Facile fabrication of multi-pocket nanoparticles with stepwise size transition for promoting deep penetration and tumor targeting

Background Nanocarriers-derived antitumor therapeutics are often associated with issues of limited tumor penetration and dissatisfactory antitumor efficacies. Some multistage delivery systems have been constructed to address these issues, but they are often accompanied with complicated manufacture processes and undesirable biocompatibility, which hinder their further application in clinical practices. Herein, a novel dual-responsive multi-pocket nanoparticle was conveniently constructed through self-assembly and cross-linking of amphiphilic methoxypolyethylene glycol-lipoic acid (mPEG-LA) conjugates to enhance tumor penetration and antitumor efficacy. Results The multi-pocket nanoparticles (MPNs) had a relatively large size of ~ 170 nm at physiological pH which results in prolonged blood circulation and enhanced accumulation at the tumor site. But once extravasated into acidic tumor interstices, the increased solubility of PEG led to breakage of the supramolecular nanostructure and dissolution of MPNs to small-sized (< 20 nm) nanoparticles, promoting deep penetration and distribution in tumor tissues. Furthermore, MPNs exhibited not only an excellent stable nanostructure for antitumor doxorubicin (DOX) loading, but rapid dissociation of the nanostructure under an intracellular reductive environment. With the capacity of long blood circulation, deep tumor penetration and fast intracellular drug release, the DOX-loaded multi-pocket nanoparticles demonstrated superior antitumor activities against large 4T1 tumor (~ 250 mm3) bearing mice with reduced side effect. Conclusions Our facile fabrication of multi-pocket nanoparticles provided a promising way in improving solid tumor penetration and achieving a great therapeutic efficacy. Graphic Abstract

A Novel Anti-Tumor/Anti-Tumor-Associated Fibroblast/Anti-mPEG Tri-Specific Antibody to Maximize the Efficacy of mPEGylated Nanomedicines against Fibroblast-Rich Solid Tumor

The therapeutic efficacy of methoxypolyethylene glycol (mPEG)-coated nanomedicines in solid tumor treatment is hindered by tumor-associated fibroblasts (TAFs), which promote tumor progression and form physical barriers. We developed an anti-HER2/anti-FAP/anti-mPEG...

Differential Leukocyte miRNA Responses Following Pan T Cell, Allorecognition and Allosecretome-Based Therapeutics Activation

Background Effective immunomodulation of T cell responses is critical in treating both autoimmune diseases and cancer. Our previous studies have demonstrated that secretomes derived from control or methoxypolyethylene glycol (mPEG) mixed lymphocyte alloactivation assays exerted potent immunomodulatory activity that was mediated by microRNAs (miRNA). In this study, the immunomodulatory effects of biomanufactured miRNA-based allo-secretome therapeutics (SYN, TA1, IA1 and IA2) were compared to Pan T cell activators (PHA and anti-CD3/CD28) and alloactivation (MHC-disparate donors; ± mPEG grafting). The differential effects of these activation strategies on resting PBMC were assessed via T cell differentiation and proliferation as well as the differential expression of multiple miRNA.Results Mitogen-induced PBMC proliferation (average of > 85%) significantly exceed that arising from either allostimulation (~ 30%) or the proinflammatory IA1 secretome product (~ 12%). Consequent to stimulation, the ratio of CD4 to CD8 cells of the resting PBMC (CD4:CD8; 1.7 ± 0.1) decreased in the Pan-T cell, allrecognition and IA1 activated cells (average of 1.1 ± 0.2; 1.2 ± 0.1 and 1.0 ± 0.1). These changes arose consequent to the expansion of both CD4+CD8+ and CD4-CD8- populations and the shrinkage of the CD4 subset relative to the expansion of the CD8 T cells. Most importantly, this study demonstrated that these activation strategies exert profoundly unique effects on the differential expression of miRNA within the treated PBMC and that these 'differential patterns of miRNA expression' are associated with significant differences in cellular differentiation and biological function.Conclusions These findings support the concept that the 'differential pattern of miRNA expression', not a change in a single miRNA, governs the biologic immune response in a 'lock and key' manner. The biomanufacturing of miRNA-enriched secretome biotherapeutics may be a successful approach for producing miRNA cocktails (e.g., TA1 and IA1) that replicate the normal biological 'lock and key' miRNA configuration necessary for the systemic treatment of autoimmune diseases (TA1) or enhancing the endogenous immune response to cancer (IA1).

