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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. Photoacoustic Imaging Quantifies Drug Release from Nanocarriers via Redox Chemistry of Dye‐Labeled Cargo

   https://doi.org/10.1002/ange.201914120  

   Jeevarathinam, Ananthakrishnan Soundaram ; Lemaster, Jeanne E. ; Chen, Fang ; Zhao, Eric ; Jokerst, Jesse V. ( January 2020 , Angewandte Chemie)

   We report a new approach to monitor drug release from nanocarriers via a paclitaxel–methylene blue conjugate (PTX‐MB) with redox activity. This construct is in a photoacoustically silent reduced state inside poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles (PTX‐MB@PLGA NPs). During release, PTX‐MB is spontaneously oxidized to produce a concentration‐dependent photoacoustic signal. An in vitro drug‐release study showed an initial burst release (25 %) between 0–24 h and a sustained release between 24–120 h with a cumulative release of 40.6 % and a 670‐fold increase in photoacoustic signal. An in vivo murine drug release showed a photoacoustic signal enhancement of up to 649 % after 10 hours. PTX‐MB@PLGA NPs showed an IC₅₀of 78 μg mL⁻¹and 44.7±4.8 % decrease of tumor burden in an orthotopic model of colon cancer via luciferase‐positive CT26 cells.

    

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3. Photoacoustic Imaging Quantifies Drug Release from Nanocarriers via Redox Chemistry of Dye‐Labeled Cargo

   https://doi.org/10.1002/anie.201914120  

   Jeevarathinam, Ananthakrishnan Soundaram ; Lemaster, Jeanne E. ; Chen, Fang ; Zhao, Eric ; Jokerst, Jesse V. ( January 2020 , Angewandte Chemie International Edition)

   We report a new approach to monitor drug release from nanocarriers via a paclitaxel–methylene blue conjugate (PTX‐MB) with redox activity. This construct is in a photoacoustically silent reduced state inside poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles (PTX‐MB@PLGA NPs). During release, PTX‐MB is spontaneously oxidized to produce a concentration‐dependent photoacoustic signal. An in vitro drug‐release study showed an initial burst release (25 %) between 0–24 h and a sustained release between 24–120 h with a cumulative release of 40.6 % and a 670‐fold increase in photoacoustic signal. An in vivo murine drug release showed a photoacoustic signal enhancement of up to 649 % after 10 hours. PTX‐MB@PLGA NPs showed an IC₅₀of 78 μg mL⁻¹and 44.7±4.8 % decrease of tumor burden in an orthotopic model of colon cancer via luciferase‐positive CT26 cells.

    

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4. Programmable Delivery of Synergistic Cancer Drug Combinations Using Bicompartmental Nanoparticles

   https://doi.org/10.1002/adhm.202000564  

   Gregory, Jason V. ; Vogus, Douglas R. ; Barajas, Alexandra ; Cadena, Melissa A. ; Mitragotri, Samir ; Lahann, Joerg ( September 2020 , Advanced Healthcare Materials)

   Delivery of multiple therapeutics has become a preferred method of treating cancer, albeit differences in the biodistribution and pharmacokinetic profiles of individual drugs pose challenges in effectively delivering synergistic drug combinations to and at the tumor site. Here, bicompartmental Janus nanoparticles comprised of domains are reported with distinct bulk properties that allow for independent drug loading and release. Programmable drug release can be triggered by a change in the pH value and depends upon the bulk properties of the polymers used in the respective compartments, rather than the molecular structures of the active agents. Bicompartmental nanoparticles delivering a synergistic combination of lapatinib and paclitaxel result in increased activity against HER2+ breast cancer cells. Surprisingly, the dual drug loaded particles also show significant efficacy toward triple negative breast cancer, even though this cancer model is unresponsive to lapatinib alone. The broad versatility of the nanoparticle platform allows for rapid exploration of a wide range of drug combinations where both their relative drug ratios and temporal release profiles can be optimized.

    

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5. 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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