CD44: a validated target for improved delivery of cancer therapeutics

Ghosh, Sukhen C.; Alpay, S. Neslihan; Klostergaard, Jim

doi:10.1517/14728222.2012.687374

Cited by 108 publications

(88 citation statements)

References 95 publications

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“…We hypothesize that once the paclitaxel conjugate is in the tumor interstitial space, the ultra-small nanoconjugate ($2-3 nm) actively targets the metastatic cancer cell by CD44 receptor-mediated endocytosis (11,12). CD44 (clusters of differentiation 44) is a cell surface receptor that binds to hyaluronic acid and undergoes receptor-mediated endocytosis to internalize hyaluronic acid (13).…”

Section: Introductionmentioning

confidence: 99%

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

Mittapalli

Liu

Adkins

et al. 2013

Molecular Cancer Therapeutics

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Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate ($5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor-mediated endocytocis. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able to bypass p-glycoprotein-mediated efflux on the surface of the cancer cells. In vitro cytoxicity of the conjugate and free paclitaxel were similar in that they (i) both caused cell-cycle arrest in the G 2 -M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC 50 values when compared with paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate in vivo efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer.

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Section: Introductionmentioning

confidence: 99%

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

Mittapalli

Liu

Adkins

et al. 2013

Molecular Cancer Therapeutics

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Section: Hyaluronic Acidmentioning

confidence: 99%

“…HA binds to cluster determinant 44 (CD44) (19), a cell surface protein upregulated in many cancers of epithelial origin (20). Due to this property, HA has been incorporated into various nanomedicine constructs as a targeting ligand (20,21). As a natural component of extracellular matrix tissues, HA is also biocompatible and biodegradable, making an excellent building block for engineered tissue scaffolds and drug delivery systems (22).…”

Section: Hyaluronic Acidmentioning

confidence: 99%

Drug Carriers: Not an Innocent Delivery Man

Yeo

Kim

2015

AAPS J

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Abstract. Biomaterials used as drug carriers are often considered inactive and assumed to have no other roles than modifying pharmacokinetics and biodistribution of a drug. On the other hand, there are several examples in which the carrier materials show bioactivities in the body, which may have been underestimated or inadvertently ignored. This review highlights several examples where biomaterials used as drug carriers bring biological effects, known or newly discovered, and discusses their implications in development of new drug delivery systems.

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“…Moreover, a number of recent studies suggest that CD44 fulfil some of the special properties that are displayed by CSCs, including selfrenewal, niche preparation, EMT and resistance to apoptosis [71]. Therefore, targeting CD44 by monoclonal antibodies appears as a reasonable strategy to eliminate CSCs [27,72].…”

Section: Anti-cd44mentioning

confidence: 99%

Targeting Human Cancer Stem Cells with Monoclonal Antibodies

Naujokat¹

2012

J Clin Cell Immunol

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Cancer stem cells (CSCs) constitute a distinct subpopulation of tumor cells that exhibit self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of cancer cells that comprise the tumor. CSCs possess various intrinsic mechanisms of resistance to conventional chemotherapeutics, novel tumor-targeted drugs and radiation therapy, permitting them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Different cell surface and transmembrane proteins expressed by CSCs, including CD44, CD47, EpCAM (CD326), CD123, CD133, GD2, Lgr5, insulin-like growth factor receptor I (IGF-IR), and members of the Notch and Wnt signaling pathways, have been identified and mainly used for the characterization of CSCs in experimental settings. Recently, monoclonal antibodies and antibody constructs such as Triomabs and BiTEs raised against these CSC proteins have shown efficacy against CSCs in human xenograft mice, and some of them have been demonstrated to induce tumor regression in clinical trials.Since current cancer therapies fail to eliminate CSCs, ultimately leading to cancer recurrence and progression, selective targeting of CSCs with mAbs and antibody constructs reviewed herein may represent a novel and promising therapeutic strategy to eradicate cancer.

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CD44: a validated target for improved delivery of cancer therapeutics

Abstract: The future should see development of drug targeting approaches that exploit CD44 expression on CSCs/TICs, including applications to cytotoxic agents currently in the clinic.

Cited by 108 publications

References 95 publications

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

Drug Carriers: Not an Innocent Delivery Man

Targeting Human Cancer Stem Cells with Monoclonal Antibodies

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