) due to the reduction of hypoxia by MIL-100(Fe). A microneedle technique was adopted to directly deliver the nanoplatform into superficial tumors rather than via systemic circulation. Hence, this study provides a new strategy for more efficient chemophototherapy of hypoxic superficial tumors.

Intelligent and spatiotemporal drug release based on multifunctional nanoparticle-integrated dissolving microneedle system for synergetic chemo-photothermal therapy to eradicate melanoma.

Cutaneous melanoma is one of the most common malignant skin cancer with high lethality. Chemotherapy and photothermal therapy are important and extensively studied treatment modalities for melanoma. However, these therapies still face some challenges, which severely restrict their further applications, such as unsatisfactory efficacy of monotherapy, nonspecific uptake and release during drug delivery, and unexpected adverse effects from system administration. Recently, the strategies of collaboration, functional modification, stimuli-responsive design, and topical administration all show great prospect for solving above problems. In this research, a multifunctional nanoparticle-integrated dissolving microneedle drug delivery system was constructed, in which the nanoparticles were prepared based on the framework with the incorporation of photothermal agent (CuS) into Zeolitic imidazolate framework-8 and functionalized by hyaluronic acid. This system can co-load multi-modal drugs, improve specific uptake and distribution of targeted tumor, deliver drug locally, and release drug intelligently and spatiotemporally, thereby promising a low-dose administration with high efficiency. The high inhibiting tumor performance and excellent systematic safety were verified both in vitro and in vivo. Together, this smart design overcame the drawbacks of monotherapy and conventional system administration. We believe the nanoparticle-integrated dissolving microneedles will be in prospect of clinical application for more superficial tumors with further delicate optimization. STATEMENT OF SIGNIFICANCE: Melanoma is one of the most common skin cancers with high lethality. Extensively studied chemotherapy and photothermal therapy still face some challenges, such as the limited therapeutic efficacy and the severe system adverse effects. In order to overcome these drawbacks, the multifunctional nanoparticle-integrated dissolving microneedles (DMNs) were designed. Especially, the nanoparticles could co-load multi-modal drugs, improve specific uptake, and release drug intelligently and spatiotemporally. The microneedles could increase the drug accumulation in tumor, thus achieving excellent therapeutic efficacy and reducing side effects. This system paved the way to a less invasive, more focused and efficient therapeutic strategy for melanoma therapy.

A novel scalable fabrication process for the production of dissolving microneedle arrays.

Microneedle arrays have emerged as an alternative method for transdermal drug delivery. Although micromolding using a centrifugation method is widely used to prepare microneedles in laboratory, few researchers were focused on manufacturing processes capable of facile scale-up. A novel female mold was initially designed in this study, namely double-penetration female mold (DPFM) with the pinpoints covered by waterproof breather membrane which was beneficial to reduce the influence of gas resistance and solution viscosity. In addition, DPFM-based positive-pressure microperfusion technique (PPPT) was proposed for the scale-up fabrication of dissolving microneedle arrays (DMNA). In this method, polymer solution and base solution were poured into the DPFM by pressure difference, followed by drying and demolding. The results of optimal microscopy and SEM revealed that the obtained microneedles were uniformly distributed conical-shaped needles. The skin penetration test showed that DMNA prepared using PPPT were able to penetrate the rat skin with a high penetration rate. To realize the transition of microneedles fabrication from laboratory to industry, an automatic equipment was further designed in this study. Different from micromolding method using centrifugation, the equipment based on PPPT and DPFM has superiorities in the scale-up fabrication of microneedles in a highly effective, controllable, and scalable way.

Formation Mechanism and In Vitro Evaluation of Risperidone-Containing PLGA Microspheres Fabricated by Ultrafine Particle Processing System.

Ultrafine particle processing system (UPPS) was developed previously by our group to provide a new solution to microsphere fabrication. The UPPS was supposed to possess many featured advantages, but the microsphere formation mechanism during UPPS processing was still unknown. The objective of this study was to perform the formation mechanism investigation and in vitro evaluation on risperidone-containing poly(d, l-lactic-co-glycolic acid) microspheres (RIS-PLGA MS) fabricated by UPPS. Evaporation profile and viscosity of the PLGA-containing solutions were considered as the critical factors for the microsphere formation mechanism and were determined in present study. The formation mechanism of RIS-PLGA MS was put forward by semiquantitative analysis on the basis of the evaporation profile, viscosity, and scanning electron microscopy results. It was established that the evaporation profile and viscosity would have an impact on the evaporation velocity and PLGA molecular diffusion velocity during solidification process, resulting in different appearance of the microspheres. Furthermore, comprehensive in vitro evaluations of RIS-PLGA MS were conducted, including particle size distribution, micromeritics, morphology, drug loading, encapsulation efficiency, residual organic solvent, syringeability, and in vitro release behavior. The results revealed that RIS-PLGA MS was a promising candidate for intramuscular administration, and meanwhile UPPS was a qualified technology for microsphere production.

Enhancing oral bioavailability of quercetin using novel soluplus polymeric micelles.

