How does digital transformation improve new product development performance from the perspective of resource orchestration?-Analysis based on configuration.

The new product development (NPD) activities of enterprises serve as a critical source of competitiveness. To effectively harness the opportunities presented by digital transformation and enhance the performance of NPD in organizations amidst the digital revolution is an area of concern that warrants attention. In this context, we conducted research using data from the annual reports of 35 listed mainboard enterprises in 2021. This research used the resource arrangement theory and the resource-structure-capability research framework. In addition, we utilized the quantitative comparative analysis (QCA) method to investigate how digital transformation capability, R&D investment capability, and heterogeneity synergies impact the performance of NPD. The findings indicate that: (1) Four distinct paths (i.e., digital innovation-driven, large-scale multi-talent, mature and robust, and digital start-up) drive improvements in NPD performance. Notably, there exists an asymmetric causal relationship between these four paths and the performance; (2) Digital transformation capability, firm R&D investment, and firm heterogeneity all contribute to enhancing NPD performance. However, they do not individually guarantee high performance. A synergistic effect of at least two factors is required to yield notable NPD performance; (3) Enterprise heterogeneity plays a pivotal role. Companies with different characteristics must opt for distinct digital transformation paths to improve their NPD performance; (4) In the initial stage of digital transformation, enterprises can enhance NPD performance by augmenting their investment in R&D personnel.

A novel GSH-triggered polymeric nanomicelles for reversing MDR and enhancing antitumor efficiency of hydroxycamptothecin.

Tumor multidrug resistance (MDR) is one of the main reasons for the failure of clinical chemotherapy. Here, a bio-responsive anti-drug-resistant polymer micelle that can respond to the reductive GSH in the tumor microenvironment (TME) for delivery of HCPT was designed. A new type of polymer with anti-drug resistance and anti-tumor effect was synthesized and used to encapsulated HCPT to form reduction-sensitive micelles (PDSAH) by a thin-film dispersion method. It is demonstrated that the micelle formulation improves the anti-tumor activity and biosafety of HCPT, and also plays a significant role in reversing the drug resistance, which contributes to inhibiting the tumor growth and prolonging the survival time of H22 tumor-bearing mice. The results indicate that this nanoplatform can serve as a flexible and powerful system for delivery of other drugs that are tolerated by tumors or bacteria.

Reduction-sensitive poly(ethylene glycol)-polypeptide conjugate micelles for highly efficient intracellular delivery and enhanced antitumor efficacy of hydroxycamptothecin.

The non-specific biodistribution of traditional chemotherapeutic drugs against tumors is the key factor that causes systemic toxicity and hinders their clinical application. In this study, a reduction-sensitive polymer conjugate micelle was manufactured to achieve tumor-specific targeting, reduce toxic side-effects and improve anti-tumor activity of a natural anti-cancer drug, hydroxycamptothecin (HCPT). Therefore, HCPT was conjugated with methoxy-poly(ethylene glycol)-poly(ß-benzyl-L-aspartate) (mPEG-PBLA) by a disulfide bond or succinate bond for the first time to obtain the mPEG-PBLA-SS-HCPT (PPSH) and mPEG-PBLA-CC-HCPT (PPCH) that would form micelles after high-speed agitation and dialysis. The PPSH micelles showed an average particle size of 126.3 nm, a low polydispersity index of 0.209, and a negative surface charge of -21.1 mV zeta potential. Transmission electron microscopy showed the PPSH micelles to have spherical morphology. PPSH had a low critical micelle concentration of 1.29 µg ml-1 with high dilution stability, storage stability and reproducibility. Moreover, the particle size of the PPSH micelles had no significant change after incubation with rat plasma for 72 h, probably resulting in high long circulation in the blood. The PPSH micelles showed significant reduction sensitivity to glutathione. Their sizes increased by 403.2 nm after 24 h post-incubation, and 87.6% drug release was achieved 48 h post-incubation with 40 mM glutathione solutions. The PPSH micelles showed stronger inhibition of HepG2 cells in vitro and growth of H-22 tumor in vivo than the PPCH and HCPT solutions after intravenous injection. The accumulation of PPSH micelles in the tumor tissue contributed to the high anti-tumor effect with little side-effect on the normal tissues. The reduction-sensitive PPSH micelles were a promising carrier of HCPT and other poorly soluble anti-cancer drugs.

