Structure‐Based Rational Design of Prodrugs To Enable Their Combination with Polymeric Nanoparticle Delivery Platforms for Enhanced Antitumor Efficacy

Wang, Hangxiang; Xie, Haiyang; Wu, Jiaping; Wei, Xuyong; Zhou, Lin; Xu, Xiao; Zheng, Shusen

doi:10.1002/ange.201406685

Cited by 37 publications

(35 citation statements)

References 36 publications

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“…When the D/T ratio reached 1:10, the EE% became lower (63.21%). The loading capacity of NPM for SN-38 was 5.45% (1.09 mg/mL), which increased the solubility of SN-38 in aqueous solution up to 500 times 38 . The morphology and size distribution of the nanoparticles were characterized by TEM and DLS, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…SN-38 is the active metabolite of irinotecan hydrochloride (CPT-11), which is 100- to 1000-fold more cytotoxic than CPT-11 30,32–35 . The conversion rate from CPT-11 to SN-38 by carboxylesterases after administration is typically inefficient and usually yields only 2–8% 30,36–38 . Direct administration of SN-38 instead of CPT-11 would bypass the inefficient enzymatic activation, and therefore improve anticancer efficacy of this drug.…”

Section: Introductionmentioning

confidence: 99%

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Sub-100 nm, long tumor retention SN-38-loaded photonic micelles for tri-modal cancer therapy

Yang¹,

Xue

Luo

et al. 2017

Journal of Controlled Release

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The tumor penetration and accumulation of nanoparticle-based drug delivery systems are highly dependent on the particle size. Nanomedicines in the sub-100 nm range have been suggested by previous studies to have superior antitumor efficacy on various solid tumors. SN-38 is a very important and highly potent drug for several cancers including colon cancer. However, due to the ultra-flat aromatic structure of SN-38, it is typically very difficult to produce sub-100 nm, SN-38-encapsulated nanoparticles without modification of the chemical structure. Here, we report on the successful production of 20–30 nm, SN-38-encapsulated photonic micelles for effectively trimodal cancer therapy. Taking advantages of the supramolecular “π -π” stacking and hydrophobicity interaction between SN-38, and a unique class of photonic nanoporphyrin micelles (NPM), the extremely hydrophobic SN-38 was successfully encapsulated into NPM with significantly increased water solubility (up to 500 times). At equivalent dose of drug photosensitizer and light irradiation, combination therapy with SN-38-encapsulated nanoporphyrin micelles (SN-NPM) enhanced the in vitro antitumor activity by 78 and 350 times over single treatment with SN-38 and phototherapy alone, respectively. Due to the relatively small size, SN-NPM possessed superior long tumor retention time (> 5 days) and much higher accumulation in tumors than in normal organs, as shown by near-infrared fluorescence (NIRF) imaging. Furthermore, the trimodal therapy (photothermal-, photodynamic- and chemo-therapy) with SN-NPM demonstrated dramatically enhanced in vivo antitumor efficacy over single treatment on nude mice bearing HT-29 colon cancer xenograft. Therefore, these sub-100 nm, SN-38-encapsulated photonic micelles show great promise for multimodal cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sub-100 nm, long tumor retention SN-38-loaded photonic micelles for tri-modal cancer therapy

Yang¹,

Xue

Luo

et al. 2017

Journal of Controlled Release

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“…Another possibility is binding of the pharmacon to a hydrophilic polymer directly or by a linker; PEG, [38].…”

Section: Prodrugs With Improved Aqueous Solubilitymentioning

confidence: 99%

Prodrug Strategy in Drug Development

Kelemen

Hancu

Rusu

et al. 2016

Acta Medica Marisiensis

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Prodrugs are chemically modified derivatives introduced in therapy due to their advantageous physico-chemical properties (greater stability, improved solubility, increased permeability), used in inactive form. Biological effect is exerted by the active derivatives formed in organism through chemical transformation (biotransformation). Currently, 10% of pharmaceutical products are used as prodrugs, nearly half of them being converted to active form by hydrolysis, mainly by ester hydrolysis. The use of prodrugs aims to improve the bioavailability of compounds in order to resolve some unfavorable characteristics and to reduce first-pass metabolism. Other objectives are to increase drug absorption, to extend duration of action or to achieve a better tissue/organ selective transport in case of non-oral drug delivery forms. Prodrugs can be characterized by chemical structure, activation mechanism or through the presence of certain functional groups suitable for their preparation. Currently we distinguish in therapy traditional prodrugs prepared by chemical derivatisation, bioprecursors and targeted delivery systems. The present article is a review regarding the introduction and applications of prodrug design in various areas of drug development.