To improve its poor aqueous solubility and stability, the potential chemotherapeutic drug quercetin was encapsulated in soluplus polymeric micelles by a modified film dispersion method. With the encapsulation efficiency over 90%, the quercetin-loaded polymeric micelles (Qu-PMs) with drug loading of 6.7% had a narrow size distribution around mean size of 79.00 ± 2.24 nm, suggesting the complete dispersibility of quercetin in water. X-ray diffraction (XRD) patterns illustrated that quercetin was in amorphous or molecular form within PMs. Fourier transform infrared spectroscopy (FTIR) indicated that quercetin formed intermolecular hydrogen bonding with carriers. An in vitro dialysis test showed the Qu-PMs possessed significant sustained-release property, and the formulation was stable for at least 6 months under accelerated conditions. The pharmacokinetic study in beagle dogs showed that absorption of quercetin after oral administration of Qu-PMs was improved significantly, with a half-life 2.19-fold longer and a relative oral bioavailability of 286% as compared to free quercetin. Therefore, these novel soluplus polymeric micelles can be applied to encapsulate various poorly water-soluble drugs towards a development of more applicable therapeutic formulations.

Preparation and in vitro evaluation of silk fibroin microspheres produced by a novel ultra-fine particle processing system.

The objective of this study was to prepare silk fibroin SF microspheres containing the enhanced green fluorescent protein (EGFP) by using a novel ultra-fine particle processing system (UPPS) and to evaluate the microspheres as possible carriers for long-term delivery of sensitive biologicals. The drug content, encapsulation efficiency, and in vitro release were evaluated by Microplate Absorbance Reader. The particle size distribution and morphology of the microspheres were analyzed by Malvern Master Sizer 2000 and scanning electron microscopy. The distribution of EGFP and the interactions between SF and EGFP were investigated by Confocal Laser Scanning Microscopy, FTIP, Raman and NMR spectroscopy. The results showed that spherical microspheres with narrow size distribution, glossy and dense surface were successfully manufactured by using UPPS technology and over 95% of EGFP encapsulation efficiency and uniform drug distribution in the microspheres were achieved. Furthermore, a burst free and sustained release of encapsulated EGFP for a period of 50 days in deionized water was obtained. In conclusion, the novel UPPS technology could be used to manufacture SF matrix microspheres as a potential long-term protein delivery system to improve patient compliance and convenience.

Transarterial chemoembolization using docetaxel-loaded phytantriol cubic phase precursor for the treatment of hepatocellular carcinoma.

The purpose of this study was to evaluate the transarterial chemoembolic agent based on docetaxel-loaded phytantriol cubic phase precursor (DTX PCPP) by in vitro cytotoxicity study and in vivo evaluation of antitumor efficacy as well as the histological examination. The methythiazolyl tereazolium bromide assay in Hep G2 cell line revealed that DTX PCPP generated high cytotoxicity by causing cell apoptosis and G2/M phase arrest. In vivo studies conducted in rabbits bearing VX2 tumors, which were treated with DTX PCPP, used as a transarterial chemoembolic agent, showed a significant antitumor efficacy and prominent higher DTX concentrations in tumor and liver than those in other organs. The histology presented typical necrosis in tumor that demonstrated excellent therapeutic effect. In conclusion, the DTX PCPP could achieve an excellent antitumor effect with low systemic toxicity for the treatment of hepatocellular carcinoma and therefore implied the prospect of DTX PCPP for clinical applications.

Design and in vitro evaluation of capsaicin transdermal controlled release cubic phase gels.

The purpose of this study was to design and investigate the transdermal controlled release cubic phase gels containing capsaicin using glycerol monooleate (MO), propylene glycol (1,2-propanediol, PG), and water. Three types of cubic phase gels were designed based on the ternary phase diagram of the MO-PG-water system, and their internal structures were confirmed by polarizing light microscopy (PLM) and small-angle X-ray scattering (SAXS). Release results showed the cubic phase gels could provide a sustained system for capsaicin, while the initial water content in the gels was the major factor affecting the release rate. Release kinetics was determined to fit Higuchi's square-root equation indicating that the release was under diffusion control. The calculated diffusion exponent showed the release from cubic phase gels was anomalous transport. The unique structure of the cubic phases, capsaicin distributed in the lipid bilayers, and cubic phase gel swelling contributed to the release mechanism. The cubic phase gel may be an interesting application for transdermal delivery system of capsaicin in alleviating the post-incision pain.

Novel compaction techniques with pellet-containing granules.

OBJECTIVE: The purpose of this investigation was to introduce a new concept of admixing coated pellets with excipients to obtain a segregation-free combination of pellet-containing granules and cushioning granules during mixing and compression. METHODS: Acrylic polymeric-coated pellets were granulated by centrifugal granulation method with excipients; then, the pellet-containing granules were compacted into tablets with the cushioning granules, which were prepared in mixer or fluidized bed-granulator. Tablets were also made in a traditional method by directly compressing the mixtures of coated pellets and cushioning granules for control. Drug-release profiles, weights and drug content of tables were tested to compare this new method with the traditional method. RESULTS: The granulation process changed the surface morphology of coated pellets from smooth to rough and increased the angle of repose of pellets to close to that of the cushioning granules. Weight and drug content RSD values of tablets prepared by pellet-containing granules were much lower than those of tablets prepared by coated pellets. The similarity factor f(2) values for drug-release profiles of tablets prepared from pellet-containing granules and the original coated pellets were above 50 when microcrystalline cellulose (MCC), Polyplasdone(R) XL (PVPP), and lactose were used as granulating excipients. CONCLUSIONS: The granulation process could roughen the surface of coated pellets and increase the angle of repose and uniformity of the mixture with cushioning granules. Compared with the tablets directly compressed from coated pellets, the tablets prepared by pellet-containing granules showed improved uniformity in both weight and drug content. The granulation and compression processes did not significantly influence the drug-release behavior of coated pellets, and the enteric dissolution was retained.