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Simple Summary: Despite the availability of numerous therapeutic approaches, pancreatic ductal adenocarcinoma still stands as one of the most fatal cancers worldwide. Nanoliposomes could potentially be helpful in improving the pharmacokinetic and anticancer efficacy of drug molecules. Gemcitabine is the first line of therapy, but due to its hydrophilic nature, entrapment within nanoliposomes is very limited. To overcome this problem, we explored the lipophilic form of gemcitabine, i.e., Gemcitabine Elaidate. The present study is aimed towards investigating the antitumor activity of Gemcitabine Elaidate and further designing an appropriate nano-liposomal formulation in combination with Palmitoyl-DL-carnitine chloride as a Protein kinase C (PKC) inhibitor. Our combination therapy in a nano-liposomal carrier resulted in enhanced cellular uptake, inhibition of angiogenesis potential and augmented anticancer potency in both 2D and 3D in vitro models of pancreatic tumors. The promising results indicate the successful development of a nano-liposomal carrier incorporating Gemcitabine Elaidate and Palmitoyl-DL-carnitine chloride as a more effective approach for the treatment of pancreatic cancer by overcoming the key drawbacks of the current first-line therapy. Being the fourth most fatal malignancy worldwide, pancreatic cancer is on track to become the second leading cause of cancer-related deaths in the United States by 2030. Gemcitabine is a first-line chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine Elaidate (Gem Elaidate) is a lipophilic derivative which allows hENT1-independent intracellular delivery of gemcitabine and better pharmacokinetics and entrapment in a nanocarrier. Cancer cells and neovasculature are negatively charged compared to healthy cells. Palmitoyl-DL-carnitine chloride (PC) is a Protein kinase C (PKC) inhibitor which also provides a cationic surface charge to nanoliposomes for targeting tumor neovasculature and augmented anticancer potency. The objectives of our study are: (a) to develop and characterize a PKC inhibitor-anchored Gem Elaidate-loaded PEGylated nanoliposome (PGPLs) and (b) to investigate the anticancer activity of Gem Elaidate and PGPLs in 2D and 3D models of pancreatic cancer. The optimized PGPLs resulted in a particle size of 80 ± 2.31 nm, a polydispersity index of 0.15 ± 0.05 and a ζ-potential of +31.6 ± 3.54 mV, with a 93.25% encapsulation efficiency of Gem Elaidate in PGPLs. Our results demonstrate higher cellular uptake, inhibition in migration, as well as angiogenesis potential and significant apoptosis induced by PGPLs in 3D multicellular tumor spheroids of pancreatic cancer cells. Hence, PGPLs could be an effective and novel nanoformulation for the neovasculature-specific delivery of Gemcitabine Elaidate to treat PDAC. [ABSTRACT FROM AUTHOR]

Melt extrusion pretreatment of poly(ethylene terephthalate) (PET) prior to enzymatic depolymerization with an unpurified leaf branch compost cutinase enzyme cocktail is explored to ascertain the efficiency gained by different processing methods on the enzymatic depolymerization of PET. Specific surface area (SSA) is investigated as a key factor in reducing depolymerization time. Higher SSA substrates (>5.6 mm2 mg−1) show higher depolymerization rates (≈0.88 g L−1 terephthalic acid [TPA] per day) and no induction phase, while lower SSA substrates (≈4.3, 4.4, and 5.6 mm2 mg−1) show, after an initial induction phase, similar depolymerization rates (≈0.46, 0.45, and 0.44 g L−1 TPA per day) despite increases in SSA of up to 30%. The mechanism of enzymatic depolymerization manifests in the appearance of anisotropic pitting. Longer incubation time used to overcome the induction phase in low SSA substrates allows for nearly full recovery of monomeric products, but manual pregrinding of extruded PET sharply increases SSA, depolymerization rate, and substrate crystallinity which may decrease the maximum recycled yield of the product materials. An estimate of the energy cost of increasing SSA is made and its effects on material properties are discussed. This work highlights key material structure and pretreatment aspects influencing the enzymatic recycling of PET. [ABSTRACT FROM AUTHOR]

Poly(ethylene terephthalate) (PET) is a common single-use plastic and a major contributor to plastic waste. PET upcycling through enzymatic depolymerization has drawn significant interests, but lack of robust enzymes in acidic environments remains a challenge. This study investigates in-situ product removal (ISPR) of protons from enzymatic PET depolymerization via a membrane reactor, focusing on the ICCG variant of leaf branch compost cutinase. More than two-fold improvements in overall PET depolymerization and terephthalic acid yields were achieved employing ISPR for an initial PET loading of 10 mgPET mlbuffer-1. The benefit of ISPR was reduced for a lower initial loading of 1 mgPET mlbuffer-1 due to decreased need for pH stabilization of the enzyme-containing solutions. A back-of-envelop analysis suggests that at a modest dilution ratio, ISPR could help achieve savings on caustic base solutions used for pH control in a bioreactor. Our study provides valuable insights for future ISPR developments for enzymatic PET depolymerization, addressing the pressing need for more sustainable solutions towards plastic recycling and environmental conservation., (© 2024 Wiley‐VCH GmbH.)