Inetetamab combined with pyrotinib and chemotherapy in the treatment of breast cancer brain metastasis: A case report.

BACKGROUND: Breast cancer brain metastasis (BCBM) is an advanced breast disease that is difficult to treat and is associated with a high risk of death. Patient prognosis is usually poor, with reduced quality of life. In this context, we report the case of a patient with HER-2-positive BCBM treated with a macromolecular mAb (inetetamab) combined with a small molecule tyrosine kinase inhibitor (TKI). CASE SUMMARY: The patient was a 58-year-old woman with a 12-year history of type 2 diabetes. She was compliant with regular insulin treatment and had good blood glucose control. The patient was diagnosed with invasive carcinoma of the right breast (T3N1M0 stage IIIa, HER2-positive type) through aspiration biopsy of the ipsilateral breast due to the discovery of a breast tumor in February 2019. Immunohistochemistry showed ER (-), PR (-), HER-2 (3+), and Ki-67 (55-60%+). Preoperative neoadjuvant chemotherapy, i.e., the AC-TH regimen (epirubicin, cyclophosphamide, docetaxel-paclitaxel, and trastuzumab), was administered for 8 cycles. She underwent modified radical mastectomy of the right breast in November 2019 and received tocilizumab targeted therapy for 1 year. Brain metastasis was found 9 mo after surgery. She underwent brain metastasectomy in August 2020. Immunohistochemistry showed ER (-) and PR. (-), HER-2 (3+), and Ki-67 (10-20%+). In November 2020, the patient experienced headache symptoms. After an examination, tumor recurrence in the original surgical region of the brain was observed, and the patient was treated with inetetamab, pyrotinib, and capecitabine. Whole-brain radiotherapy was recommended. The patient and her family refused radiotherapy for personal reasons. In September 2021, a routine examination revealed that the brain tumor was considerably larger. The original systemic treatment was continued and combined with intensity-modulated radiation therapy for brain metastases, followed by regular hospitalization and routine examinations. The patient's condition is generally stable, and she has a relatively high quality of life. This case report demonstrates that in patients with BCBM and resistance to trastuzumab, inetetamab combined with pyrotinib and chemotherapy can prolong survival. CONCLUSION: Inetetamab combined with small molecule TKI drugs, chemotherapy and radiation may be an effective regimen for maintaining stable disease in patients with BCBM.

Facile Fabrication of Lignin-Cellulose Green Nanogels.

There has been increasing exploration of the development and production of biodegradable polymers in response to issues with petrol-based polymers and their impact on the environment. Here we report a new approach to synthesize a natural nanogel from lignin and nanocellulose. First, lignin nanobeads were synthesized by a solvent-shifting method, which showed a spherical shape with a diameter of 159.7 nm. Then the lignin nanobeads were incorporated into a nanocellulose network to form the lignin/cellulose nanogels. The nanocellulose fibrils (CNF-C) nanogels reveal a higher storage modulus than the nanocellulose crystal (CNC-C) ones due to the denser network with self-entanglement of longer cellulose chains. The presence of lignin nanobeads in the nanogels helped to increase the viscoelasticity of the nanogels. This work highlights that the new kinds of green nanogels could be potentially utilized in a variety of biomedical applications such as drug delivery and wound dressing.

Nonvolatile modulation of luminescence in perovskite oxide thin films by ferroelectric gating.

Nonvolatile and giant modulation of luminescence can be realized by the ferroelectric gating effect in a Ga3+/Pr3+ co-doped BaTiO3 ultra-thin film epitaxially grown on a [Pb(Mg1/3Nb2/3)O3]0.7-[PbTiO3]0.3 single-crystallized substrate. The change behavior of the emission intensity matches that of the ferroelectric polarization hysteresis loop with a giant enhancement of over 13 times with negative polarization orientation. The interaction of O2- at the O2p orbital in the valence band and Pr3+ with injected holes by the ferroelectric gating effect promotes the formation of excited state O-, Pr4+, or Pr3+q. This ferroelectric gating method can promote the development of controllable photo-, electroluminescent, and other optoelectronic devices for display, sensing, communication, and so on.

Unprecedented Acid-Promoted Polymerization and Gelation of Acrylamide: A Serendipitous Discovery.

