Liposomal drug delivery systems: from concept to clinical applications.

PEGylation as a strategy for improving nanoparticle-based drug and gene delivery

/pdf/nanoparticle-pegylation-for-imaging-and-therapy-45vkc0dds0.pdf

Nanoparticle PEGylation for imaging and therapy

Nanoparticles show their promise for improving the efficacy of drugs with a narrow therapeutic window or low bioavailability, such as anticancer drugs and nucleic acid-based drugs. The pharmacokinetics (PK) and tissue distribution of the nanoparticles largely define their therapeutic effect and toxicity. Chemical and physical properties of the nanoparticles, including size, surface charge, and surface chemistry, are important factors that determine their PK and biodistribution. The intracellular fate of the nanoparticles after cellular internalization that affects the drug bioavailability is also discussed. Strategies for overcoming barriers for intracellular delivery and drug release are presented. Finally, future directions for improving the PK of nanoparticles and perspectives in the field are discussed.

Pharmacokinetics and biodistribution of nanoparticles.

Tumor targeting via EPR: Strategies to enhance patient responses

Purpose: Pharmacokinetic studies on liposomal drugs have previously measured total drug levels in tumors, which include nonbioavailable drug However, drugs must be released from liposomes to have activity We have developed a method for measuring levels of bioavailable (released) doxorubicin in vivo in tumors that will allow therapeutic activity to be correlated with bioavailable drug levels Experimental Design: Mice orthotopically implanted with mammary carcinoma (4T1) were injected iv 10 days after implantation with free doxorubicin or formulations of liposomal doxorubicin with different drug release rates Tumors were excised at various times after injection, and total tumor doxorubicin levels were determined by acidified isopropanol extraction of whole tumor homogenates Bioavailable doxorubicin levels were determined by extraction of doxorubicin from isolated tumor nuclei Results: Free doxorubicin had high levels of bioavailability in tumor tissue; 95% of the total doxorubicin in tumors was bound to nuclear DNA by 24 hours after injection Administration of Doxil, a slow release liposomal formulation of doxorubicin, gave an area under the time-versus-concentration curve (AUC) for total doxorubicin 7 days after injection that was 87-fold higher than that obtained for free doxorubicin, and 49% of the liposomal doxorubicin was bioavailable For liposomes with a more rapid doxorubicin release rate, by 7 days after injection, the AUC 0-7 days for total doxorubicin was only 14-fold higher than that for free doxorubicin and only 27% of liposomal doxorubicin was bioavailable Conclusions: This technique allows correlations to be made between drug bioavailability and therapeutic activity and will help in the rational design of drug carriers

https://clincancerres.aacrjournals.org/content/clincanres/11/19/6944.full.pdf

Determination of Doxorubicin Levels in Whole Tumor and Tumor Nuclei in Murine Breast Cancer Tumors

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Determination of Doxorubicin Levels in Whole Tumor and Tumor Nuclei in Murine Breast Cancer Tumors