Formulation of functionalized PLGA–PEG nanoparticles for in vivo targeted drug delivery

Abstract

Nanoparticle (NP) size has been shown to significantly affect the biodistribution of targeted and non-targeted NPs in an organ specific manner. Herein we have developed NPs from carboxy-terminated poly(d,L-lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG-COOH) polymer and studied the effects of altering the following formulation parameters on the size of NPs: (1) polymer concentration, (2) drug loading, (3) water miscibility of solvent, and (4) the ratio of water to solvent. We found that NP mean volumetric size correlates linearly with polymer concentration for NPs between 70 and 250 nm in diameter (linear coefficient=0.99 for NPs formulated with solvents studied). NPs with desirable size, drug loading, and polydispersity were conjugated to the A10 RNA aptamer (Apt) that binds to the prostate specific membrane antigen (PSMA), and NP and NP-Apt biodistribution was evaluated in a LNCaP (PSMA+) xenograft mouse model of prostate cancer. The surface functionalization of NPs with the A10 PSMA Apt significantly enhanced delivery of NPs to tumors vs. equivalent NPs lacking the A10 PSMA Apt (a 3.77-fold increase at 24h; NP-Apt 0.83%+/-0.21% vs. NP 0.22%+/-0.07% of injected dose per gram of tissue; mean+/-SD, n=4, p=0.002). The ability to control NP size together with targeted delivery may result in favorable biodistribution and development of clinically relevant targeted therapies.

Poly(ethylene glycol) with Observable Shedding

“…The spectrum of (10) reveals an additional peak at 490 nm, which is consistent with the absorption wavelength of OG488. This double-peak feature of the UV absorption spectrum confirms FRET pair formation in the final product (10).…”

“…After the solvent is removed by vacuum, the molecule (9) is immediately mixed with (4) in water to avoid potential thiol oxidation. The coupling reaction between thiol and pyridyl disulfide results in the formation of the final FRETbearing PEG molecule (10). Notably, the amine group preserved in the final molecular structure provides a functional end-group for further conjugation of FRET-bearing PEG to different NP systems.…”

“…PLGA-PEG NPs are well-studied polymeric drug delivery systems, which we can now use to observe the PEG-shedding effect. [10][11][12] To form PLGA-(FRET)-PEG copolymers, carboxyl-terminated PLGA (PLGA-COOH) was first activated using EDC/NHS to form PLGA-NHS, and then conjugated to the free amine of the FRET-bearing PEG molecule (10). By using the nanoprecipitation method as previously reported, we formulated PLGA-(FRET)-PEG NPs with sizes that are approximately 100 -120 nm.…”

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

“…Hydrophilic polymers can be useful at the surface of NPs by adsorption of surfactants or by utilize of block copolymers or branched copolymers (Stolnik et al, 1995;Storm et al, 1995;Torchilin and Trubetskoy, 1995;Mahapatro and Singh, 2011). Surface chemistry Analysis is determined by X-ray photoelectron spectroscopy (Mu and Feng, 2003;Si-Shen et al, 2004;Kim et al, 2005), Fourier transform infrared spectroscopy (Li et al, 2001;Choi and Kim, 2007;Yang et al, 2007) and Nuclear magnetic resonance spectroscopy (Li et al, 2001;Avgoustakis et al, 2002;Cheng et al, 2007;Dinarvand et al, 2011).…”

In vivo efficacy of paclitaxel-loaded injectable in situ-forming gel against subcutaneous tumor growth

“…Taxol must be repeatedly administered and thus causes serious side-effects, particularly hypersensitivity reactions, some of which are life-threatening. Efforts to eliminate these problems have focused on developing new drug delivery systems for Ptx that achieve site-specific delivery, prolong action periods, and improve patient compliance (Cheng et al, 2007).…”