Dilute acid polymerizes degassed, aqueous acrylamide with concomitant gelation, without the need for added free radical initiator or cross-linking agent. This reaction is accelerated by sonication or UV irradiation, but inhibited by adventitious oxygen or the addition of a free radical inhibitor, suggesting an acid-accelerated free radical process. The resulting hydrogels are thixotropic in nature and partially disrupted by the addition of chaotropic agents, indicating the importance of hydrogen bonding to the 3D network. This discovery was made while trying to prepare pectin-polyacrylamide hydrogels. We observed that pectin initiated the gelation of acrylamide, but only if the aqueous pectin samples had a pH lower than ca. 5.

Poly(carbonate urethane)-Based Thermogels with Enhanced Drug Release Efficacy for Chemotherapeutic Applications.

In this study, we report the synthesis and characterisation of a thermogelling poly(carbonate urethane) system comprising poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG) and poly(polytetrahydrofuran carbonate) (PTHF carbonate). The incorporation of PTHF carbonate allowed for the control of the lower critical solution temperature (LCST) and decreased critical gelation concentration (CGC) of the thermogels significantly. In addition, the as-prepared thermogels displayed low toxicity against HepG2, L02 and HEK293T cells. Drug release studies were carried out using doxorubicin (Dox). Studies conducted using nude mice models with hepatocellular carcinoma revealed that the Dox-loaded poly(PEG/PPG/PTHF carbonate urethane) thermogels showed excellent in vivo anti-tumour performance and effectively inhibited tumour growth in the tested model.

Bioimaging and biodetection assisted with TTA-UC materials.

Upconversion of light has attracted intensive studies for biomedical research, because it enables deeper tissue analysis owing to the longer wavelength of incident light, compared with conventional downconversion fluorescent materials. Triplet-triplet annihilation (TTA), as a typical mechanism of upconversion, does not necessitate high power excitation and exhibits a higher quantum yield than rare earth upconversion owing to more sensitizer options with higher absorption coefficients. A desirable wavelength range of excitation and emission can be realized by careful selection of the combination of sensitizer and activator. Therefore, TTA-UC is worth exploring further for biorelated applications, such as bioimaging and biodetection. Recent developments are reviewed in this article.

Long-Term Real-Time In Vivo Drug Release Monitoring with AIE Thermogelling Polymer.

A new drug concentration meter is developed. In vivo drug release can be monitored precisely via a self-indicating drug delivery system consisting of a new aggregation-induced emission thermoresponsive hydrogel. By taking the advantage of a self-indicating system, one can easily detect the depletion of drugs, and reinject to maintain a dosage in the optimal therapeutic window.

New Linear and Star-Shaped Thermogelling Poly([R]-3-hydroxybutyrate) Copolymers.

The synthesis of multi-arm poly([R]-3-hydroxybutyrate) (PHB)-based triblock copolymers (poly([R]-3-hydroxybutyrate)-b-poly(N-isopropylacrylamide)-b-[[poly(methyl ether methacrylate)-g-poly(ethylene glycol)]-co-[poly(methacrylate)-g-poly(propylene glycol)]], PHB-b-PNIPAAM-b-(PPEGMEMA-co-PPPGMA), and their subsequent self-assembly into thermo-responsive hydrogels is described. Atom transfer radical polymerization (ATRP) of N-isopropylacrylamide (NIPAAM) followed by poly(ethylene glycol) methyl ether methacrylate (PEGMEMA) and poly(propylene glycol) methacrylate (PPGMA) was achieved from bromoesterified multi-arm PHB macroinitiators. The composition of the resulting copolymers was investigated by (1) H and (13) C J-MOD NMR spectroscopy as well as size-exclusion chromatography (SEC), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The copolymers featuring different architectures and distinct hydrophilic/hydrophobic contents were found to self-assemble into thermo-responsive gels in aqueous solution. Rheological studies indicated that the linear one-arm PHB-based copolymer tend to form a micellar solution, whereas the two- and four-arm PHB-based copolymers afforded gels with enhanced mechanical properties and solid-like behavior. These investigations are the first to correlate the gelation properties to the arm number of a PHB-based copolymer. All copolymers revealed a double thermo-responsive behavior due to the NIPAAM and PPGMA blocks, thus allowing first the copolymer self-assembly at room temperature, and then the delivery of a drug at body temperature (37 °C). The non-significant toxic response of the gels, as assessed by the cell viability of the CCD-112CoN human fibroblast cell line with different concentrations of the triblock copolymers ranging from 0.03 to 1 mg mL(-1) , suggest that these PHB-based thermo-responsive gels are promising candidate biomaterials for drug-delivery applications.