Study on Formulation, in vivo Exposure, and Passive Targeting of Intravenous Itraconazole Nanosuspensions.

The pharmacokinetic profile of a drug can be different when delivered as a nanosuspension compared with a true solution, which may in turn affect the therapeutic effect of the drug. The goal of this study was to prepare itraconazole nanosuspensions (ITZ-Nanos) stabilized by an amphipathic polymer, polyethylene glycol-poly (benzyl aspartic acid ester) (PEG-PBLA), by the precipitation-homogenization, and study the pharmacokinetic profile of the ITZ-Nanos. The particle size and morphology of nanosuspensions were determined by Zetasizer and field emission scanning electron microscope (SEM), respectively. The dissolution profile was evaluated using a paddle method according to Chinese Pharmacopoeia 2015. The level of ITZ in plasma and tissues was measured by a HPLC method. The optimized ITZ-Nanos had an average particle size of 268.1 ± 6.5 nm and the particles were in a rectangular form. The dissolution profile of ITZ-Nanos was similar to that of commercial ITZ injections, with nearly 90% ITZ released in the first 5 min. The ITZ-Nanos displayed different pharmacokinetic properties compared with the commercial ITZ injections, including a decreased initial drug concentration, increased plasma half-life and mean residence time (MRT), and increased concentration in the liver, lung, and spleen. The ITZ-Nanos can change the in vivo distribution of ITZ and result in passive targeting to the organs with mononuclear phagocyte systems (MPS).

A polymeric micelle with an endosomal pH-sensitivity for intracellular delivery and enhanced antitumor efficacy of hydroxycamptothecin.

Amphiphilic poly(ethylene glycol)-imino-poly(benzyl-l-aspartate) (PIPA) and poly(ethylene glycol)-poly(benzyl-l-aspartate) (PPA) block copolymers were synthesized as pH-responsive and pH-nonresponsive copolymers, respectively. Polymer micelles were fabricated by the film dispersion method, and hydroxycamptothecin (HCPT) was physically encapsulated into the micelles. The average diameter of the HCPT-loaded PIPA micelles (PIPAH micelles) was approximately 230 nm, which was slightly smaller than that of the HCPT-loaded PPA micelles (PPAH micelles, approximately 260 nm). The drug-loading content and encapsulation efficiency of the PIPAH micelles (3.33% and 68.89%, respectively) were slightly higher than those of the PPAH micelles (2.90% and 59.68%, respectively). The PIPAH micelles exhibited better colloid stability, storage stability, and plasma stability than the PPAH micelles. Drug release from the PIPAH micelles with imino groups was pH dependent, and more than 75% or 65% of the loaded HCPT was released within 24 h in weakly acidic media (pH 5.0 or 6.0, respectively). An in vitro cell assay demonstrated that the pH-sensitive micelles exhibited potent suppression of cancer cell proliferation and little cytotoxicity on normal cells. Additionally, these micelles could be efficiently internalized by the tumor cells through macropinocytosis- and caveolin-mediated endocytotic pathways. HCPT-loaded micelles had longer circulation time than the HCPT solution in a pharmacokinetic study. In vivo antitumor experiments indicate that the PIPAH micelles had better antitumor efficacy than the pH-insensitive PPAH micelles and the HCPT solution. Therefore, the pH-responsive PIPAH micelles have great potential for high-efficiency delivery of HCPT. STATEMENT OF SIGNIFICANCE: In this study, a new type of pH-responsive amphiphilic copolymer, poly(ethylene glycol)-imino-poly(benzyl-l-aspartate) (PIPA) block copolymer, was synthesized. This copolymer had then self-assembled to form nanomicelles for tumor intracellular delivery of hydroxycamptothecin (HCPT) for the first time. In in vitro test, the PIPAH micelles exhibited adequate stability and pH-dependent drug release. To one's excitement, the PIPAH micelles exhibited better antitumor efficacy and biosafety than the pH-insensitive micelles (PPAH) and the HCPT solution in in vitro and in vivo antitumor experiments. Therefore, the pH-responsive micelles in this study have significant potential to be used for high-performance delivery of HCPT and potentially for the targeted delivery of other cancer therapeutic agents. The polymer designed in this study can be used as a carrier of poorly soluble drugs or other active ingredients.