Pharmaceutical Nanotechnology (v.4, #1)

Meet Our Editorial Board Member: by Farid A. Dorkoosh (1-1).

IT-143, A Polymer Micelle Nanoparticle, Widens Therapeutic Window of Daunorubicin by Tara Lee Costich, Adam Carie, J. Edward Semple, Brad Sullivan, Tomas Vojkovsky, Tyler Ellis, Taylor Buley, Suzanne Bakewell, Kevin Sill (3-15).
Background: Daunorubicin is an anthracycline family chemotherapeutic indicated for the treatment of acute myelogenous and acute lymphoblastic leukemia. Daunorubicin has a narrow therapeutic window.
Objective: To extend circulation time, decrease toxicity and improve the efficacy of daunorubicin, we encapsulated the drug in our nanoparticle drug delivery platform.
Method: IT-143 is a lyophilized formulation of daunorubicin, non-covalently encapsulated in the hydrophobic core of a polymer micelle. Hydroxamic acid-containing triblock polymers (ITP-102) support ferric crosslinking between the polymer chains, increasing stability for improved drug circulation and allowing a tumor targeted pH dependent release of the encapsulated daunorubicin.
Results: Formulation characterization demonstrates a 3.7% weight loading (w/w) of daunorubicin and an average particle diameter of 58 nm. IT-143 has an in vitro cytotoxicity of 60-100 nM, comparable to free drug cytotoxicity of 67-114 nM. We compared daunorubicin pharmacokinetics between free drug and IT-143 in vivo and the maximum serum concentration of daunorubicin from IT-143 was increased 50-fold. At equivalent doses IT-143 eliminated in vivo gross toxicity observed at daunorubicin's maximum tolerated dose of 7.5 mg/kg, and increased the equitoxic dose to 17.5 mg/kg. Furthermore, IT-143 improved anti-tumor efficacy. Studies in 3 xenograft models (HCT116, HT-1080 and MNNG-HOS) compared intravenous bolus administration of IT-143 at equivalent and equitoxic doses to daunorubicin treatment. IT-143 increased the inhibition of tumor volume growth in all models.
Conclusion: These studies indicate that the encapsulation of daunorubicin by IT-143 widens the therapeutic window of daunorubicin treatment with reduced toxicity and increased antitumor efficacy.

Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen by Jeong Yeon Kang, Jieming Gao, Dae Hwan Shin, Celeste Alvarez, Weixiong Zhong, Glen S. Kwon (16-23).
Background: Delivery of monomeric Amphotericin B (AmB), i.e. deaggregated AmB, has been a major tactic in the reduction of renal toxicity at a membrane level, taking advantage of the selectivity of monomeric AmB for binding ergosterol over cholesterol.
Objective: The aim of this study was to characterize the pharmacokinetic (PK) and renal toxicity of monomeric AmB in rats following a multiple dose regimen.
Method: AmB existed primarily in a monomeric state in poly(ethylene glycol)-block-poly(N-hexyl stearate Laspartamide) (PEG-b-PHSA) micelles (mAmB) at 2:1 ratio (mol:mol), whereas AmB as its standard formulation, Fungizone®, was highly self-aggregated based on absorption spectroscopy.
Results: After single intravenous injection, mAmB significantly (p < 0.001) increased the area under the plasma drug concentration-time curve (AUC) and reduced the volume of distribution (Vd) and total systemic clearance (CL) relative to Fungizone®. After daily intravenous injections at dose of 1.0 mg/kg for 7 days, PK parameters of mAmB and Fungizone® were similar to day 1. The treatment of Fungizone® also significantly (p < 0.05) increased levels of urinary enzymes, N-acetyl-β-D-glucosaminidase (NAG) and kidney injury molecule-1 (KIM-1) by 3.1- and 3.0 fold, respectively, whereas levels of NAG and KIM-1 were unchanged for mAmB, consistent with hematoxylin and eosin (H&E) staining of excised kidneys.
Conclusion: In summary, mAmB causes less renal toxicity than AmB as Fungizone® in rats after a multiple dose regimen, validating the aggregation state hypothesis of AmB in vivo.

