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. 2007 Feb;28(5):869-76.
doi: 10.1016/j.biomaterials.2006.09.047. Epub 2006 Oct 20.

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

Jianjun Cheng  1 , Benjamin A Teply, Ines Sherifi, Josephine Sung, Gaurav Luther, Frank X Gu, Etgar Levy-Nissenbaum, Aleksandar F Radovic-Moreno, Robert Langer, Omid C Farokhzad
Affiliations

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

Jianjun Cheng et al. Biomaterials. 2007 Feb.

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.

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Figures

Figure 1
Figure 1
Effect of varying formulation parameters on NP size. (A) Varying the solvent:water ratio (1:1, 1:2, 1:5, 1:10) while keeping the PLGA-b-PEG polymer constant at 10 mg/ml, and (B) varying the polymer concentrations in organic phase (5, 10, 20 or 50 mg/ml) while keeping the solvent:water ratio constant at 1:2.
Figure 2
Figure 2
Correlation of NP volumetric sizes with polymer concentrations at constant solvent:water ratio.
Figure 3
Figure 3
Effect of the docetaxel loading on PLGA-b-PEG NP polydispersity.
Figure 4
Figure 4
PLGA-b-PEG NP size stability. (A) Effect of centrifugation vs ultrafiltration on NP size (12000 ×g, 15 min vs. 3000 ×g, 15min); (B) effect of sucrose prior to lyopholization on NP size, after storage and resuspension.
Figure 5
Figure 5
Confirmation of NP-Apt conjugation. The A10 PSMA aptamer (Apt) was incubated with PLGA-b-PEG NP in the absence (-) or presence (+) of EDC and the reactions were resolved on a 10% TBE-Urea PAGE directly, or after washing to remove any unconjugated Apt, The bands corresponding to the A10 PSMA Apt and NP-Apt are indicated by arrows. Nucleic acid molecular weight marker (MW) is shown on left,
Figure 6
Figure 6
Tumor targeting by PLGA-b-PEG NP and NP-Apt after systemic administration, (mean ± SD; n = 4; * P < 0.002)
Figure 7
Figure 7
Systemic biodistribution of (A) PLGA-b-PEG NP and (B) NP-Apt (mean ± SD; n = 4)
Scheme 1
Scheme 1
Synthesis of PLGA-b-PEG-COOH NP, and conjugation of aptamer to NP. Docetaxel was encapsulated within PLGA-b-PEG-COOH NP using the nanoprecipitation method. The PLGA-PEG NP/Docetaxel was covalently conjugated to amine-terminated A10 PSMA aptamer (Apt) in the presence of EDC.
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