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“…5 For this reason, efforts to develop alternative chemotherapy treatments have focused on designing nanoscale agents that are more specific against cancer cells to minimize toxic side effects and improve therapeutic efficacy. [6][7][8][9][10][11][12][13] The use of nanoscale agents enhances tumor selectivity via passive and active targeting. 14 The combination of therapeutic and diagnostic agents within a single nanoscale "theranostic" platform offers significant potential to make personalized nanomedicine a clinical reality for cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin-loaded protease-activated near-infrared fluorescent polymeric nanoparticles for imaging and therapy of cancer

Yildiz¹,

Gu²,

Zauscher³

et al. 2018

IJN

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IntroductionDespite significant progress in the field of oncology, cancer remains one of the leading causes of death. Chemotherapy is one of the most common treatment options for cancer patients but is well known to result in off-target toxicity. Theranostic nanomedicines that integrate diagnostic and therapeutic functions within an all-in-one platform can increase tumor selectivity for more effective chemotherapy and aid in diagnosis and monitoring of therapeutic responses.Material and methodsIn this work, theranostic nanoparticles were synthesized with commonly used biocompatible and biodegradable polymers and used as cancer contrast and therapeutic agents for optical imaging and treatment of breast cancer. These core–shell nanoparticles were prepared by nanoprecipitation of blends of the biodegradable and biocompatible amphiphilic copolymers poly(lactic-co-glycolic acid)-b-poly-l-lysine and poly(lactic acid)-b-poly(ethylene glycol). Poly-l-lysine in the first copolymer was covalently decorated with near-infrared fluorescent Alexa Fluor 750 molecules.ResultsThe spherical nanoparticles had an average size of 60–80 nm. The chemotherapeutic drug doxorubicin was encapsulated in the core of nanoparticles at a loading of 3% (w:w) and controllably released over a period of 30 days. A 33-fold increase in near-infrared fluorescence, mediated by protease-mediated cleavage of the Alexa Fluor 750-labeled poly-l-lysine on the surface of the nanoparticles, was observed upon interaction with the model protease trypsin. The cytocompatibility of drug-free nanoparticles and growth inhibition of drug-loaded nanoparticles on MDA-MB-231 breast cancer cells were investigated with a luminescence cell-viability assay. Drug-free nanoparticles were found to cause minimal toxicity, even at high concentrations (0.2–2,000 µg/mL), while doxorubicin-loaded nanoparticles significantly reduced cell viability at drug concentrations >10 µM. Finally, the interaction of the nanoparticles with breast cancer cells was studied utilizing fluorescence microscopy, demonstrating the potential of the nanoparticles to act as near-infrared fluorescence optical imaging agents and drug-delivery carriers.ConclusionDoxorubicin-loaded, enzymatically activatable nanoparticles of less than 100 nm were prepared successfully by nanoprecipitation of copolymer blends. These nanoparticles were found to be suitable as controlled drug delivery systems and contrast agents for imaging of cancer cells.

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Structure‐Based Rational Design of Prodrugs To Enable Their Combination with Polymeric Nanoparticle Delivery Platforms for Enhanced Antitumor Efficacy

Cited by 37 publications

References 36 publications

Sub-100 nm, long tumor retention SN-38-loaded photonic micelles for tri-modal cancer therapy

Sub-100 nm, long tumor retention SN-38-loaded photonic micelles for tri-modal cancer therapy

Prodrug Strategy in Drug Development

Doxorubicin-loaded protease-activated near-infrared fluorescent polymeric nanoparticles for imaging and therapy of cancer

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