Dually Enzyme- and Acid-Triggered Self-Immolative Ketal Glycoside Nanoparticles for Effective Cancer Prodrug Monotherapy.

The use of glycoside prodrugs is a promising strategy for developing new targeted medicines for chemotherapy. However, the in vivo utility of such prodrugs is hindered by insufficient activation and the lack of convenient synthetic methods. We have developed an innovative strategy for synthesizing ketal glycoside prodrugs that are unique in being activated by a dual enzyme- and acid-triggered self-immolative mechanism. Amphiphilic glucosyl acetone-based ketal-linked etoposide glycoside prodrug isomers were synthesized and fabricated into excipient-free nanoparticles for effective cancer prodrug monotherapy. Hydrolysis of the glycosidic linkage or the ketal linkage triggered hydrolysis of the other linkage, which resulted in spontaneous self-immolative hydrolysis of the prodrugs. Nanoparticles of the prodrug isomer that was the most labile in a lysosome-mimicking environment displayed high intratumoral accumulation and strong antitumor activity in an A549 xenograft mouse model. Our strategy may be useful for the development of stimulus-responsive self-immolative prodrugs and their nanomedicines.

[1]  D. Kohane,et al.  Light-triggered release of conventional local anesthetics from a macromolecular prodrug for on-demand local anesthesia , 2020, Nature Communications.

[2]  Xing-jie Liang,et al.  Modular Acid-Activatable Acetone-Based Ketal-Linked Nanomedicine by Dexamethasone Prodrugs for Enhanced Anti-Rheumatoid Arthritis with Low Side Effects. , 2020, Nano letters.

[3]  Beob Soo Kim,et al.  Systemic Brain Delivery of Antisense Oligonucleotides across the Blood–Brain Barrier with a Glucose‐Coated Polymeric Nanocarrier , 2020, Angewandte Chemie.

[4]  Shutao Guo,et al.  Acid-Triggered Release of Native Gemcitabine Conjugated in Polyketal Nanoparticles for Enhanced Anticancer Therapy. , 2020, Biomacromolecules.

[5]  Jianxun Ding,et al.  Editorial: Applications of Nanobiotechnology in Pharmacology , 2019, Front. Pharmacol..

[6]  Gangliang Huang,et al.  Application of glycosylation in targeted drug delivery. , 2019, European journal of medicinal chemistry.

[7]  Fabian Kiessling,et al.  Smart cancer nanomedicine , 2019, Nature Nanotechnology.

[8]  Qiang Zhao,et al.  Upconversion-like Photolysis of BODIPY-Based Prodrugs via a One-Photon Process. , 2019, Journal of the American Chemical Society.

[9]  D. Kohane,et al.  Polymer-tetrodotoxin conjugates to induce prolonged duration local anesthesia with minimal toxicity , 2019, Nature Communications.

[10]  Junqing Wang,et al.  Nanobuffering of pH-Responsive Polymers: A Known but Sometimes Overlooked Phenomenon and Its Biological Applications. , 2019, ACS nano.

[11]  O. Farokhzad,et al.  Glutathione-Responsive Prodrug Nanoparticles for Effective Drug Delivery and Cancer Therapy. , 2018, ACS nano.

[12]  O. Farokhzad,et al.  Glutathione-Scavenging Poly(disulfide amide) Nanoparticles for the Effective Delivery of Pt(IV) Prodrugs and Reversal of Cisplatin Resistance. , 2018, Nano letters.

[13]  Fabian Kiessling,et al.  Tumor targeting via EPR: Strategies to enhance patient responses. , 2018, Advanced drug delivery reviews.

[14]  N. Meanwell,et al.  The expanding role of prodrugs in contemporary drug design and development , 2018, Nature Reviews Drug Discovery.

[15]  Weijian Chen,et al.  Polymer Prodrug-Based Nanoreactors Activated by Tumor Acidity for Orchestrated Oxidation/Chemotherapy. , 2017, Nano letters.

[16]  Feng Li,et al.  Lipid-Drug Conjugate for Enhancing Drug Delivery. , 2017, Molecular pharmaceutics.

[17]  S. Lippard,et al.  Chemical Approach to Positional Isomers of Glucose-Platinum Conjugates Reveals Specific Cancer Targeting through Glucose-Transporter-Mediated Uptake in Vitro and in Vivo. , 2016, Journal of the American Chemical Society.

[18]  Kristofer J. Thurecht,et al.  Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date , 2016, Pharmaceutical Research.

[19]  D. Kohane,et al.  Extended Release of Native Drug Conjugated in Polyketal Microparticles. , 2016, Journal of the American Chemical Society.

[20]  S. Lippard,et al.  A Potent Glucose-Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells. , 2016, Angewandte Chemie.

[21]  Ahmed Alouane,et al.  Self-immolative spacers: kinetic aspects, structure-property relationships, and applications. , 2015, Angewandte Chemie.

[22]  Y. Ni,et al.  Relationship Between 18F-FDG Accumulation and Lactate Dehydrogenase A Expression in Lung Adenocarcinomas , 2014, The Journal of Nuclear Medicine.

[23]  F. Liu,et al.  Disulfide Bond Bridge Insertion Turns Hydrophobic Anticancer Prodrugs into Self-Assembled Nanomedicines , 2014, Nano letters.

[24]  Martin G Pomper,et al.  State-of-the-art in design rules for drug delivery platforms: lessons learned from FDA-approved nanomedicines. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[25]  T. Nakajima,et al.  Biological significance of 18F-FDG uptake on PET in patients with non-small-cell lung cancer. , 2014, Lung cancer.

[26]  Paul J Hergenrother,et al.  Glucose conjugation for the specific targeting and treatment of cancer. , 2013, Chemical science.

[27]  P. Couvreur,et al.  Squalenoylation: a generic platform for nanoparticular drug delivery. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[28]  D. Leigh,et al.  Rotaxane-based propeptides: protection and enzymatic release of a bioactive pentapeptide. , 2009, Angewandte Chemie.

[29]  A. V. Pavlovsky,et al.  A randomised Phase III trial of glufosfamide compared with best supportive care in metastatic pancreatic adenocarcinoma previously treated with gemcitabine. , 2009, European journal of cancer.

[30]  P. Couvreur,et al.  Squalenoyl nanomedicines as potential therapeutics. , 2006, Nano letters.

[31]  L. Tietze,et al.  Antitumor agents: development of highly potent glycosidic duocarmycin analogues for selective cancer therapy. , 2006, Angewandte Chemie.

[32]  A new paclitaxel prodrug for use in ADEPT strategy. , 2003, Organic & biomolecular chemistry.

[33]  J. Backman,et al.  Dose optimization of a doxorubicin prodrug (HMR 1826) in isolated perfused human lungs: low tumor pH promotes prodrug activation by beta-glucuronidase. , 2002, The Journal of pharmacology and experimental therapeutics.

[34]  H. W. Scheeren,et al.  Anticancer prodrugs for application in monotherapy: targeting hypoxia, tumor-associated enzymes, and receptors. , 2001, Current medicinal chemistry.

[35]  H. Haisma,et al.  A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer , 2001, British Journal of Cancer.

[36]  C. Monneret,et al.  Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy. , 1998, Journal of medicinal chemistry.

[37]  J. Backman,et al.  The Role of β-Glucuronidase in Drug Disposition and Drug Targeting in Humans , 1997 .

[38]  M. Beller,et al.  Development of Tailor-Made Cytostatics Activable by Acid-Catalyzed Hydrolysis for Selective Tumor Therapy† , 1990 .