Enhancing Intestinal &Brain Uptake of Anti-AIDS Drugs.

Project Details

Description

DESCRIPTION (Provided by the applicant): The challenges associated with the
effective oral delivery of novel and complex but poorly bioavailable (BA) drugs
stems primarily from their poor biopharmaceutical and physicochemical
characteristics. Very hydrophilic or lipophilic small (less than 500 Da) drugs
cannot readily pass through biological membranes or the adjacent aqueous
boundary layers. Furthermore, the low efficiency of endocytosis and the
restricted substrate specificity of transport proteins further limits the
nonpassive absorption of drugs that are larger than 500 Da. Our observation
that a 30kDa bioconjugate can be taken up by and pass through intestinal and
brain cell monolayers with polymeric drug carriers to overcome normal cell
permeability barriers enabling enhanced bioefficacy. Our preliminary in vivo
brain uptake data supports this hypothesis. Furthermore, recent preliminary
data demonstrates that our Tat-conjugate inhibits HIV in cell culture similar
to clinically relevant RTIs. The proposed strategy utilizes a bioconjugate
composed of a targeting agent to enhance cell uptake and multiple copies of a
drug or drugs linked to a PEG-based polymer. The bioconjugate appears to be
absorbed by a novel mechanism that bypasses normal permeability barriers that
often limits drug entry into cells. We have identified the mechanistic causes
of the poor and variable oral BA of three drugs: saquinavir, UC781, and a Tat
inhibitor. Bioconjugates of these three drugs will be prepared. The main
objective of the proposed studies is to design, synthesize, characterize and
evaluate bioconjugates that will enhance bioefficacy by facilitating transport
of anti-AIDS drugs through endothelial, epithelial and target cell barriers.
Therefore, the specific aims of the proposed investigations are: (1) To
synthesize and characterize a diverse conformational ensemble of placebo
bioconjugates by systematically varying the type, number and position of
targeting moieties and the molecular weight and branching characteristics of
the polymer; (2 ) To establish relationships between bulk property,
surface-based, topological and novel composite descriptors of placebo
bioconjugates and the transport/uptake kinetics and mechanisms in cultured
cells; (3) To design, synthesize and characterize drug bioconjugates using
optimal molecular and transport /uptake characteristics of placebo
bioconjugates and to characterize the stability, metabolism, and release of
drug; (4) To determine oral absorption and brain uptake of drug bioconjugates
in model epithelial and endothelial cell culture systems, as well as in
well-established animal models. The effectiveness of bioconjugates against
HIV-1 infections in cultured cells will also be quantified. The proposed
studies will fill important gaps in our understanding of the mechanisms of
bioconjugate delivery into and through cells enabling the development of new
strategies to overcome biopharmaceutical (e.g., blood-semen or placental) or
target cell barriers.
StatusFinished
Effective start/end date3/1/022/28/17

Funding

  • National Institute of Allergy and Infectious Diseases: $334,415.00
  • National Institute of Allergy and Infectious Diseases: $337,008.00
  • National Institute of Allergy and Infectious Diseases: $46,597.00
  • National Institute of Allergy and Infectious Diseases: $509,440.00
  • National Institute of Allergy and Infectious Diseases: $337,793.00
  • National Institute of Allergy and Infectious Diseases: $272,125.00
  • National Institute of Allergy and Infectious Diseases: $272,125.00
  • National Institute of Allergy and Infectious Diseases: $546,378.00
  • National Institute of Allergy and Infectious Diseases: $272,125.00
  • National Institute of Allergy and Infectious Diseases: $623,475.00
  • National Institute of Allergy and Infectious Diseases: $509,440.00
  • National Institute of Allergy and Infectious Diseases: $324,218.00
  • National Institute of Allergy and Infectious Diseases: $503,315.00
  • National Institute of Allergy and Infectious Diseases: $327,953.00
  • National Institute of Allergy and Infectious Diseases: $272,125.00

ASJC

  • Infectious Diseases
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Pharmacology
  • Immunology

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