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1. Self-Assembly of pH-Labile Polymer Nanoparticles for Paclitaxel Prodrug Delivery: Formulation, Characterization, and Evaluation

   https://doi.org/10.3390/ijms21239292  

   Levit, Shani L.; Gade, Narendar Reddy; Roper, Thomas D.; Yang, Hu; Tang, Christina (December 2020, International Journal of Molecular Sciences)

   null (Ed.)

   The efficacy of paclitaxel (PTX) is limited due to its poor solubility, poor bioavailability, and acquired drug resistance mechanisms. Designing paclitaxel prodrugs can improve its anticancer activity and enable formulation of nanoparticles. Overall, the aim of this work is to improve the potency of paclitaxel with prodrug synthesis, nanoparticle formation, and synergistic formulation with lapatinib. Specifically, we improve potency of paclitaxel by conjugating it to α-tocopherol (vitamin E) to produce a hydrophobic prodrug (Pro); this increase in potency is indicated by the 8-fold decrease in half maximal inhibitory concentration (IC50) concentration in ovarian cancer cell line, OVCA-432, used as a model system. The efficacy of the paclitaxel prodrug was further enhanced by encapsulation into pH-labile nanoparticles using Flash NanoPrecipitation (FNP), a rapid, polymer directed self-assembly method. There was an 1100-fold decrease in IC50 concentration upon formulating the prodrug into nanoparticles. Notably, the prodrug formulations were 5-fold more potent than paclitaxel nanoparticles. Finally, the cytotoxic effects were further enhanced by co-encapsulating the prodrug with lapatinib (LAP). Formulating the drug combination resulted in synergistic interactions as indicated by the combination index (CI) of 0.51. Overall, these results demonstrate this prodrug combined with nanoparticle formulation and combination therapy is a promising approach for enhancing paclitaxel potency. 

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2. Photothermal-responsive nanosized hybrid polymersome as versatile therapeutics codelivery nanovehicle for effective tumor suppression

   https://doi.org/10.1073/pnas.1817251116  

   Zhang, Hongbo; Cui, Wenguo; Qu, Xiangmeng; Wu, Huayin; Qu, Liangliang; Zhang, Xu; Mäkilä, Ermei; Salonen, Jarno; Zhu, Yueqi; Yang, Zhou; et al (March 2019, Proceedings of the National Academy of Sciences)

   Effective cancer therapies often demand delivery of combinations of drugs to inhibit multidrug resistance through synergism, and the development of multifunctional nanovehicles with enhanced drug loading and delivery efficiency for combination therapy is currently a major challenge in nanotechnology. However, such combinations are more challenging to administer than single drugs and can require multipronged approaches to delivery. In addition to being stable and biodegradable, vehicles for such therapies must be compatible with both hydrophobic and hydrophilic drugs, and release drugs at sustained therapeutic levels. Here, we report synthesis of porous silicon nanoparticles conjugated with gold nanorods [composite nanoparticles (cNPs)] and encapsulate them within a hybrid polymersome using double-emulsion templates on a microfluidic chip to create a versatile nanovehicle. This nanovehicle has high loading capacities for both hydrophobic and hydrophilic drugs, and improves drug delivery efficiency by accumulating at the tumor after i.v. injection in mice. Importantly, a triple-drug combination suppresses breast tumors by 94% and 87% at total dosages of 5 and 2.5 mg/kg, respectively, through synergy. Moreover, the cNPs retain their photothermal properties, which can be used to significantly inhibit multidrug resistance upon near-infrared laser irradiation. Overall, this work shows that our nanovehicle has great potential as a drug codelivery nanoplatform for effective combination therapy that is adaptable to other cancer types and to molecular targets associated with disease progression. 

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3. Development and Characterization of PLGA‐Based Multistage Delivery System for Enhanced Payload Delivery to Targeted Vascular Endothelium

   https://doi.org/10.1002/mabi.202000377  

   Palma‐Chavez, Jorge A.; Fuentes, Kevin; Applegate, Brian E.; Jo, Javier A.; Charoenphol, Phapanin (January 2021, Macromolecular Bioscience)

