Current Update of a Carboxymethylcellulose-PEG Conjugate Platform for Delivery of Insoluble Cytotoxic Agents to Tumors.

Cytotoxic chemotherapeutic agents are used as the standard therapy for a range of significant cancers, but many of these drugs suffer from poor water solubility and low selectivity, limiting their clinical efficacy. To overcome these shortcomings, Cellax™ drug delivery platform was developed. Cellax™ is a polymer-based nanoparticle drug delivery system designed to solubilize hydrophobic drugs and target them to solid tumors, thereby enhancing the efficacy and reducing the side effects. Cellax-docetaxel (Cellax-DTX) displayed improved pharmacokinetic, safety, and efficacy profiles compared to native DTX (Taxotere®) and Nab-paclitaxel (Nab-PTX, Abraxane®) in multiple animal models. Cellax-DTX was shown to interact with serum albumin and SPARC (secreted protein acidic and rich in cysteine) that is highly expressed by tumor stromal cells, leading to superior stroma depleting activity in orthotopic breast and pancreatic tumor models and subsequently reduced incidence of visceral metastases compared to free DTX and Nab-PTX. The Cellax™ platform was employed to deliver podophyllotoxin (Cellax-PPT) and cabazitaxel (Cellax-CBZ), and increased their safety and efficacy against multidrug-resistant tumors. This review discusses the rational design of the Cellax™ platform and summarizes the preclinical results. A multifunctional version of Cellax™ and a biomarker for predicting Cellax™ efficacy were developed and identified to promote the personalized use. Perspectives and future plans for this platform technology are also provided.

Docetaxel-carboxymethylcellulose nanoparticles target cells via a SPARC and albumin dependent mechanism.

Cellax, a polymer-docetaxel (DTX) conjugate that self-assembled into 120 nm particles, displayed significant enhancements in safety and efficacy over native DTX across a number of primary and metastatic tumor models. Despite these exciting preclinical data, the underlying mechanism of delivery of Cellax remains elusive. Herein, we demonstrated that serum albumin efficiently adsorbed onto the Cellax particles with a 4-fold increased avidity compared to native DTX, and the uptake of Cellax by cells was primarily driven by an albumin and SPARC (secreted protein acidic and rich in cysteine, an albumin binder) dependent internalization mechanism. In the SPARC-positive cells, a >2-fold increase in cellular internalization of Cellax was observed in the presence of albumin. In the SPARC-negative cells, no difference in Cellax internalization was observed in the presence or absence of albumin. Evaluation of the internalization mechanism using endocytotic inhibitors revealed that Cellax was internalized predominantly via a clathrin-mediated endocytotic mechanism. Upon internalization, it was demonstrated that Cellax was entrapped within the endo-lysosomal and autophagosomal compartments. Analysis of the tumor SPARC level with tumor growth inhibition of Cellax in a panel of tumor models revealed a positive and linear correlation (R(2) > 0.9). Thus, this albumin and SPARC-dependent pathway for Cellax delivery to tumors was confirmed both in vitro and in vivo.

Docetaxel-carboxymethylcellulose nanoparticles display enhanced anti-tumor activity in murine models of castration-resistant prostate cancer.

Docetaxel (DTX) remains the only effective drug for prolonging survival and improving quality of life of metastatic castration resistant prostate cancer (mCRPC) patients. Despite some clinical successes with DTX-based therapies, advent of cumulative toxicity and development of drug resistance limit its long-term clinical application. The integration of nanotechnology for drug delivery can be exploited to overcome the major intrinsic limitations of DTX therapy for mCRPC. We evaluated whether reformulation of DTX by facile conjugation to carboxymethylcellulose nanoparticles (Cellax) can improve the efficacy and safety of the drug in s.c. and bone metastatic models of CRPC. A single dose of the nanoparticles completely regressed s.c. PC3 tumor xenografts in mice. In addition, Cellax elicited fewer side effects compared to native DTX. Importantly, Cellax did not increase the expression of drug resistance molecules in androgen-independent PC3 prostate cancer cells in comparison with DTX. Lastly, in a bone metastatic model of CRPC, Cellax treatment afforded a 2- to 3-fold improvement in survival and enhancements in quality-of-life of the animals over DTX and saline controls. These results demonstrate the potential of Cellax in improving the treatment of mCRPC.