Design, development and clinical translation of CriPec®-based core-crosslinked polymeric micelles

Rijcken, Cristianne J.F.; Lorenzi, Federica; Biancacci, Ilaria; Hanssen, Rob; Thewissen, Mariëlle; Hu, Qizhi; Atrafi, Florence; Liskamp, Rob M. J.; Mathijssen, Ron H.J.; Miedema, Iris H C; Oordt, Catharina W. Menke-van der Houven van; Dongen, Guus A.M.S. van; Vugts, Daniëlle J.; Timmers, Matt; Hennink, Wim E.; Lammers, Twan

doi:10.1016/j.addr.2022.114613

Cited by 16 publications

(15 citation statements)

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“…The study rationale was based on the prolonged pharmacokinetics and hence improved therapeutic index of CPC634 based on previous results 10 18 19 33. The Simon 2-stage design allowed flexibility regarding the null and alternative hypotheses while also allowing stopping for futility.…”

Section: Discussionmentioning

confidence: 99%

“…Nanomedicines are designed to improve systemic circulation times and biodistribution, enhance drug-accumulation at the site of disease, and reduce off-target effects. An example is the nanoparticle CPC634, which entraps docetaxel in core-linked polymeric micelles 17 18. CPC634 consists of docetaxel conjugated to a linker agent, and this docetaxel–linker conjugate is covalently entrapped in stabilized, approximately 65 nm sized CriPec nanoparticles, and administered intravenously 18.…”

Section: Introductionmentioning

confidence: 99%

“…An example is the nanoparticle CPC634, which entraps docetaxel in core-linked polymeric micelles 17 18. CPC634 consists of docetaxel conjugated to a linker agent, and this docetaxel–linker conjugate is covalently entrapped in stabilized, approximately 65 nm sized CriPec nanoparticles, and administered intravenously 18. Due to the biodegradable nature of the nanoparticles, native docetaxel is released over time at physiological pH 18 19.…”

Section: Introductionmentioning

confidence: 99%

“…CPC634 consists of docetaxel conjugated to a linker agent, and this docetaxel–linker conjugate is covalently entrapped in stabilized, approximately 65 nm sized CriPec nanoparticles, and administered intravenously 18. Due to the biodegradable nature of the nanoparticles, native docetaxel is released over time at physiological pH 18 19. The design, development, and clinical translation of this and other CriPec-based drugs have been previously published 18.…”

Section: Introductionmentioning

confidence: 99%

“…Due to the biodegradable nature of the nanoparticles, native docetaxel is released over time at physiological pH 18 19. The design, development, and clinical translation of this and other CriPec-based drugs have been previously published 18. CPC634 has enhanced tumor uptake in patients with advanced solid tumors and a better safety profile with less neurotoxicity and neutropenia than conventional docetaxel at the same dose 19.…”

Section: Introductionmentioning

confidence: 99%

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CINOVA: a phase II study of CPC634 (nanoparticulate docetaxel) in patients with platinum resistant recurrent ovarian cancer

Boere

Vergote

Hanssen

et al. 2023

Int J Gynecol Cancer

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ObjectiveRecurrent platinum-resistant ovarian cancer has a poor prognosis with limited therapeutic options. Sub‐therapeutic intra-tumoral drug concentrations may add to therapy resistance. CPC634 (docetaxel entrapped in CriPec nanoparticles) was designed to enhance tumor accumulation of drug with localized drug release at the target site to increase therapeutic efficacy. This study investigated the therapeutic effect of CPC634 in patients with platinum-resistant ovarian cancer.MethodsAccording to a Simon 2-stage design trial, the first stage included 13 patients, and 12 patients were enrolled in the second stage. Eligible patients had measurable disease and had progressed ≤6 months after the last platinum-based therapy. Platinum-refractory disease was excluded. In stage 1, the number of previous treatment lines was unlimited; in the second stage, a maximum of two prior lines altogether were allowed. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumor (RECIST) V1.1. Secondary endpoints included safety, progression-free survival at 6 months, cancer antigen 125 (CA125) response, and disease control rate.ResultsThe patients’ median age was 66 years (range 22–77) and most were International Federation of Gynecology and Obstetrics (FIGO) stage III (56%). The median number of previous treatment lines was 3 (range 3–5) in stage I and 2 (range 1–4) in stage II of the study. None of the patients had an objective response, one patient had a CA125 response (5%), and seven patients had stable disease at first evaluation (35%). Median progression-free survival was 1.4 months in stage 1 and 3.0 months in stage 2. Adverse events (all grades) were mainly gastrointestinal in 24 patients (96%), fatigue in 11 (44%), dyspnea in 10 (40%), and infections in 10 (40%) of patients. Grade 3 or higher adverse events occurred in 14 patients (36%), including gastrointestinal in 4 (16%), anemia in 3 (12%), and febrile neutropenia, fatigue, chronic kidney disease, dehydration, and hypertension each in 1 (4%) patient. The trial was stopped prematurely due to futility.ConclusionsTreatment with CPC634 was feasible, but without apparent clinical activity in patients with recurrent platinum-resistant ovarian cancer. Side effects were mainly gastrointestinal in 24 (96%) patients, including nausea, vomiting, and decreased appetite, fatigue, anemia, and dyspnea.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

