We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL-TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb-DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic.

Amphiphilic homopolymers of the hydroxy-functional macromonomer poly(ethylene glycol) monomethacrylate (PEGMA) and its copolymers with methyl methacrylate (MMA) were prepared by atom transfer radical polymerization. Commercially available PEGMA (Aldrich) contains nonfunctional poly(ethylene glycol) (PEG), monofunctional PEGMA, and difunctional poly(ethylene glycol) dimethacrylate (PEGDMA) in a 1:3:1 ratio as analyzed by HPLC. A solvent extraction procedure yielded a PEGMA enriched mixture (PEG:PEG-MA:PEGDMA = 5:92:3) with PEGMA M n values of 480 and 410 Da based on HPLC and 1H NMR, respectively. ATRP homopolymerization of this purified PEGMA in the hydroxyl-bearing solvents, cyclohexanol and ethanol (ε = 16.4 and 25.3, respectively), yielded well-defined homopolymers (M w/M n < 1.1). On the other hand, ATRP copolymerizations with MMA (PEGMA content = 10, 18, 24, 30, and 40 mol %) yielded best results in non-hydrogen-bonding diphenyl ether (ε = 3.37). The homopolymer and copolymers containing more than 24 mol % (57 wt %) PEGMA were water-soluble and exhibited sharp lower critical solution temperatures (LCST) that increased with increasing PEGMA content as expected. Unlike similar PEGMA-based amphiphilic copolymers prepared by conventional free radical polymerizations, the ATR polymerizations reported here proceeded to high conversions (60−100%) and yielded well-defined polymers (M w/M n = 1.1−1.15) with no gel fraction that remained linear and water-soluble after storage in ambient conditions for several months.

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A technique for encapsulation of polar organic solvents using atom transfer radical polymerization (ATRP) by suspension polymerization was developed to encapsulate diphenyl ether (solubility parameter δ = 20.9 MPa1/2) for the first time. An amphiphilic terpolymer was prepared by suspension polymerization, by first preparing poly(methyl methacrylate-co-poly(ethylene glycol) methacrylate), P(MMA-co-PegMA), oligomers in solution conditions, followed by addition of a cross-linking monomer, diethylene glycol dimethacrylate, to the polymerization solution, and then transfer of this oil phase to a stirred aqueous phase. The thermodynamic requirement for encapsulation of polar core oils is that the polymer has low interfacial tensions with both the oil phase and the water phase. Therefore, increasing the polarity of the copolymer by increasing its PegMA content (0−31 mol %) led to a transition in suspension particle morphology from matrix to multihollow and hollow particles. Furthermore, particles prepared with similar monomer feed ratios by conventional free radical polymerization (CFRP) did not exhibit a multihollow structure. We attribute this difference in ATRP and CFRP suspension particle morphology to the slow rate of the ATRP reaction which allows sufficient time for diffusion of the forming polymer chains to the oil−water interface, resulting in the thermodynamically favored hollow particle morphology.

The suspension copolymerization of methyl methacrylate with hydroxy‐functional poly(ethylene glycol) monomethacrylate (PEGMA) by atom transfer radical polymerization (ATRP) yielded soluble, controlled‐molecular‐weight amphiphilic copolymers (weight‐average molecular weight/number‐average molecular weight <1.3). Despite extensive partitioning of PEGMA into the water phase, copolymers containing up to 24 mol % PEGMA were formed in the oil phase, from comonomer feeds containing 30 mol % PEGMA. Conversions by suspension polymerization were comparable to those obtained by solution polymerization, at over 70%. Suspension copolymers with high PEGMA contents contained high‐molecular‐weight polymer formed by uncontrolled polymerization, unless poly(vinyl pyrrolidone) was added to displace the growing polymer from the interface. The addition of diethylene glycol dimethacrylate gave capsules at 17 mol % PEGMA with ATRP, whereas conventional free‐radical polymerization required 24 mol % PEGMA to form capsules. The lower PEGMA level required for capsule formation with ATRP was attributed to the lower rates of propagation and crosslinking and to improved incorporation of PEGMA into the final gels. Suspension ATRP with 24 mol % PEGMA in the feed gave two‐layer capsule walls consisting of an inner layer visible by transmission electron microscopy and an outer layer visible by both transmission electron microscopy and environmental scanning electron microscopy, which indicated a compositional gradient across the capsule wall. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 156–171, 2006

These corrections do not change the interpretation of the results.

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