HPMA Copolymer-Aminohexylgeldanamycin Conjugates Targeting Cell Surface Expressed GRP78 in Prostate Cancer

Larson, Nate; Ray, Abhijit; Malugin, Alexander; Pike, Daniel B.; Ghandehari, Hamidreza

doi:10.1007/s11095-010-0267-7

Cited by 34 publications

(22 citation statements)

References 42 publications

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“…A 13-mer peptide that targets GRP78 on melanoma cells induced apoptosis when coupled to either taxol (45) or D (KLAKLAK) 2 (18). The GRP78 ligand we describe here has been coupled to N-(2-hydroxypropyl)methacrylamide copolymers containing aminohexylgeldanamycin, resulting in apoptosis in prostate cancer cells in vitro (46). Another peptide that targets GRP78 on irradiated tumors, coupled to paclitaxel-encapsulating nanoparticles, extended tumor doubling time in mice bearing MDA-MB-231 or GL261 tumors (47).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Established Micrometastases by Targeted Drug Delivery via Cell Surface–Associated GRP78

Miao

Eckhardt

Cao

et al. 2013

Clinical Cancer Research

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Purpose The major cause of morbidity in breast cancer is development of metastatic disease, for which few effective therapies exist. Since tumor cell dissemination is often an early event in breast cancer progression and can occur prior to diagnosis, new therapies need to focus on targeting established metastatic disease in secondary organs. We report an effective therapy based on targeting cell surface-localized glucose regulated protein 78 (GRP78). GRP78 is expressed normally in the endoplasmic reticulum, but many tumors and disseminated tumor cells are subjected to environmental stresses and exhibit elevated levels of GRP78, some of which is localized at the plasma membrane. Experimental Design and Results Here we show that matched primary tumors and metastases from patients who died from advanced breast cancer also express high levels of GRP78. We utilized a peptidomimetic targeting strategy that employs a known GRP78-binding peptide fused to a pro-apoptotic moiety (designated BMTP78) and show that it can selectively kill breast cancer cells that express surface-localized GRP78. Further, in preclinical metastasis models, we demonstrate that administration of BMTP78 can inhibit primary tumor growth as well as prolong overall survival by reducing the extent of outgrowth of established lung and bone micrometastases. Conclusions The data presented here provide strong evidence that it is possible to induce cell death in established micrometastases by peptide mediated targeting of cell surface localized GRP in advanced breast cancers. The significance to patients with advanced breast cancer of a therapy that can reduce established metastatic disease should not be underestimated.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Established Micrometastases by Targeted Drug Delivery via Cell Surface–Associated GRP78

Miao

Eckhardt

Cao

et al. 2013

Clinical Cancer Research

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“…In addition, new promising lines of research are being followed to achieve active targeting by polymer-drug conjugates that inhibit specific kinases [186][187][188][189], activate apoptosis [190][191][192] or decrease angiogenesis [183][184][185][193][194][195][196], being all these lines of research in preclinical status, except for a polyacetal-fumagillin (antiangiogenic) conjugate (XMT-1107) which is under a phase I trial [18,197].…”

Section: Polymer Therapeuticsmentioning

confidence: 99%

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Pérez-Herrero

Fernández‐Medarde

2015

European Journal of Pharmaceutics and Biopharmaceutics

1,466

754

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Cancer is the second worldwide cause of death, exceeded only by cardiovascular diseases. It is characterized by uncontrolled cell proliferation and an absence of cell death that, except for hematological cancers, generates an abnormal cell mass or tumor. This primary tumor grows thanks to new vasculatization and, in time, adquires metastatic potential and spreads to other body sites, which causes metastasis and finally death. Cancer is caused by damage or mutations in the genetic material of the cells due to environmental or inherited factors. While surgery and radiotherapy are the primary treatment used for local and non-metastatic cancers, anti-cancer drugs (chemotherapy, hormone and biological therapies) are the choice currently used in metastasic cancers. Chemotherapy is based on the inhibition of the division of rapidly growing cells, which is a characteristic of the cancerous cells, but unfortunately, it also affects normal cells with fast proliferation rates, like the hair follicles, bone marrow and gastrointestinal tract cells, generating the characteristic side effects of chemotherapy. The indiscriminate destruction of normal cells, the toxicity of conventional chemotherapeutic Código de campo cambiado

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“…Sophisticated analytical techniques such as small angle neutron scattering (SANS), 2D 1 H NOESY and TOCSY NMR and pulsed gradient NMR have been used to characterize polymer-drug nanoconjugates (45,46). The release of the drug from the polymeric carrier as well as its safety and efficacy, are critical parameters that should also be monitored as the nanoconjugates frequently exhibit altered biodistribution and pharmacokinetics (47,48). If the release of the drug from the conjugates occurs prematurely during the systemic transport, undesirable side effects and toxicities may arise, reducing the overall safety profile of the drug.…”

Section: Polymer-drug Conjugatesmentioning

confidence: 99%

Polymer-Drug Nanoconjugate – An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs

Abioye

Chi-Tangyie²,

Kola-Mustapha³

et al. 2016

PNT

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Background: Over the last four decades, the use of water soluble polymers in rational formulation design has rapidly evolved into valuable drug delivery strategies to enhance the safety and therapeutic effectiveness of poorly soluble drugs, particularly anticancer drugs. Novel advances in polymer chemistry have provided new generations of well defined polymeric architectures for specific applications in polymer-drug conjugate design. However, total control of crucial parameters such as particle size, molecular weight distribution, polydispersity, localization of charges, hydrophilic-lipophilic balance and non site-specific coupling reactions during conjugation has been a serious challenge. Objective: This review briefly describes the current advances in polymer-drug nanoconjugate design and various challenges hindering their transformation into clinically useful medicines. Method: Existing literature was reviewed. Results: This review provides insights into the significant impact of covalent and non-covalent interactions between drug and polymer on drug loading (or conjugation) efficiency, conjugate stability, mechanism of drug release from the conjugate and biopharmaceutical properties of poorly soluble drugs. The utility values and application of Quality by Design principles in rational design, optimization and control of the Critical Quality Attributes (CQA) and Critical Process Parameters (CPP) that underpin the safety, quality and efficacy of the nanoconjugates are also presented. Conclusion: It was apparent that better understanding of the physicochemical properties of the nanoconjugates as well as the drug-polymer interaction during conjugation process is essential to be able to control the biodistribution, pharmacokinetics, therapeutic activity and toxicity of the nanoconjugates which will in turn enhance the prospect of successful transformation of these promising nanoconjugates into clinically useful nanomedicines.

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HPMA Copolymer-Aminohexylgeldanamycin Conjugates Targeting Cell Surface Expressed GRP78 in Prostate Cancer

Abstract: HPMA copolymer aminohexylgeldanamycin conjugates bearing WIFPWIQL peptide have the ability to bind to cell-surface-expressed GRP78 and inhibit the growth of human prostate cancer cells, suggesting that the conjugates have the potential to target solid prostate cancer tumors.

Cited by 34 publications

References 42 publications

Inhibition of Established Micrometastases by Targeted Drug Delivery via Cell Surface–Associated GRP78

Inhibition of Established Micrometastases by Targeted Drug Delivery via Cell Surface–Associated GRP78

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Polymer-Drug Nanoconjugate – An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs

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