Ionic Species Affect the Self-Propulsion of Urease-Powered Micromotors

Enzyme-powered motors self-propel through the catalysis of in situ bioavailable fuels, which makes them excellent candidates for biomedical applications. However, fundamental issues like their motion in biological fluids and the understanding of the propulsion mechanism are critical aspects to be tackled before a future application in biomedicine. Herein, we investigated the physicochemical effects of ionic species on the self-propulsion of urease-powered micromotors. Results showed that the presence of PBS, NaOH, NaCl, and HEPES reduced self-propulsion of urease-powered micromotors pointing towards ion-dependent mechanisms of motion. We studied the 3D motion of urease micromotors using digital holographic microscopy to rule out any motor-surface interaction as the cause of motion decay when salts are present in the media. In order to protect and minimize the negative effect of ionic species on micromotors’ performance, we coated the motors with methoxypolyethylene glycol amine (mPEG) showing higher speed compared to noncoated motors at intermediate ionic concentrations. These results provide new insights into the mechanism of urease-powered micromotors, study the effect of ionic media, and contribute with potential solutions to mitigate the reduction of mobility of enzyme-powered micromotors.

A Novel Gel Polymer Electrolyte by Thiol-Ene Click Reaction Derived from CO2-Based Polycarbonate for Lithium-Ion Batteries

Here, we describe the synthesis of a CO2-based polycarbonate with pendent alkene groups and its functionalization by grafting methoxypolyethylene glycol in view of its application possibility in gel polymer electrolyte lithium-ion batteries. The gel polymer electrolyte is prepared by an in-situ thiol-ene click reaction between polycarbonate with pendent alkene groups and thiolated methoxypolyethylene glycol in liquid lithium hexafluorophosphate electrolyte and exhibits conductivity as remarkably high as 2.0×10−2 S cm−1 at ambient temperature. To the best of our knowledge, this gel polymer electrolyte possesses the highest conductivity in all relevant literatures. A free-standing composite gel polymer electrolyte membrane is obtained by incorporating the gel polymer electrolyte with electrospun polyvinylidene fluoride as a skeleton. The as-prepared composite membrane is used to assemble a prototype lithium iron phosphate cell and evaluated accordingly. The battery delivers a good reversible charge-discharge capacity close to 140 mAh g-1 at 1 C rate and 25°C with only 0.022% per cycle decay after 200 cycles. This work provides an interesting molecular design for polycarbonate application in gel electrolyte lithium-ion batteries.

Humanized Bispecific Antibody (mPEG×HER2) Rapidly Confers PEGylated nanoaparticles Tumor Specificity for Multimodality Imaging in Breast Cancer

Background: Developing a universal strategy to improve the specificity and sensitivity of PEGylated nanoaparticles (PEG-NPs) for assisting in the diagnosis of tumors is important in multimodality imaging. Here, we developed the anti-methoxypolyethylene glycol (mPEG) bispecific antibody (BsAb; mPEG×HER2), which has dual specificity for mPEG and human epidermal growth factor receptor 2 (HER2), with a diverse array of PEG-NPs to confer nanoparticles with HER2 specificity and stronger intensity. Result: We used a one-step formulation to rapidly modify the nanoprobes with mPEG×HER2 and optimized the modified ratio of BsAbs on several PEG-NPs (Lipo-DiR, SPIO, Qdot and AuNP). The αHER2/PEG-NPs could specifically target MCF7/HER2 cells (HER2+) but not MCF7/neo1 cells (HER2-). The αHER2/Lipo-DiR and αHER2/SPIO could enhance the sensitivity of untargeted PEG-NPs on MCF7/HER2 (HER2+). In in vivo imaging, αHER2/Lipo-DiR and αHER2/SPIO increased the specific targeting and enhanced mPEG-nanoprobe accumulation 161% and 187%, respectively, in HER2-overexpressing tumors. Conclusion: mPEG×HER2, therefore, provided a simple one-step formulation to confer HER2-specific targeting and enhanced sensitivity and contrast intensity on HER2 positive tumors for multimodality imaging.