In vitro Toxicity Evaluation and in vivo Biodistribution of Polymeric Micelles Derived from Poly(ethylene glycol)-b-poly(benzyl malate) Copolyme by Elise Vene, Kathleen Jarnouen, Zhi Wei Huang, Bedhouche Wahib, Tristan Montier, Sandrine Cammas-Marion, Pascal Loyer (24-37).
Background: The development of polymeric micelles for site-specific drug delivery is an exponentially growing field of research. In this context, we have designed two degradable amphiphilic copolymers, the poly(ethylene glycol)-b-poly(benzyl malate) (PEG42-b-PMLABe73) and the biotin-poly(ethylene glycol)- b-poly(benzyl malate) (Biot-PEG62-b-PMLABe73). The copolymer bearing biotin residue was synthesized in order to formulate micelles for grafting biotinylated cyclic RGD peptide onto their surface via the bridging streptavidin.
Objective: Our study aimed at investigating the in vitro and in vivo toxicity of such micelles and to evaluate the potential of these nanovectors for hepatocyte-targeted drug delivery. Methods: The toxicity of micelles obtained by the nanoprecipitation method and characterized by dynamic light scattering and zeta potential measurement was evaluated in vitro using the differentiated hepatocyte-like HepaRG cells and in vivo in mice.
Results: The micelles derived from PEG42-b-PMLABe73, Biot-PEG62-b-PMLABe73 and RGDBiot-Strept- Biot-PEG62-b-PMLABe73 did not affect the cell proliferation and apoptotic indexes in HepaRG hepatoma cells and were well tolerated in mice following systemic injection. The hydrophobic fluorescent probes DiD oil and DiR were efficiently encapsulated in PEG-b-PMLABe-derived micelles allowing the visualization of their uptake into HepaRG cells. Furthermore, the addition of RGD peptide onto micelles strongly enhanced the cell uptake in vitro and liver targeting in vivo.
Conclusion: These data demonstrate the low toxicity of poly(benzyl malate) derived copolymers towards hepatocyte- like cells and emphasize their potential use for the design of liver targeting nanovectors.

Polymer-Drug Nanoconjugate - An Innovative Nanomedicine: Challenges and Recent Advancements in Rational Formulation Design for Effective Delivery of Poorly Soluble Drugs by Amos O. Abioye, George Tangyie Chi, Adeola T. Kola-Mustapha, Ketan Ruparelia, Ken Beresford, Randolph Arroo (38-79).
Background: Over the last four decades, the use of water soluble polymers in rational formulation design has rapidly evolved into valuable drug delivery strategies to enhance the safety and therapeutic effectiveness of poorly soluble drugs, particularly anticancer drugs. Novel advances in polymer chemistry have provided new generations of well defined polymeric architectures for specific applications in polymer-drug conjugate design.
However, total control of crucial parameters such as particle size, molecular weight distribution, polydispersity, localization of charges, hydrophilic-lipophilic balance and non site-specific coupling reactions during conjugation has been a serious challenge.
Objective: This review briefly describes the current advances in polymer-drug nanoconjugate design and various challenges hindering their transformation into clinically useful medicines.
Method: Existing literature was reviewed.
Results: This review provides insights into the significant impact of covalent and non-covalent interactions between drug and polymer on drug loading [or conjugation] efficiency, conjugate stability, mechanism of drug release from the conjugate and biopharmaceutical properties of poorly soluble drugs. The utility values and application of Quality by Design principles in rational design, optimization and control of the Critical Quality Attributes [CQA] and Critical Process Parameters [CPP] that underpin the safety, quality and efficacy of the nanoconjugates are also presented.
Conclusion: It was apparent that better understanding of the physicochemical properties of the nanoconjugates as well as the drug-polymer interaction during conjugation process is essential to be able to control the biodistribution, pharmacokinetics, therapeutic activity and toxicity of the nanoconjugates which will in turn enhance the prospect of successful transformation of these promising nanoconjugates into clinically useful nanomedicines.