Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

Yurkovetskiy, Alex; Hiller, Alexander; Syed, S.; Yin, Mao; Lu, Xiaoyan; Aj, Fischman; Papisov, Mikhail

doi:10.1021/mp0499306

Cited by 40 publications

(27 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Camptothecin, along with its analogues and/or prodrugs, has been clinically investigated in the context of liposomes (LE-SN-38) (74) or polymer-based nanoparticles containing poly-L-glutamate (CT-2106) (75), poly(1-hydroxymethylethylene hydroxylmethyl formal) (PHF; MER-1001) (76), HPMA copolymer (MAG-CPT or PNU166148) (77,78), or a β-cyclodextrincontaining polymer (IT-101) (79). Of this group, IT-101 is unique in that it is a multifunctional nanoparticle that dramatically extends circulations times and, upon entering the target cells, facilitates a slow release of the drug (23) giving good antitumor results in many different cancer types (80).…”

Section: Nanoparticle/nanoscaled Formulations Of Small Moleculesmentioning

confidence: 99%

Clinical Developments in Nanotechnology for Cancer Therapy

2010

View full text Add to dashboard Cite

Nanoparticle approaches to drug delivery for cancer offer exciting and potentially "game-changing" ways to improve patient care and quality of life in numerous ways, such as reducing off-target toxicities by more selectively directing drug molecules to intracellular targets of cancer cells. Here, we focus on technologies being investigated clinically and discuss numerous types of therapeutic molecules that have been incorporated within nanostructured entities such as nanoparticles. The impacts of nanostructured therapeutics on efficacy and safety, including parameters like pharmacokinetics and biodistribution, are described for several drug molecules. Additionally, we discuss recent advances in the understanding of ligand-based targeting of nanoparticles, such as on receptor avidity and selectivity.

show abstract

Section: Nanoparticle/nanoscaled Formulations Of Small Moleculesmentioning

confidence: 99%

Clinical Developments in Nanotechnology for Cancer Therapy

2010

View full text Add to dashboard Cite

show abstract

“…In this novel polymer prodrug, CPT is conjugated with an approximately 60 kDa biodegradable hydrophilic polyacetal, poly (1-hydroxymethylethylene hydroxymethylformal) (PHF; ref. 28). In contrast to other polymer-CPT conjugates, such as IT-101 (or CRLX-101) or pegamotecan (EZN-246; ref.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Antitumor Efficacy of XMT-1001, a Novel, Polymeric Topoisomerase I Inhibitor, in Mice Bearing HT-29 Human Colon Carcinoma Xenografts

Walsh

Hanna

Sen

et al. 2012

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: To evaluate the pharmacokinetics and tissue disposition of macromolecular camptothecin (CPT) drug conjugate, XMT-1001, and irinotecan (CPT-11) in mice bearing HT-29 xenograft tumors. Experimental Design: The antitumor efficacy of XMT-1001 was evaluated in the mouse HT-29 human colon carcinoma xenograft model. XMT-1001 was administered intravenously to female athymic nude (nu/nu) mice bearing established HT-29 xenograft tumors (n = 10) at 15, 30, and 60 mg CPT equivalents/kg on weekly or biweekly schedules. The tumor growth inhibition and tumor growth delay endpoints were used for efficacy evaluation. In the pharmacokinetic study, XMT-1001 was administered intravenously at a pharmacologically relevant dose of 60 mg CPT equivalents/kg × 1 via tail vein or an equimolar dose of CPT-11 at 100 mg/kg i.p. × 1. Mice (n = 3 per time point) were euthanized from 0.083 to 336 hours after XMT-1001 administration and from 0.083 to 24 hours after CPT-11. Plasma, tumor, and tissues were collected from all animals. A liquid chromatography–tandem mass spectrometry assay was used to measure XMT-1001, conjugate release products, CPT-20-O-(N-succinimido-glycinate; CPT-SI) and CPT-20-O-(N-succinamidoyl-glycinate; CPT-SA), and CPT. Results: After XMT-1001 administration, the majority of the plasma exposure is accounted for by conjugated CPT. XMT-1001 exhibited a prolonged exposure of conjugated drug, active conjugate primary release products, CPT-SI and CPT-SA, and active CPT, which was associated with greater antitumor response compared with CPT-11. Conclusions: XMT-1001 provides an extended systemic and tumor exposure of conjugated drug and shows improved antitumor effect compared with CPT-11. Clin Cancer Res; 18(9); 2591–602. ©2012 AACR.

show abstract

“…The nomenclature used to describe the pharmacokinetic disposition of carrier-mediated drugs is encapsulated or conjugated (drug within or bound to the carrier), released (active drug released from the carrier), and sum total (encapsulated or conjugated drug plus released drug) [17,21] ( Table 2). The released drug has also been called the legacy drug, regular drug, or warhead [17,20,21]. The released drug consists of drug that is protein bound and unbound or free drug.…”

Section: Introductionmentioning

confidence: 99%

Concept and Clinical Evaluation of Carrier-Mediated Anticancer Agents

2008

View full text Add to dashboard Cite

Major advances in the use of carrier vehicles delivering pharmacologic agents and enzymes to sites of disease have occurred over the past 10 years. This review focuses on the concepts and clinical evaluation of carrier-mediated anticancer agents that are administered i.v. or orally. The primary types of carrier-mediated anticancer agents are nanoparticles, nanosomes, which are nanoparticle-sized liposomes, and conjugated agents. Nanosomes are further subdivided into stabilized and nonstabilized or conventional nanosomes. Nanospheres and dendrimers are subclasses of nanoparticles. Conjugated agents consist of polymer-linked and pegylated agents. The theoretical advantages of carrier-mediated drugs are greater solubility, longer duration of exposure, selective delivery of entrapped drug to the site of action, superior therapeutic index, and the potential to overcome resistance associated with the regular anticancer agent. The pharmacokinetic disposition of carrier-mediated agents depends on the physiochemical characteristics of the carrier, such as size, surface charge, membrane lipid packing, steric stabilization, dose, and route of administration. The primary sites of accumulation of carrier-mediated agents are the tumor, liver, and spleen, compared with noncarrier formulations. The drug that remains encapsulated in or linked to the carrier (e.g., the nanosome or nanoparticle) is an inactive prodrug, and thus the drug must be released from the carrier to be active. The factors affecting the pharmacokinetic and pharmacodynamic variability of these agents remain unclear, but most likely include the reticuloendothelial system, which has also been called the mononuclear phagocyte system. Future studies need to evaluate the mechanism of clearance of carrier-mediated agents and identify the factors associated with the pharmacokinetic and pharmacodynamic variability of carrier agents in patients and specifically in tumors. The Oncologist 2008;13: 248 -260

show abstract

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

Cited by 40 publications

References 17 publications

Clinical Developments in Nanotechnology for Cancer Therapy

Clinical Developments in Nanotechnology for Cancer Therapy

Pharmacokinetics and Antitumor Efficacy of XMT-1001, a Novel, Polymeric Topoisomerase I Inhibitor, in Mice Bearing HT-29 Human Colon Carcinoma Xenografts

Concept and Clinical Evaluation of Carrier-Mediated Anticancer Agents

Contact Info

Product

Resources

About