   Abstract Vascular‐targeted drug delivery remains an attractive platform for therapeutic and diagnostic interventions in human diseases. This work focuses on the development of a poly‐lactic‐co‐glycolic‐acid (PLGA)‐based multistage delivery system (MDS). MDS consists of two stages: a micron‐sized PLGA outer shell and encapsulated drug‐loaded PLGA nanoparticles. Nanoparticles with average diameters of 76, 119, and 193 nm are successfully encapsulated into 3–6 µm MDS. Sustained in vitro release of nanoparticles from MDS is observed for up to 7 days. Both MDS and nanoparticles arebiocompatible with human endothelial cells. Sialyl‐Lewis‐A (sLe^A) is successfully immobilized on the MDS and nanoparticle surfaces to enable specific targeting of inflamed endothelium. Functionalized MDS demonstrates a 2.7‐fold improvement in endothelial binding compared to PLGA nanoparticles from human blood laminar flow. Overall, the presented results demonstrate successful development and characterization of MDS and suggest that MDS can serve as an effective drug carrier, which can enhance the margination of nanoparticles to the targeted vascular wall. 

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4. Paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapes

   https://doi.org/10.1038/s41598-021-86484-9  

   Zhen, Yuhong; Ewert, Kai K.; Fisher, William S.; Steffes, Victoria M.; Li, Youli; Safinya, Cyrus R. (March 2021, Scientific Reports)

   Abstract Lipid carriers of hydrophobic paclitaxel (PTX) are used in clinical trials for cancer chemotherapy. Improving their loading capacity requires enhanced PTX solubilization. We compared the time-dependence of PTX membrane solubility as a function of PTX content in cationic liposomes (CLs) with lipid tails containing one (oleoyl; DOPC/DOTAP) or two (linoleoyl; DLinPC/newly synthesized DLinTAP)cisdouble bonds by using microscopy to generate kinetic phase diagrams. The DLin lipids displayed significantly increased PTX membrane solubility over DO lipids. Remarkably, 8 mol% PTX in DLinTAP/DLinPC CLs remained soluble for approximately as long as 3 mol% PTX (the solubility limit, which has been the focus of most previous studies and clinical trials) in DOTAP/DOPC CLs. The increase in solubility is likely caused by enhanced molecular affinity between lipid tails and PTX, rather than by the transition in membrane structure from bilayers to inverse cylindrical micelles observed with small-angle X-ray scattering. Importantly, the efficacy of PTX-loaded CLs against prostate cancer cells (their IC50 of PTX cytotoxicity) was unaffected by changing the lipid tails, and toxicity of the CL carrier was negligible. Moreover, efficacy was approximately doubled against melanoma cells for PTX-loaded DLinTAP/DLinPC over DOTAP/DOPC CLs. Our findings demonstrate the potential of chemical modifications of the lipid tails to increase the PTX membrane loading while maintaining (and in some cases even increasing) the efficacy of CLs. The increased PTX solubility will aid the development of liposomal PTX carriers that require significantly less lipid to deliver a given amount of PTX, reducing side effects and costs. 

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5. Longer Acting Injectable: Continuous, Linear Release of a Progestin Contraceptive From an Oxidized Porous Silicon Host

   https://doi.org/10.1002/adhm.202403802  

   Hollett, Geoffrey; Fan, Ruhan; Kumeria, Tushar; Leonard, Heidi; Kim, Byungji; Martin, Taylor_R; Ipekci, Irmak; Wang, Joanna; Byun, Jiuk; Chan, Nicole_A; et al (February 2025, Advanced Healthcare Materials)

   Abstract Maintaining stable drug concentrations in the bloodstream is a challenge for injectable hydrophobic progestin contraceptives. This work investigates porous silicon dioxide (pSiO₂) microparticles as a delivery vehicle for progestins via melt‐infiltration of drugs into the mesopores. The pSiO₂is prepared through electrochemical anodization of single‐crystalline silicon followed by thermal oxidation, yielding vertically oriented pores (≈50 nm diameter) with porosity varied (between 35–75%) to optimize drug loading and release. Among the progestins tested, etonogestrel and levonorgestrel (LNG) decompose near their melting points, preventing melt infiltration. However, addition of 20% cholesterol by mass suppresses the melting point of LNG sufficiently to enable loading without degradation. Mass loadings exceeding 50% (drug: drug + carrier) are achieved for segesterone acetate (SEG) and LNG, retaining drug crystallinity as confirmed by X‐ray diffraction. In vitro, both SEG and LNG‐loaded pSiO₂display sustained drug release for up to 3 months, with reduced burst release, more constant steady‐state concentrations, and a substantially reduced tail compared to pure LNG or SEG, or SEG loaded into pSiO₂from a chloroform solution. In a pilot in vivo study, SEG‐loaded pSiO₂microparticles are well tolerated in 20‐week‐old female rats over a 25‐week period, with no signs of toxicity. 

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