Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form


Lu, Jianqin (2014) TARGETED DELIVERY OF ANTICANCER AGENTS TO CANCER. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

PDF (Corrected Version with Erratum)
Updated Version

Download (10MB) | Preview
[img] PDF (Original ETD with errors (see Erratum version))
Primary Text
Restricted to University of Pittsburgh users only

Download (10MB) | Request a Copy


Our research focuses on developing dual functional polymeric micelles for the targeted delivery of anticancer agents to tumors.
We first developed a poly(ethylene) glycol (PEG)-derivatized anticancer agent-Embelin (EB) (PEG-EB2) as an effective nanomicellar carrier for the delivery of Paclitaxel (PTX) to tumors. Our data demonstrated that PEG-EB2 retained similar biological effect as EB. Surprisingly, it can self-assemble into micelles (~20 nm) in aqueous solution and was also efficient in delivering the Paclitaxel (PTX) to cancers with enhanced antitumor activity. Further, folate (FA), a tumor specific ligand, was anchored into PEG5K-EB2 micelles (FA-PEG5K-EB2) to realize the active tumor targeting. The intracellular uptake of Doxorubicin (DOX) was markedly improved when incorporated into FA-PEG5K-EB2 over the one without FA, resulting in the significant higher level in inhibiting tumor growth.
Moreover, structure activity relationship (SAR) study was performed in PEG-derivatized Vitamin E (PEG-VE), in which our data has shown that PEG-VE with longer PEG length (5K) and double VE chains (PEG5K-VE2) garnered significant better PTX loading, stability and improved antitumor efficacy. Additionally, aiming to improve the DOX loading and stability, a drug-interactive motif-Fmoc was placed in the interfacial region of the PEG5K-VE2 (PEG5K-Fmoc-VE2). The data suggested that introduction of Fmoc to PEG5K-VE2 brought about dramatic augmentation in DOX loading and formulation stability, which consequently led to an enhanced inhibition on tumor development. Another finding in my research is to formulate Camptothecin (CPT), a highly lipophilic antineoplastic drug, in an innovative fashion. CPT was conjugated with VE at its hydroxyl group via carbonate ester bond (CPT-VE) or disulfide linkage (CPT-S-S-VE), which can self-assemble into nanofiber upon stabilized by PEG5K-Fmoc-VE2. VE-derivatized CPT prodrugs significantly buttressed the stability of CPT due to the additional steric hindrance to the lactone ring on CPT. Meanwhile, compared to CPT-VE, CPT-S-S-VE can more readily liberate CPT at tumors in a controlled manner (high GSH conc. in tumor), leading to the superior tumor growth suppression in vivo.
To reiterate, our data demonstrated that PEG-derivatized anticancer agents can serve as effective nanocarriers for the targeted delivery of chemotherapeutics. Additionally, incorporation of Fmoc into the interfacial region of dual functional carriers led to significantly increased drug loading and formulation stability, resulting in improved antitumor activity. Furthermore, coupling of VE to anticancer drugs may represent a novel platform in ameliorating their compatibility with utilized carrier.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorLi, Songsol4@pitt.eduSOL4
Committee ChairLi, Songsol4@pitt.eduSOL4
Committee MemberXie, Wenwex6@pitt.eduWEX6
Committee MemberVenkataramanan, Romanrv@pitt.eduRV
Committee MemberRohan, Lisa C.rsilcr@mwri.magee.eduROHANL
Committee MemberTyagi, Pradeepprtst2@pitt.eduPRTST2
Date: 8 December 2014
Date Type: Publication
Defense Date: 19 November 2014
Approval Date: 8 December 2014
Submission Date: 3 December 2014
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 271
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Nanomicelles, drug delivery, cancer chemotherapy, multidrug resistance
Additional Information: Corrected version with erratum uploaded on 11/19/2020
Date Deposited: 08 Dec 2014 12:54
Last Modified: 19 Nov 2020 16:43


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item