https://digital.csic.es/bitstream/10261/134282/5/ADVANCED%20TARGETED.pdf

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy.

Nanoparticles have many potential applications in tumor therapy. Systemically administered nanoparticles should remain in circulation for a long time to increase their accumulation in targeted tissues before being cleared by the reticuloendothelial system, and be effectively internalized by the targeted cells, which can be influenced significantly by the physicochemical characteristics of nanoparticles, such as particle size, surface properties, and particle shape. This review highlights the impact of the main affects of physicochemical properties on nanoparticle transport behavior in blood, their uptake and clearance by macrophages and their consequent biodistribution, as well as their interaction with targeted cells.

Physicochemical characteristics of nanoparticles affect circulation, biodistribution, cellular internalization, and trafficking.

PEGylation of Biopharmaceuticals: A Review of Chemistry and Nonclinical Safety Information of Approved Drugs.

Anticancer drugs embedded in or conjugated with inert nanocarriers, referred to as nanomedicines, show many therapeutic advantages over free drugs, but the inert carrier materials are the major component (generally more than 90%) in nanomedicines, causing low drug loading contents and thus excessive uses of parenteral excipients. Herein, we demonstrate a new concept directly using drug molecules to fabricate nanocarriers in order to minimize use of inert materials, substantially increase the drug loading content, and suppress premature burst release. Taking advantage of the strong hydrophobicity of the anticancer drug camptothecin (CPT), one or two CPT molecule(s) were conjugated to a very short oligomer chain of ethylene glycol (OEG), forming amphiphilic phospholipid-mimicking prodrugs, OEG-CPT or OEG-DiCPT. The prodrugs formed stable liposome-like nanocapsules with a CPT loading content as high as 40 or 58 wt % with no burst release in aqueous solution. OEG-DiCPT released CPT once inside cells, which sh...

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Prodrugs forming high drug loading multifunctional nanocapsules for intracellular cancer drug delivery.

The effects of polymeric nanostructure shape on drug delivery.

Poly(ethylene glycol) (PEG) is the most widely used polymer in delivering anticancer drugs clinically. PEGylation (i.e., the covalent attachment of PEG) of peptides proteins, drugs, and bioactives is known to enhance the aqueous solubility of hydrophobic drugs, prolong circulation time, minimize nonspecific uptake, and achieve specific tumor targetability through the enhanced permeability and retention effect. Numerous PEG-based therapeutics have been developed, and several have received market approval. A vast amount of clinical experience has been gained which has helped to design PEG prodrug conjugates with improved therapeutic efficacy and reduced systemic toxicity. However, more efforts in designing PEG-based prodrug conjugates are anticipated. In light of this, the current paper highlights the synthetic advances in PEG prodrug conjugation methodologies with varied bioactive components of clinical relevance. In addition, this paper discusses FDA-approved PEGylated delivery systems, their intended clinical applications, and formulations under clinical trials.

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Poly(ethylene glycol)-Prodrug Conjugates: Concept, Design, and Applications

Doxorubicin remains the first line of treatment for various cancers ever since its discovery in 1971. Cardiotoxicity and nephrotoxicity associated with unformulated doxorubicin triggered the development of doxorubicin nanocarriers. Although the therapeutic profile of doxorubicin is appreciably improved by entrapping in nanocarriers, they are largely taken up by organs of the reticuloendothelial system. Engineered nanocarriers of doxorubicin refer to carriers modified to escape recognition by reticuloendothelial system and/or functionalized with target specific ligands for selective accumulation at the target site. The first developments in engineered nanocarriers were the stealth carriers. These effectively bypassed the reticuloendothelial system and enhanced the therapeutic profile of doxorubicin by enabling passive accumulation in tumors. Stealth nanocarriers of doxorubicin revealed significant decrease in cardiotoxicity and nephrotoxicity, which led to the approval of liposomal doxorubicin for clinical applications. Success of liposomal doxorubicin was soon dulled by the appearance of newer toxicities like palmar-plantar erythrodysesthesia commonly referred as hand foot syndrome. The search for the magic bullet of doxorubicin has further intensified and resulted in design of engineered nanocarriers with high specificity for cancer cells. This review charts the progress from nanocarriers to engineered nanocarriers of doxorubicin, and highlights the current status of engineered nanocarriers of doxorubicin in clinical trials.

Engineered nanocarriers of doxorubicin: a current update.

Particle Shape: A New Design Parameter for Passive Targeting In Splenotropic Drug Delivery

Probing in vivo trafficking of polymer/DNA micellar nanoparticles using SPECT/CT imaging.

One or more stabilized polymeric nanoparticles comprising: (a) polycationic polymers, (b) at least one or more polyribonucleotide molecules, and (c) an anionic stabilization reagent are provided. The stabilized polymeric nanoparticles exhibited high uniformity with small size, and showed increased stability in physiological ionic strength and serum containing medium. The transfection and gene silencing efficiency of the stabilized polymeric nanoparticles was markedly improved over nanoparticles which did not contain the stabilization reagent in serum-containing medium. Methods of making the stabilized polymeric nanoparticles, pharmaceutical compositions comprising same, and methods for their use are also provided.

Rajesh R. Patil

Papers

Poly(ethylene glycol)-Prodrug Conjugates: Concept, Design, and Applications

Engineered nanocarriers of doxorubicin: a current update.

Particle Shape: A New Design Parameter for Passive Targeting In Splenotropic Drug Delivery

Probing in vivo trafficking of polymer/DNA micellar nanoparticles using SPECT/CT imaging.

Stabilized polyribonucleotide nanoparticles