Emerging Supramolecular Therapeutic Carriers Based on Host-Guest Interactions.

Recent advances in host-guest chemistry have significantly influenced the construction of supramolecular soft biomaterials. The highly selective and non-covalent interactions provide vast possibilities of manipulating supramolecular self-assemblies at the molecular level, allowing a rational design to control the sizes and morphologies of the resultant objects as carrier vehicles in a delivery system. In this Focus Review, the most recent developments of supramolecular self-assemblies through host-guest inclusion, including nanoparticles, micelles, vesicles, hydrogels, and various stimuli-responsive morphology transition materials are presented. These sophisticated materials with diverse functions, oriented towards therapeutic agent delivery, are further summarized into several active domains in the areas of drug delivery, gene delivery, co-delivery and site-specific targeting deliveries. Finally, the possible strategies for future design of multifunctional delivery carriers by combining host-guest chemistry with biological interface science are proposed.

Modification of Thermal and Mechanical Properties of PEG-PPG-PEG Copolymer (F127) with MA-POSS.

Pluronic F127 exhibits thermogelling behaviour at 20⁻30 °C via a micelle packing mechanism. Disruption of the micelle packing increases the sol-gel temperature, but results in the decrease of modulus. Herein, we reported a method to modify F127 with polyhedral oligosilsesquioxane (POSS) to impart a higher gelling temperature without yielding the property and strength of the thermogel. The thermal degradation temperature was enhanced to 15 °C after POSS incorporation and the gelling temperature shifted 10 °C higher, without sacrificing the modulus of the gel. Rheological studies supported the claim that the gel property was reinforced after POSS incorporation. F127-POSS copolymer matrix stored more energy from POSS reinforcement, which saw larger Lissajous curve areas before the collapse of the microstructure for the same amount of stress applied. These results indicated that modification with POSS would raise the sol-gel transition temperature without sacrificing the modulus of the gel.

Thermogels: In Situ Gelling Biomaterial.

In situ gel delivery systems are preferred over conventional systems due to sustained and prolonged release action of therapeutic payload onto the targeted site. Thermogel, a form of in situ gel-forming polymeric formulation, undergoes sol-gel transition after administration into the body. At room temperature, the system is an aqueous polymer solution that easily entraps therapeutic payload by mixing. Upon injection, the higher physiological temperature causes gelation in situ because of the presence of thermosensitive polymers. The gel degrades gradually over time, allowing sustained release of therapeutics localized to the site of interest. This minimizes systemic toxicity and improved efficacy of drug release to the targeted site. Thermogel properties can be easily altered for specific applications via substitution and modification of components in diblock and triblock copolymer systems. The feasibility of fine-tuning allows modifications to biodegradability, biocompatibility, biological functionalization, mechanical properties, and drug release profile. This review summarized recent development in thermogel research with a focus on synthesis and self-assembly mechanisms, gel biodegradability, and applications for drug delivery, cell encapsulation and tissue engineering. This review also assessed inadequacy of material properties as a stand-alone factor on therapeutic action efficacy in human trials, with a focus on OncoGel, an experimental thermogel that demonstrated excellent individual or synergistic drug delivery system in preclinical trials but lacked therapeutic impact in human trials. Detailed analysis from all aspects must be considered during technology development for a successful thermogel platform in drug delivery and tissue engineering.

Utilising inorganic nanocarriers for gene delivery.

The delivery of genetic materials into cells to elicit cellular responses has been extensively studied by biomaterials scientists globally. Many materials such as lipids, peptides, viruses, synthetically modified cationic polymers and certain inorganic nanomaterials could be used to complex the negatively charged plasmids and deliver the formed package into cells. The recent literature on the delivery of genetic materials utilising inorganic nanoparticles is carefully examined in this review. We have picked out the most relevant references and concisely summarised the findings with illustrated examples. We further propose alternative approaches and suggest future pathways towards the practical use of multifunctional nanocarriers.

