Synthesis of MCC-PEG conjugate and its evaluation as a superdisintegrant.

PEGylated conjugate of microcrystalline cellulose (MCC) was synthesized by reacting MCC with polyethylene glycol (PEG) 200 in the presence of catalyst at elevated temperature. Conjugation between MCC and PEG was confirmed by FT-IR and (1)H NMR studies. The conjugate showed 61% PEG content increase in molecular weight determined by mass spectroscopy. PEGylation did not improve solubility of cellulose significantly. The physico-chemical properties of conjugate were compared against MCC. This conjugate was evaluated for water vapor uptake isotherms, maximum water saturation, water penetration rate, disintegration time, superdisintegration power, and dissolution study. After comparing its results with that of commercial superdisintegrants, it can be concluded that MCC-PEG conjugate can prove to be a good superdisintegrant.

Nanogels: An overview of properties, biomedical applications and obstacles to clinical translation.

Nanogels have emerged as a versatile hydrophilic platform for encapsulation of guest molecules with a capability to respond to external stimuli that can be used for a multitude of applications. These are soft materials capable of holding small molecular therapeutics, biomacromolecules, and inorganic nanoparticles within their crosslinked networks, which allows them to find applications for therapy as well as imaging of a variety of disease conditions. Their stimuli-responsive behavior can be easily controlled by selection of constituent polymer and crosslinker components to achieve a desired response at the site of action, which imparts nanogels the ability to participate actively in the intended function of the carrier system rather than being passive carriers of their cargo. These properties not only enhance the functionality of the carrier system but also help in overcoming many of the challenges associated with the delivery of cargo molecules, and this review aims to highlight the distinct and unique capabilities of nanogels as carrier systems for the delivery of an array of cargo molecules over other nanomaterials. Despite their obvious usefulness, nanogels are still not a commonplace occurrence in clinical practice. We have also made an attempt to highlight some of the major challenges that need to be overcome to advance nanogels further in the field of biomedical applications.

Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition.

Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance receptor endocytosis and lysosomal routing can provide a novel strategy to significantly improve therapy with ANPs and ADCs.

Polymer-based vehicles for therapeutic peptide delivery.

During the last decades increasing attention has been paid to peptides as potential therapeutics. However, clinical applications of peptide drugs suffer from susceptibility to degradation, rather short circulation half-life, limited ability to cross physiological barriers and potential immunogenicity. These challenges can be addressed by using polymeric materials as peptide delivery systems, owing to their versatile structures and properties. A number of polymer-based vehicles have been developed to stabilize the peptides and to control their release rates. Unfortunately, no single polymer or formulation strategy has been considered ideal for all types of peptide drugs. In this review, currently used and potential polymer-based systems for the peptide delivery will be discussed.

Targeted delivery of platinum-taxane combination therapy in ovarian cancer.

Biodegradable polypeptide-based nanogels have been developed from amphiphilic block copolymers, poly(ethylene glycol)-b-poly(L-glutamic acid)-b-poly(L-phenylalanine), which effectively co-incorporate cisplatin and paclitaxel, the clinically used drug combination for the treatment of advanced ovarian cancer. In order to target both drugs selectively to the tumor cells, we explored the benefits of ligand-mediated drug delivery by targeting folate receptors, which are overexpressed in most ovarian cancers. Drug-loaded nanogels were surface-functionalized with folic acid (FA) with the help of a PEG spacer without affecting the ligand binding affinity and maintaining the stability of the carrier system. FA-decorated nanogels significantly suppressed the growth of intraperitoneal ovarian tumor xenografts outperforming their nontargeted counterparts without extending their cytotoxicity to the normal tissues. We also confirmed that synchronized co-delivery of the platinum-taxane drug combination via single carrier to the same targeted cells is more advantageous than a combination of targeted single drug formulations administered at the same drug ratio. Lastly, we demonstrated that the same platform can also be used for localized chemotherapy. Our data indicate that intraperitoneal administration can be more effective in the context of targeted combination therapy. Our findings suggest that multifunctional nanogels are promising drug delivery carriers for improvement of current treatment for ovarian cancer.

Polypeptide-based nanogels co-encapsulating a synergistic combination of doxorubicin with 17-AAG show potent anti-tumor activity in ErbB2-driven breast cancer models.

ErbB2-driven breast cancers constitute 20-25% of the cases diagnosed within the USA. The humanized anti-ErbB2 monoclonal antibody, Trastuzumab (Herceptin™; Genentech), with chemotherapy is the current standard of treatment. Novel agents and strategies continue to be explored, given the challenges posed by Trastuzumab-resistance development in most patients. The HSP90 inhibitor, 17-allylaminodemethoxygeldanamycin (17-AAG), which induces ErbB2 degradation and attenuates downstream oncogenic signaling, is one such agent that showed significant promise in early phase I and II clinical trials. Its low water solubility, potential toxicities and undesirable side effects observed in patients, partly due to the Cremophor-based formulation, have been discouraging factors in the advancement of this promising drug into clinical use. Encapsulation of 17-AAG into polymeric nanoparticle formulations, particularly in synergistic combination with conventional chemotherapeutics, represents an alternative approach to overcome these problems. Herein, we report an efficient co-encapsulation of 17-AAG and doxorubicin, a clinically well-established and effective modality in breast cancer treatment, into biodegradable and biocompatible polypeptide-based nanogels. Dual drug-loaded nanogels displayed potent cytotoxicity in a breast cancer cell panel and exerted selective synergistic anticancer activity against ErbB2-overexpressing breast cancer cell lines. Analysis of ErbB2 degradation confirmed efficient 17-AAG release from nanogels with activity comparable to free 17-AAG. Furthermore, nanogels containing both 17-AAG and doxorubicin exhibited superior antitumor efficacy in vivo in an ErbB2-driven xenograft model compared to the combination of free drugs. These studies demonstrate that polypeptide-based nanogels can serve as novel nanocarriers for encapsulating 17-AAG along with other chemotherapeutics, providing an opportunity to overcome solubility issues and thereby exploit its full potential as an anti-cancer agent.

Biodegradable hybrid polymer micelles for combination drug therapy in ovarian cancer.

The co-delivery of drug combination at a controlled ratio via the same vehicle to the cancer cells is offering the advantages such as spatial-temporal synchronization of drug exposure, synergistic therapeutic effects and increased therapeutic potency. In an attempt to develop such multidrug vehicle this work focuses on functional biodegradable and biocompatible polypeptide-based polymeric micelles. Triblock copolymers containing the blocks of ethylene glycol, glutamic acid and phenylalanine (PEG-PGlu-PPhe) were successfully synthesized via NCA-based ring-opening copolymerization and their composition was confirmed by (1)H NMR. Self-assembly behavior of PEG-PGlu90-PPhe25 was utilized for the synthesis of hybrid micelles with PPhe hydrophobic core, cross-linked ionic PGlu intermediate shell layer, and PEG corona. Cross-linked (cl) micelles were about 90nm in diameter (ξ-potential=-20mV), uniform (narrow size distribution), and exhibited nanogels-like behavior. Degradation of cl-micelles was observed in the presence of proteolytic enzymes (cathepsin B). The resulting cl-micelles can incorporate the combination of drugs with very different physical properties such as cisplatin (15 w/w% loading) and paclitaxel (9 w/w% loading). Binary drug combination in cl-micelles exhibited synergistic cytotoxicity against human ovarian A2780 cancer cells and exerted a superior antitumor activity by comparison to individual drug-loaded micelles or free cisplatin in cancer xenograft model in vivo. Tunable composition and stability of these hybrid biodegradable micelles provide platform for drug combination delivery in a broad range of cancers.