In addition to the enhanced permeation and retention (EPR) effect, nanocarriers can be actively targeted to improve the efficacy of treatment and minimize side effects by surface grafting target ligands to impart an affinity for cellular upregulated receptors or components on tumor cells. However, the effects of the presence of a targeting moiety on the pharmacokinetics, biodistribution and tumor accumulation of nanocarriers still remain to be quantified and can be controversial in some cases. In addition to the biological factors such as tumor physiology, the influence of a targeting moiety on the in vivo pathway and fate of nanocarriers should depend on the nature of the targeting moiety as well as its spatial distribution on the nanocarrier surface. In contrast to well-regulated structural contrl seen in viruses, there is limited structural control in existing nanocarriers over the spatial distribution of ligands and the orientation of ligand relative to the particle surface that determies the availability of ligand binding sites. We have designed and synthesized so-called "3-helix micelles" that are uniform in size from 10-20 nm based on amphiphilic 3-helix peptide-polyethylene glycol (PEG) conjugates. The in vivo stability of the radiolabeled 3-helix micelles have been confirmed using positron emission tomography (PET) and the alpha circulatory half-life of PEGylated 15 nm micelle is ~28 h. 3-helix micelles already overcame several difficulties encountered to prepare effective nanocarriers such as size, cargo leakage, in vivo stability and clearance. Upon attaching target ligands to the surface of micelles, we should be able to achieve control over oligomeric state of ligand presentation. We propose to (1) synthesize ligand decorated nanocarriers, 10-20 nm in size with control over the inter-ligand distance and local multivalency of ligand presentation;(2) perform in vitro studies to evaluate the carrier internalization as a function of ligand density and multivalency;and (3) carry out in vivo studies use two cancer models, i.e. breast cancer and prostate cancer, to evaluate the effect of ligand density, inter-ligand distance and ligand clustering on the pharmacokinetics and biodistribution of these new 3-helix micelles. We will also perform immunogenicity tests on promising micellar nanoparticles to ensure their clinical viability as nanocarriers. Coiled-coil is the most common protein motif to control ligand presentation. The targeted micelles are ideal model system to answer several critical questions regarding the design principle of active targeting nanocarriers. Practically, our studies are based on micellar nanoparticles that have already demonstrated many desirable attributes as nanocarriers. Proposed studies may potentially lead to effective therapeutics with the combined advantages of both passive targeting via EPR effect and active targeting for breast tumors.
The central goal of this proposal is to design new, slow-release nanocarriers with control over the ligand presentation on the surface of nanocarrier. Due to poor aqueous solubility and short tissue half-lives, many small molecule drugs requires nanocarriers to improve their solubility, stability, pharmacokinetics, biodistribution, toxicity prfile and efficacy. An increased site specificity and internalization via passive and/or active targeting can improve the therapeutic index of cancer treatment by delivering drug molecules to desirable sites to reduce and eliminate tumors without damaging healthy tissues. In order to address key issues in cancer treatment, we have designed a new family of highly stable, long circulating micelles with a diameter ~15 nm and our proposed studies will develop and validate the required chemistries for molecular targeting. Basic knowledge gained here can be readily translated to develop formulations for drugs for the treatments of other diseases.
|Dube, Nikhil; Seo, Jai W; Dong, He et al. (2014) Effect of alkyl length of peptide-polymer amphiphile on cargo encapsulation stability and pharmacokinetics of 3-helix micelles. Biomacromolecules 15:2963-70|
|Dube, Nikhil; Shu, Jessica Y; Dong, He et al. (2013) Evaluation of doxorubicin-loaded 3-helix micelles as nanocarriers. Biomacromolecules 14:3697-705|