CINOVA: a phase II study of CPC634 (nanoparticulate docetaxel) in patients with platinum resistant recurrent ovarian cancer

Boere

Vergote

Hanssen

et al. 2023

Int J Gynecol Cancer

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Nanomedicine Tumor Targeting

Lammers

2024

Advanced Materials

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Nanomedicines are extensively explored for cancer therapy. By delivering drug molecules more efficiently to pathological sites and by attenuating their accumulation in healthy organs and tissues, nanomedicine formulations aim to improve the balance between drug efficacy and toxicity. More than 20 cancer nanomedicines are approved for clinical use, and 100′s of formulations are in (pre)clinical development. Over the years, several key pitfalls have been identified as bottlenecks in nanomedicine tumor targeting and translation. These go beyond materials‐ and production‐related issues, and particularly also encompass biological barriers and pathophysiological heterogeneity. In this manuscript, I describe the most important principles, progress and products in nanomedicine tumor targeting, delineate key current problems and challenges, and discuss the most promising future prospects for cancer nanomedicines.This article is protected by copyright. All rights reserved

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Repurposing Tamoxifen for Tumor Microenvironment Priming and Enhanced Tumor‐Targeted Drug Delivery

Biancacci,

De Santis,

Rama

et al. 2023

Advanced Therapeutics

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The dense stromal matrix in fibrotic tumors hinders tumor‐targeted drug delivery. Tamoxifen (TMX), an estrogen receptor modulator that is clinically used for the treatment of breast cancer, is shown to reprogram the tumor microenvironment (TME) and to alleviate desmoplasia. It is investigated if TMX, administered in free and nano‐formulated form, can be repurposed as a TME remodeling agent to improve tumor accumulation of nano‐formulations in pancreatic ductal adenocarcinoma and triple‐negative breast cancer mouse models, evaluated using clinical‐stage Cy7‐labeled core‐crosslinked polymeric micelles (CCPM). Under control conditions, higher levels of Cy7‐CCPM are found in PANC‐1 tumors (16.7% ID g−1 at 48 h post i.v. injection) than in 4T1 tumors (11.0% ID g−1). In both models, free and nano‐formulated TMX failed to improve CCPM delivery. These findings are congruent with the results from histopathological immunofluorescence analysis of tumor tissue, which indicate that TMX treatment does not significantly change vascularization, perfusion, macrophage infiltration, collagen density, and collagen fiber thickness. Altogether, these results demonstrate that in PANC‐1 and 4T1 mouse models, TMX treatment does not contribute to beneficial TME priming and enhanced tumor‐targeted drug delivery.

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Design, development and clinical translation of CriPec®-based core-crosslinked polymeric micelles

Cited by 16 publications

References 104 publications

CINOVA: a phase II study of CPC634 (nanoparticulate docetaxel) in patients with platinum resistant recurrent ovarian cancer

CINOVA: a phase II study of CPC634 (nanoparticulate docetaxel) in patients with platinum resistant recurrent ovarian cancer

Nanomedicine Tumor Targeting

Repurposing Tamoxifen for Tumor Microenvironment Priming and Enhanced Tumor‐Targeted Drug Delivery

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