Mimicking cellular transport mechanism in stem cells through endosomal escape of new peptide-coated quantum dots.

Protein transport is an important phenomenon in biological systems. Proteins are transported via several mechanisms to reach their destined compartment of cell for its complete function. One such mechanism is the microtubule mediated protein transport. Up to now, there are no reports on synthetic systems mimicking the biological protein transport mechanism. Here we report a highly efficient method of mimicking the microtubule mediated protein transport using newly designed biotinylated peptides encompassing a microtubule-associated sequence (MTAS) and a nuclear localization signaling (NLS) sequence, and their final conjugation with streptavidin-coated CdSe/ZnS quantum dots (QDs). Our results demonstrate that these novel bio-conjugated QDs enhance the endosomal escape and promote targeted delivery into the nucleus of human mesenchymal stem cells via microtubules. Mimicking the cellular transport mechanism in stem cells is highly desirable for diagnostics, targeting and therapeutic applications, opening up new avenues in the area of drug delivery.

Sandwich-structured upconversion nanoparticles with tunable color for multiplexed cell labeling.

The need for a more efficient biological label to meet their burgeoning utility in rapidly developing multiplexing applications may be realized through the recent advent of upconversion nanoparticles (UCNs). UCNs fabricated to-date, however, are either not displaying strong fluorescence or have limited available colors. Here, we report on fabricating sandwich-structured UCNs with a NaYbF(4) matrix sandwiched between two NaYF(4) layers. Such sandwich design allows for efficient absorption of the excitation energy by the absorber ion-rich NaYbF(4) layer that then transfers it to the adjacent NaYF(4) layers on either side for an improved fluorescence efficiency. By doping different emitters into each of the shells and adjusting their thickness, different color output tunable based on the RGB color model were obtained. In this study, multicolor UCNs with strong emission intensity have been facilely synthesized and used for multiplex detection of three subcellular targets with a single near-infrared excitation wavelength.

Tuning the autophagy-inducing activity of lanthanide-based nanocrystals through specific surface-coating peptides.

The induction of autophagy on exposure of cells to a variety of nanoparticles represents both a safety concern and an application niche for engineered nanomaterials. Here, we show that a short synthetic peptide, RE-1, identified by means of phage display, binds to lanthanide (LN) oxide and upconversion nanocrystals (UCN), forms a stable coating layer on the nanoparticles' surface, and effectively abrogates their autophagy-inducing activity. Furthermore, RE-1 peptide variants exhibit a differentially reduced binding capability, and correspondingly, a varied ability to reduce the autophagic response. We also show that the addition of an arginine-glycine-aspartic acid (RGD) motif to RE-1 enhances autophagy for LN UCN through the interaction with integrins. RE-1 and its variants provide a versatile tool for tuning material-cell interactions to achieve the desired level of autophagy, and may prove useful for the various diagnostic and therapeutic applications of LN-based nanomaterials and nanodevices.

Tuning of the structure and emission spectra of upconversion nanocrystals by alkali ion doping.

Recently, lanthanide based nanocrystals with upconversion fluorescence emission have attracted a lot of interest and the nanocrystals have been used for bioimaging, biodetection, and therapeutic applications. Use of the nanocrystals for multiplexed detection has also been explored; however, nanocrystals with multicolor emission are required. Some efforts have been made to tune the emission spectra of the nanocrystals based on manipulation of upconverting lanthanide ions doped in the crystals or creation of core/shell structures. In this work, alkali ions with an ionic radius slightly larger or smaller than Na such as Li and K were doped into NaYF(4):Yb,Er nanocrystals and their effect on the crystal structure and subsequently the upconversion emission spectra were studied. It was found that the phase transition occurs in the nanocrystals when a different amount of Li and K was doped. Furthermore, the intensity ratios between the blue, green, and red emission peaks changed accordingly, and make it possible to tune the upconversion fluorescence of the nanocrystals by Li and K doping.