Preparation of Pentablock Nanomicellar Formulations for Prostate Cancer Drug Delivery Systems
Abstract
This study is divided into three specific aims. Specific aim #1 focused on
synthesis of pentablock co-polymer using monomers of L-lactide, ε-caprolactone and
ethylene-glycol with varied molecular weights, (ii) characterization of the synthesized
block co-polymers using X-ray diffraction crystallography (XRD), nuclear magnetic
resonance (NMR), Fourier transform infra-red (FTIR) and critical micellar
concentration (CMC).
Specific aim #2 focused on: (i) preparation of nanomicelles with polymers
synthesized in specific aim 1, loading hydrophobic paclitaxel drug or hydrophobic ion
pairing complex(HIP) of doxorubicin molecules, and characterizing them for shape,
size and polydispersity indices, (ii) conjugation of a ligand( PSMA antibody) on the
surfaces of nanomicelles to ensure selectivity and targeted delivery, (iii) Optimization
of parameters such as drug-to-polymer ratio on experimental design using JMP
software and, (iv) determination of pentablock stability at different temperatures, and
in vitro drug release of the drug-loaded nanomicellar formulation.
Specific aim #3 was focused on: (i) assessing the safety of the synthesized
pentablock copolymers by cytotoxicity studies on prostate cancer cell lines, (ii)
determining cellular uptake and accumulation of the nanomicellar formulation from
specific aim 2 in prostate cancer cell lines (PC-3), and (iii) evaluating the targetability
of PSMA antibody conjugated nanomicelles in prostate cancer cells.
Chapter # 1 outlines the overview of literature review on prostate cancer
prevalence, available treatment options, as well as the current challenges faced by
both the patients and the health practitioners during the treatment of prostate cancer.
Chapter #2 discusses the common nanoformulations used in drug delivery
systems. There are many promising drug delivery strategies such as liposomes,
polymeric nanoparticles, nanomicelles, and combination of techniques have been
studied in order to develop a sustained tumor drug delivery system.
Nanomicelles (NM) enhance solubility and absorption of active pharmaceutical
ingredients (APIs). Various polymers and non-polymers are being utilized to prepare
nanomicellar formulations to achieve high absorption and delivery of drugs. In this
study, we hypothesized that drug-loaded nanomicelles could be developed using
pentablock copolymers for delivery of either paclitaxel or doxorubicin.
Chapter #3 discusses how monomers of lactide, ε-caprolactone and
polyethylene-glycol were utilized to prepare pentablock copolymer by ring opening
technique. The pentablock nanomicelles (PBNM) were formulated by evaporation
rehydration technique.
Chapter #4 elucidates how PSMA antibody conjugated drug-loaded
nanomicelles were prepared using MPEG--PLA-PCL-PLA-PEG-NH2 Pentablock
copolymer for targeted delivery of hydrophobic anticancer drug (paclitaxel) to prostate
cancer cells. The resultant pentablock nanomicelles were conjugated with PSMA
antibody resulting in PTX-PBNM-Ab. XRD, FT-IR and the H-NMR analyses confirmed
the structure of the pentablock copolymers.
Chapter #5 discusses the preparation of a hydrophobic ion-paring complex
(HIP complex) of doxorubicin using hydrophobic retinoic acid. The resultant
hydrophobic (DOX-RA) complex was utilized to prepare drug-loaded nanomicelles by
co-precipitation method The average sizes for PTX-PBNM, PTX-PBNM-Ab and DOX
RA/PBNM were 20 nm ± 5.00nm, 45nm ± 2.5nm, 25.5nm ± 5.00nm, respectively,
and ζ-potential for both PTX-PBNM and DOX-RA/PBNM was around zero, while PTX
PBNM-Ab had -28mV. In vitro release studies revealed that pentablock nanomicelles
released PTX at a slow first order rate. The DOX-RA/PBNM released doxorubicin
slowly in phosphate buffer solution (PBS) at pH 7.4 compared to pH 5.5 and pH 4.0.
Transmission electron microscopy analysis revealed well-defined
spherical nanomicellar structure for all the types of pentablock nanomicelles. The in
vitro cell uptake studies demonstrated that pentablock nanomicelles were well
uptaken in the cells and a large amount of both PTX and doxorubicin were ferried into
the cells.
Table of Contents
Statement of problem -- Literature overview -- Strategic pentablock nanomicellar formulation for paclitaxel delivery system -- PSMA antibody conjugated pentablock nanomicelles for targeted delivery to prostate cancer -- Preparation of doxorubicin-retinoic acid hip complex nanomicellar formulation -- Overall summary
Degree
Ph.D.